1. |
- Artigas Soler, María, et al.
(författare)
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1082-90
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
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2. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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3. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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4. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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5. |
- Thompson, Paul M., et al.
(författare)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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Ingår i: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Tidskriftsartikel (refereegranskat)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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6. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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7. |
- Koettgen, Anna, et al.
(författare)
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Genome-wide association analyses identify 18 new loci associated with serum urate concentrations
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:2, s. 145-154
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Tidskriftsartikel (refereegranskat)abstract
- Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SEMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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8. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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9. |
- Repapi, Emmanouela, et al.
(författare)
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Genome-wide association study identifies five loci associated with lung function.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:1, s. 36-44
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Tidskriftsartikel (refereegranskat)abstract
- Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
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10. |
- Richards, Stephen, et al.
(författare)
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Genome Sequence of the Pea Aphid Acyrthosiphon pisum
- 2010
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 8:2, s. e1000313-
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Tidskriftsartikel (refereegranskat)abstract
- Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.
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11. |
- Schunkert, Heribert, et al.
(författare)
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
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Tidskriftsartikel (refereegranskat)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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12. |
- Teslovich, Tanya M., et al.
(författare)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Tidskriftsartikel (refereegranskat)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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13. |
- Fischer, Debra A., et al.
(författare)
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M2K. II. A Triple-Planet System Orbiting Hip 57274
- 2012
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 745:1, s. 21-
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Tidskriftsartikel (refereegranskat)abstract
- Doppler observations from Keck Observatory have revealed a triple-planet system orbiting the nearby K4V star, HIP 57274. The inner planet, HIP 57274b, is a super-Earth with M sin i = 11.6 M-circle plus (0.036 M-Jup), an orbital period of 8.135 +/- 0.004 days, and slightly eccentric orbit e = 0.19 +/- 0.1. We calculate a transit probability of 6.5% for the inner planet. The second planet has M sin i = 0.4 M-Jup with an orbital period of 32.0 +/- 0.02 days in a nearly circular orbit (e = 0.05 +/- 0.03). The third planet has M sin i = 0.53 M-Jup with an orbital period of 432 +/- 8 days (1.18 years) and an eccentricity e = 0.23 +/- 0.03. This discovery adds to the number of super-Earth mass planets with M sin i < 12 M-circle plus that have been detected with Doppler surveys. We find that 56% +/- 18% of super-Earths are members of multi-planet systems. This is certainly a lower limit because of observational detectability limits, yet significantly higher than the fraction of Jupiter mass exoplanets, 20% +/- 8%, that are members of Doppler-detected, multi-planet systems.
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14. |
- Loth, Daan W, et al.
(författare)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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15. |
- Assimes, Themistocles L., et al.
(författare)
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Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
- 2010
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 56:19, s. 1552-1563
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Tidskriftsartikel (refereegranskat)abstract
- Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
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16. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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17. |
- Elks, Cathy E, et al.
(författare)
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Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1077-85
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Tidskriftsartikel (refereegranskat)abstract
- To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
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18. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
- 2011
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:8, s. 753-60
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.
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19. |
- O'Seaghdha, Conall M., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:9, s. e1003796-
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Tidskriftsartikel (refereegranskat)abstract
- Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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20. |
- Scott, Robert A., et al.
(författare)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Tidskriftsartikel (refereegranskat)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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21. |
- Smith, Bradley N., et al.
(författare)
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The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
- 2013
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Ingår i: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:1, s. 102-108
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Tidskriftsartikel (refereegranskat)abstract
- A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
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22. |
- Stolk, Lisette, et al.
(författare)
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Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
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Tidskriftsartikel (refereegranskat)abstract
- To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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23. |
- Yang, Jian, et al.
(författare)
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FTO genotype is associated with phenotypic variability of body mass index
- 2012
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
-
Tidskriftsartikel (refereegranskat)abstract
- There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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24. |
- Adare, A., et al.
(författare)
-
Cold-Nuclear-Matter Effects on Heavy-Quark Production at Forward and Backward Rapidity in d + Au Collisions at root s(NN) = GeV
- 2014
-
Ingår i: Physical Review Letters. - 1079-7114. ; 112:25
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Tidskriftsartikel (refereegranskat)abstract
- The PHENIX experiment has measured open heavy-flavor production via semileptonic decay over the transverse momentum range 1 < p(T) < 6 GeV/c at forward and backward rapidity (1.4 < vertical bar y vertical bar < 2.0) in d + Au and p + p collisions at root s(NN) = 200 GeV. In central d + Au collisions, relative to the yield in p + p collisions scaled by the number of binary nucleon-nucleon collisions, a suppression is observed at forward rapidity (in the d-going direction) and an enhancement at backward rapidity (in the Au-going direction). Predictions using nuclear-modified-parton-distribution functions, even with additional nuclear-p(T) broadening, cannot simultaneously reproduce the data at both rapidity ranges, which implies that these models are incomplete and suggests the possible importance of final-state interactions in the asymmetric d + Au collision system. These results can be used to probe cold-nuclear-matter effects, which may significantly affect heavy-quark production, in addition to helping constrain the magnitude of charmonia-breakup effects in nuclear matter.
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25. |
- Adare, A., et al.
(författare)
-
Double-spin asymmetry of electrons from heavy-flavor decays in p plus p collisions at root s=200 GeV
- 2013
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Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 87:1
-
Tidskriftsartikel (refereegranskat)abstract
- We report on the first measurement of the double-spin asymmetry, A(LL), of electrons from the decays of hadrons containing heavy flavor in longitudinally polarized p + p collisions at root s = 200 GeV for p(T) = 0.5 to 3.0 GeV/c. The asymmetry was measured at midrapidity (vertical bar eta vertical bar < 0.35) with the PHENIX detector at the Relativistic Heavy Ion Collider. The measured asymmetries are consistent with zero within the statistical errors. We obtained a constraint for the polarized gluon distribution in the proton of vertical bar Delta g/g(log(10)(x) = -1.6(-0.4)(+0.5), mu = m(T)(c)vertical bar(2) < 0.030 (1 sigma) based on a leading-order perturbative quantum chromodynamics model, using the measured asymmetry. DOI: 10.1103/PhysRevD.87.012011
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26. |
- Adare, A., et al.
(författare)
-
gamma (1S+2S+3S) production in d plus Au and p plus p collisions at root s(NN)=200 GeV and cold-nuclear-matter effects
- 2013
-
Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 87:4
-
Tidskriftsartikel (refereegranskat)abstract
- The three gamma states, gamma (1S + 2S + 3S), are measured in d + Au and p + p collisions at root s(NN) = 200 GeV and rapidities 1.2 < vertical bar y vertical bar < 2.2 by the PHENIX experiment at the Relativistic Heavy Ion Collider. Cross sections for the inclusive gamma (1S + 2S + 3S) production are obtained. The inclusive yields per binary collision for d + Au collisions relative to those in p + p collisions (R-dAu) are found to be 0.62 +/- 0.26 (stat) +/- 0.13 (syst) in the gold-going direction and 0.91 +/- 0.33 (stat) +/- 0.16 (syst) in the deuteron-going direction. The measured results are compared to a nuclear-shadowing model, EPS09 [Eskola et al., J. High Energy Phys. 04 (2009) 065], combined with a final-state breakup cross section, sigma(br), and compared to lower energy p + A results. We also compare the results to the PHENIX J/psi results [Adare et al., Phys. Rev. Lett. 107, 142301 (2011)]. The rapidity dependence of the observed gamma suppression is consistent with lower energy p + A measurements. DOI: 10.1103/PhysRevC.87.044909
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27. |
- Adare, A., et al.
(författare)
-
Inclusive double-helicity asymmetries in neutral-pion and eta-meson production in + collisions at root s=200 GeV
- 2014
-
Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 90:1
-
Tidskriftsartikel (refereegranskat)abstract
- Results are presented from data recorded in 2009 by the PHENIX experiment at the Relativistic Heavy Ion Collider for the double-longitudinal spin asymmetry, A(LL), for pi(0) and eta production in root s = 200 GeV polarized p + p collisions. Comparison of the pi(0) results with different theory expectations based on fits of other published data showed a preference for small positive values of gluon polarization, Delta G, in the proton in the probed Bjorken x range. The effect of adding the new 2009 pi(0) data to a recent global analysis of polarized scattering data is also shown, resulting in a best fit Delta G(DSSV)([0.05,0.2]) = 0.06(-0.15)(+0.11) in the range 0.05 < x < 0.2, with the uncertainty at Delta chi(2) = 9 when considering only statistical experimental uncertainties. Shifting the PHENIX data points by their systematic uncertainty leads to a variation of the best-fit value of Delta G(DSSV)([0.05,0.2]) between 0.02 and 0.12, demonstrating the need for full treatment of the experimental systematic uncertainties in future global analyses.
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28. |
- Adare, A., et al.
(författare)
-
Low-mass vector-meson production at forward rapidity in p plus p collisions at root s=200 GeV
- 2014
-
Ingår i: Physical Review D (Particles, Fields, Gravitation and Cosmology). - 1550-2368. ; 90:5
-
Tidskriftsartikel (refereegranskat)abstract
- The PHENIX experiment at the Relativistic Heavy Ion Collider has measured low-mass vector-meson ,omega, rho, and phi, production through the dimuon decay channel at forward rapidity (1.2 < vertical bar y vertical bar < 2.2) in p + p collisions at root s = 200 GeV. The differential cross sections for these mesons are measured as a function of both p(T) and rapidity. We also report the integrated differential cross sections over 1 < p(T) < 7 GeV/c and 1.2 < vertical bar y vertical bar < 2.2: d sigma/dy(omega + rho rho -> mu mu) = 80 +/- 6(stat) +/- 12(syst)nb and d sigma/dy(phi -> mu mu) = 27 +/- 3(stat) +/- 4(syst)nb. These results are compared with midrapidity measurements and calculations.
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29. |
- Austrin, Per, et al.
(författare)
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A New Point of NP-Hardness for 2-to-1 Label Cover
- 2012
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Ingår i: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - Berlin, Heidelberg : Springer Berlin Heidelberg. ; , s. 1-12
-
Konferensbidrag (refereegranskat)abstract
- We show that given a satisfiable instance of the 2-to-1 Label Cover problem, it is NP-hard to find a (23/24 + ε)-satisfying assignment
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30. |
- Clohisy, John C., et al.
(författare)
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Clinical trials in orthopaedics and the future direction of clinical investigations for femoroacetabular impingement
- 2013
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Ingår i: ; , s. 47-52
-
Konferensbidrag (refereegranskat)abstract
- Femoroacetabular impingement (FAI) represents a heterogeneous group of disorders that affect a diverse patient population. The natural history of the disease, the role of nonsurgical management, the indications for surgery, optimal surgical techniques, and the predictors of treatment outcomes need to be further defined. To date, clinical research reports have included primarily surgical case series. Future clinical investigations are needed to establish improved clinical evidence to guide patient care. Most urgent is the need to better understand the potential role of standardized nonsurgical treatment options for FAI and to define the predictors of surgical and nonsurgical outcomes. Future randomized controlled trials and large observational cohort studies targeted at these clinical research deficiencies will strengthen the evidence and improve informed decision making regarding the management of symptomatic FAI.
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31. |
- Dimitrou, Harry, et al.
(författare)
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Megaprojekt – lärdomar för beslutsfattare: Svensk kortversion av resultaten från OMEGA-projektet
- 2014
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Beslut, planering och genomförande av dyra och storskaliga transportinfrastruktursatsningar, så kallade megaprojekt är komplexa och ofta konfliktfyllda processer som involverar en mängd aktörer och intressenter, utspelar sig över lång tid och får stor påverkan i de områden där de byggs. Vad är det som avgör om megaprojekt blir lyckade eller inte? Vilka lärdomar kan man dra av att studera besluts- och planeringsprocesserna för genomförda projekt? Dessa frågor har varit grunden för den forskning som presenteras i rapporten. Resultaten är baserade på 30 fallstudier av genomförda megaprojekt i 10 länder i Euoropa, Nordamerika,Asien och Australien. Fallstudierna omfattar intervjuer med över 300 beslutsfattare och andra intressenter.Rapporten identifierar nio viktiga lärdomar beträffande planering, beslutsfattande och genomförande av megaprojekt, ger förslag på ”vem som bör göra vad annorlunda” och avslutas med ett avsnitt där några avlärdomarna diskuteras i mer detalj i förhållande till de svenska fallstudierna av Öresundsförbindelsen, Arlandabanan och Södra Länken.
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32. |
- Flores, Olivier, et al.
(författare)
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An evolutionary perspective on leaf economics : phylogenetics of leaf mass per area in vascular plants
- 2014
-
Ingår i: Ecology and Evolution. - : Wiley. - 2045-7758. ; 4:14, s. 2799-2811
-
Tidskriftsartikel (refereegranskat)abstract
- In plant leaves, resource use follows a trade-off between rapid resource capture and conservative storage. This worldwide leaf economics spectrum consists of a suite of intercorrelated leaf traits, among which leaf mass per area, LMA, is one of the most fundamental as it indicates the cost of leaf construction and light-interception borne by plants. We conducted a broad-scale analysis of the evolutionary history of LMA across a large dataset of 5401 vascular plant species. The phylogenetic signal in LMA displayed low but significant conservatism, that is, leaf economics tended to be more similar among close relatives than expected by chance alone. Models of trait evolution indicated that LMA evolved under weak stabilizing selection. Moreover, results suggest that different optimal phenotypes evolved among large clades within which extremes tended to be selected against. Conservatism in LMA was strongly related to growth form, as were selection intensity and phenotypic evolutionary rates: woody plants showed higher conservatism in relation to stronger stabilizing selection and lower evolutionary rates compared to herbaceous taxa. The evolutionary history of LMA thus paints different evolutionary trajectories of vascular plant species across clades, revealing the coordination of leaf trait evolution with growth forms in response to varying selection regimes.
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33. |
- Garcia-Rios, Antonio, et al.
(författare)
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A Period 2 Genetic Variant Interacts with Plasma SFA to Modify Plasma Lipid Concentrations in Adults with Metabolic Syndrome
- 2012
-
Ingår i: Journal of Nutrition. - : Elsevier BV. - 0022-3166 .- 1541-6100. ; 142:7, s. 1213-1218
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants of Period 2 (PER2), a circadian clock gene, have been linked to metabolic syndrome (MetS). However, it is still unknown whether these genetic variants interact with the various types of plasma fatty acids. This study investigated whether common single nucleotide polymorphisms (SNPs) in the PER2 locus (rs934945 and rs2304672) interact with various classes of plasma fatty acids to modulate plasma lipid metabolism in 381 participants with MetS in the European LIPGENE study. Interestingly, the rs2304672 SNP interacted with plasma total SFA concentrations to affect fasting plasma TG, TG-rich lipoprotein (TRL-TG), total cholesterol, apoC-II, apoB, and apoB-48 concentrations (P-interaction <0.001-0.046). Carriers of the minor allele (GC+GG) with the highest SFA concentration (>median) had a higher plasma TG concentration (P = 0.001) and higher TRL-TG (P < 0.001) than the CC genotype. In addition, participants carrying the minor G allele for rs2304672 SNP and with a higher SFA concentration (>median) had higher plasma concentrations of apo C-II (P < 0.001), apo C-III (P = 0.009), and apoB-48 (P = 0.028) compared with the homozygotes for the major allele (CC). In summary, the rs2304672 polymorphism in the PER2 gene locus may influence lipid metabolism by interacting with the plasma total SEA concentration in participants with MetS. The understanding of these gene-nutrient interactions could help to provide a better knowledge of the pathogenesis in MetS.
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34. |
- Howard, Andrew W., et al.
(författare)
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The California planet survey. I. four new giant exoplanets
- 2010
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 721:2, s. 1467-1481
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Tidskriftsartikel (refereegranskat)abstract
- We present precise Doppler measurements of four stars obtained during the past decade at Keck Observatory by the California Planet Survey (CPS). These stars, namely, HD 34445, HD 126614, HD 13931, and Gl 179, all show evidence for a single planet in Keplerian motion. We also present Doppler measurements from the Hobby-Eberly Telescope (HET) for two of the stars, HD 34445 and Gl 179, that confirm the Keck detections and significantly refine the orbital parameters. These planets add to the statistical properties of giant planets orbiting near or beyond the ice line, and merit follow-up by astrometry, imaging, and space-borne spectroscopy. Their orbital parameters span wide ranges of planetary minimum mass (M sin i = 0.38-1.9 M-Jup), orbital period (P = 2.87-11.5 yr), semimajor axis (a = 2.1-5.2 AU), and eccentricity (e = 0.02-0.41). HD 34445 b (P = 2.87 yr, M sin i = 0.79 MJup, e = 0.27) is a massive planet orbiting an old, G-type star. We announce a planet, HD 126614 Ab, and an M dwarf, HD 126614 B, orbiting the metal-rich star HD 126614 (which we now refer to as HD 126614 A). The planet, HD 126614 Ab, has minimum mass M sin i = 0.38 MJup and orbits the stellar primary with period P = 3.41 yr and orbital separation a = 2.3 AU. The faint M dwarf companion, HD 126614 B, is separated from the stellar primary by 489 mas (33 AU) and was discovered with direct observations using adaptive optics and the PHARO camera at Palomar Observatory. The stellar primary in this new system, HD 126614 A, has the highest measured metallicity ([ Fe/ H] = + 0.56) of any known planet-bearing star. HD 13931 b (P = 11.5 yr, M sin i = 1.88 MJup, e = 0.02) is a Jupiter analog orbiting a near solar twin. Gl 179 b (P = 6.3 yr, M sin i = 0.82 M-Jup, e = 0.21) is a massive planet orbiting a faint M dwarf. The high metallicity of Gl 179 is consistent with the planet-metallicity correlation among M dwarfs, as documented recently by Johnson & Apps.
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35. |
- Howard, Andrew W., et al.
(författare)
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The NASA-UC Eia-earth program. II. a planet orbiting HD 156668 with a minimum mass of four earth masses
- 2011
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 726:2, s. 73-
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of HD 156668 b, an extrasolar planet with a minimum mass of M-P sin i = 4.15 M-circle plus. This planet was discovered through Keplerian modeling of precise radial velocities from Keck-HIRES and is the second super-Earth to emerge from the NASA-UC Eta-Earth Survey. The best-fit orbit is consistent with circular and has a period of P = 4.6455 days. The Doppler semi-amplitude of this planet, K = 1.89 m s(-1), is among the lowest ever detected, on par with the detection of GJ 581 e using HARPS. A longer period (P approximate to 2.3 years), low-amplitude signal of unknown origin was also detected in the radial velocities and was filtered out of the data while fitting the short-period planet. Additional data are required to determine if the long-period signal is due to a second planet, stellar activity, or another source. Photometric observations using the Automated Photometric Telescopes at Fairborn Observatory show that HD 156668 (an old, quiet K3 dwarf) is photometrically constant over the radial velocity period to 0.1 mmag, supporting the existence of the planet. No transits were detected down to a photometric limit of similar to 3 mmag, ruling out transiting planets dominated by extremely bloated atmospheres, but not precluding a transiting solid/liquid planet with a modest atmosphere.
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36. |
- Howard, Andrew W., et al.
(författare)
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THE NASA-UC ETA-EARTH PROGRAM. III. A SUPER-EARTH ORBITING HD 97658 AND A NEPTUNE-MASS PLANET ORBITING G1 785
- 2011
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 730:1, s. 10-
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of planets orbiting two bright, nearby early K dwarf stars, HD 97658 and G1 785. These planets were detected by Keplerian modeling of radial velocities measured with Keck-HIRES for the NASA-UC Eta-Earth Survey. HD 97658 b is a close-in super-Earth with minimum mass M sin i = 8.2 +/- 1.2 M-circle plus, orbital period P = 9.494 +/- 0.005 days, and an orbit that is consistent with circular. G1 785 b is a Neptune-mass planet with M sin i = 21.6 +/- 2.0 M-circle plus, P = 74.39 +/- 0.12 days, and orbital eccentricity e = 0.30 +/- 0.09. Photometric observations with the T12 0.8 m automatic photometric telescope at Fairborn Observatory show that HD 97658 is photometrically constant at the radial velocity period to 0.09 mmag, supporting the existence of the planet.
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37. |
- Jiao, Hong, et al.
(författare)
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Genetic Association and Gene Expression Analysis Identify FGFR1 as a New Susceptibility Gene for Human Obesity
- 2011
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 96:6, s. E962-E966
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Tidskriftsartikel (refereegranskat)abstract
- Context: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Objective: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. Design: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. Setting: General community and referral centers for specialized care was the setting for the study. Participants: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. Main Outcome Measures: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. Results: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 x 10(-6), which was P = 7.0 x 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). Conclusions: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.
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38. |
- Lind, Lars, et al.
(författare)
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Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin.
- 2014
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
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39. |
- Lundberg, Max, et al.
(författare)
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Characterisation of a transcriptome to find sequence differences between two differentially migrating subspecies of the willow warbler Phylloscopus trochilus.
- 2013
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Animal migration requires adaptations in morphological, physiological and behavioural traits. Several of these traits have been shown to possess a strong heritable component in birds, but little is known about their genetic architecture. Here we used 454 sequencing of brain-derived transcriptomes from two differentially migrating subspecies of the willow warbler Phylloscopus trochilus to detect genes potentially underlying traits associated with migration.RESULTS: The transcriptome sequencing resulted in 1.8 million reads following filtering steps. Most of the reads (84%) were successfully mapped to the genome of the zebra finch Taeniopygia gutatta. The mapped reads were situated within at least 12,101 predicted zebra finch genes, with the greatest sequencing depth in exons. Reads that were mapped to intergenic regions were generally located close to predicted genes and possibly located in uncharacterized untranslated regions (UTRs). Out of 85,000 single nucleotide polymorphisms (SNPs) with a minimum sequencing depth of eight reads from each of two subspecies-specific pools, only 55 showed high differentiation, confirming previous studies showing that most of the genetic variation is shared between the subspecies. Validation of a subset of the most highly differentiated SNPs using Sanger sequencing demonstrated that several of them also were differentiated between an independent set of individuals of each subspecies. These SNPs were clustered in two chromosome regions that are likely to be influenced by divergent selection between the subspecies and that could potentially be associated with adaptations to their different migratory strategies.CONCLUSIONS: Our study represents the first large-scale sequencing analysis aiming at detecting genes underlying migratory phenotypes in birds and provides new candidates for genes potentially involved in migration.
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40. |
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41. |
- McQuillan, Ruth, et al.
(författare)
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Evidence of Inbreeding Depression on Human Height
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:7, s. e1002655-
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Tidskriftsartikel (refereegranskat)abstract
- Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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42. |
- Merlo, Domenico Franco, et al.
(författare)
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Micronuclei in Cord Blood Lymphocytes and Associations with Biomarkers of Exposure to Carcinogens and Hormonally Active Factors, Gene Polymorphisms, and Gene Expression : The NewGeneris Cohort
- 2014
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 122:2, s. 193-200
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Tidskriftsartikel (refereegranskat)abstract
- Background: Leukemia incidence has increased in recent decades among European children, -suggesting that early-life environmental exposures play an important role in disease development. Objectives: We investigated the hypothesis that childhood susceptibility may increase as a result of in utero exposure to carcinogens and hormonally acting factors. Using cord blood samples from the NewGeneris cohort, we examined associations between a range of biomarkers of carcinogen exposure and hormonally acting factors with micronuclei (MN) frequency as a proxy measure of cancer risk. Associations with gene expression and genotype were also explored. Methods: DNA and protein adducts, gene expression profiles, circulating hormonally acting factors, and GWAS (genome-wide association study) data were investigated in relation to genomic damage measured by MN frequency in lymphocytes from 623 newborns enrolled between 2006 and 2010 across Europe. Results: Malondialdehyde DNA adducts (M(1)dG) were associated with increased MN frequency in binucleated lymphocytes (MNBN), and exposure to androgenic, estrogenic, and dioxin-like compounds was associated with MN frequency in mononucleated lymphocytes (MNMONO), although no monotonic exposure-outcome relationship was observed. Lower frequencies of MNBN were associated with a 1-unit increase expression of PDCD11, LATS2, TRIM13, CD28, SMC1A, IL7R, and NIPBL genes. Gene expression was significantly higher in association with the highest versus lowest category of bulky and M(1)dG-DNA adducts for five and six genes, respectively. Gene expression levels were significantly lower for 11 genes in association with the highest versus lowest category of plasma AR CALUX (R) (chemically activated luciferase expression for androgens) (8 genes), ER alpha CALUX (R) (for estrogens) (2 genes), and DR CALUX (R) (for dioxins). Several SNPs (single-nucleotide polymorphisms) on chromosome 11 near FOLH1 significantly modified associations between androgen activity and MNBN frequency. Polymorphisms in EPHX1/ 2 and CYP2E1 were associated with MNBN. Conclusion: We measured in utero exposure to selected environmental carcinogens and circulating hormonally acting factors and detected associations with MN frequency in newborns circulating T lymphocytes. The results highlight mechanisms that may contribute to carcinogen-induced leukemia and require further research.
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43. |
- Obeidat, Ma'en, et al.
(författare)
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A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5, s. e19382-
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives: To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods: We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/-10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results: The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3 x 10(-5). The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81 x 10(-5)), CNTN5 (P = 4.37 x 10(-4)), and TRPV4 (P = 1.58 x 10(-3)). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41 x 10(-5)), followed by PDE4D (P = 1.22 x 10(-4)). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38 x 10(-4)), and ESR1 (P = 5.42 x 10(-4)) among ever-smokers. Conclusions: Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.
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44. |
- Pedersen, Marie, et al.
(författare)
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Birth Weight, Head Circumference, and Prenatal Exposure to Acrylamide from Maternal Diet : The European Prospective Mother-Child Study (NewGeneris)
- 2012
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 120:12, s. 1739-1745
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. OBJECTIVES: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother child study. METHODS: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006-2010. Maternal diet was estimated through food-frequency questionnaires. RESULTS: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g (95% CI: -207, -56); the corresponding difference for head circumference was -0.33 cm (95% CI: -0.61, -0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for Factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. CONCLUSIONS: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. IF confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women.
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45. |
- Pedersen, Marie, et al.
(författare)
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Bulky DNA Adducts in Cord Blood, Maternal Fruit-and-Vegetable Consumption, and Birth Weight in a European Mother-Child Study (NewGeneris)
- 2013
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 121:10, s. 1200-1206
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tobacco-smoke, airborne, and dietary exposures to polycyclic aromatic-hydrocarbons (PAHs) have been associated with reduced prenatal growth. Evidence from -biomarker-based studies of low-exposed populations is limited. Bulky DNA adducts in cord blood reflect the prenatal effective dose to several genotoxic agents including PAHs. Objectives: We estimated the association between bulky DNA adduct levels and birth weight in a multicenter study and examined modification of this association by maternal intake of fruits and vegetables during pregnancy. Methods: Pregnant women from Denmark, England, Greece, Norway, and Spain were recruited in 2006-2010. Adduct levels were measured by the 32P-postlabeling technique in white blood cells from 229 mothers and 612 newborns. Maternal diet was examined through questionnaires. Results: Adduct levels in maternal and cord blood samples were similar and positively correlated (median, 12.1 vs. 11.4 adducts in 108 nucleotides; Spearman rank correlation coefficient = 0.66, p < 0.001). Cord blood adduct levels were negatively associated with birth weight, with an estimated difference in mean birth weight of -129 g (95% CI: -233, -25 g) for infants in the highest versus lowest tertile of adducts. The negative association with birth weight was limited to births in Norway, Denmark, and England, the countries with the lowest adduct levels, and was more pronounced in births to mothers with low intake of fruits and vegetables (-248 g; 95% CI: -405, -92 g) compared with those with high intake (-58 g; 95% CI: -206, 90 g). Conclusions: Maternal exposure to genotoxic agents that induce the formation of bulky DNA adducts may affect intrauterine growth. Maternal fruit and vegetable consumption may be protective.
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46. |
- Perry, John R. B., et al.
(författare)
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Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m(2)) compared to obese cases (BMI >= 30 Kg/m(2)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m(2)) or 4,123 obese cases (BMI >= 30 kg/m(2)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4610 29, OR = 1.13 [95% CI 1.09-1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00-1.06]). A variant in HMG20A-previously identified in South Asians but not Europeans-was associated with type 2 diabetes in obese cases (P = 1.3 x 10(-8), OR= 1.11 [95% CI 1.07-1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02-1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10-1.17], P = 3.2 x 10(-14). This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05-1.08], P = 2.2 x 10(-16). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
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47. |
- Schwartz, Gregory G, et al.
(författare)
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Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 367:22, s. 2089-2099
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND less thanbrgreater than less thanbrgreater thanIn observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanWe randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanAt the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (Pandlt;0.001 for both comparisons). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanIn patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.)
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48. |
- Slotte, Tanja, et al.
(författare)
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Genome-Wide Evidence for Efficient Positive and Purifying Selection in Capsella grandiflora, a Plant Species with a Large Effective Population Size
- 2010
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 27:8, s. 1813-1821
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies comparing genome-wide polymorphism and divergence in Drosophila have found evidence for a surprisingly high proportion of adaptive amino acid fixations, but results for other taxa are mixed. In particular, few studies have found convincing evidence for adaptive amino acid substitution in plants. To assess the generality of this finding, we have sequenced 257 loci in the outcrossing crucifer Capsella grandiflora, which has a large effective population size and low population structure. Using a new method that jointly infers selective and demographic effects, we estimate that 40% of amino acid substitutions were fixed by positive selection in this species, and we also infer a low proportion of slightly deleterious amino acid mutations. We contrast these estimates with those for a similar data set from the closely related Arabidopsis thaliana and find significantly higher rates of adaptive evolution and fewer nearly neutral mutations in C. grandiflora. In agreement with results for other taxa, genes involved in reproduction show the strongest evidence for positive selection in C. grandiflora. Taken together, these results imply that both positive and purifying selection are more effective in C. grandiflora than in A. thaliana, consistent with the contrasting demographic history and effective population sizes of these species.
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49. |
- Snape, Katie, et al.
(författare)
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Mutations in CEP57 cause mosaic variegated aneuploidy syndrome
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:6, s. 527-529
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Tidskriftsartikel (refereegranskat)abstract
- Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division.
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50. |
- St Onge, Kate, 1982-, et al.
(författare)
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Coalescent-based analysis distinguishes between allo- and autopolyploid origin in shepherd’s purse (Capsella bursa-pastoris)
- 2012
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 29:7, s. 1721-1733
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Tidskriftsartikel (refereegranskat)abstract
- Polyploidization plays an important role in plant speciation. The most recent estimates 36 report that up to 15% of angiosperm speciation events and 31% in ferns are accompanied 37 by changes in ploidy level. Polyploids can arise either through autopolyploidy, when the 38 sets of chromosomes originate from a single species, or through allopolyploidy, when 39 they originate from different species. In this study we used two different coalescent-based 40 methods to determine the date and mode of the polyploidization event that led to the 41 tetraploid cosmopolitan weed, Capsella bursa-pastoris. We sampled 78 C. bursa-pastoris 42 accessions, and 53 and 43 accessions from the only two other members of this genus, C. 43 grandiflora and C. rubella, respectively, and sequenced these accessions at 14 unlinked 44 nuclear loci with locus-specific primers in order to be able to distinguish the two 45 homeologues in the tetraploid. A large fraction of fixed differences between 46 homeologous genes in C. bursa-pastoris are segregating as polymorphisms in C. 47 grandiflora, consistent with an autopolyploid origin followed by disomic inheritance. To 48 test this, we first estimated the demographic parameters of an isolation-with-migration 49 model in a pairwise fashion between C. grandiflora and both genomes of C. bursa- 50 pastoris and used these parameters in coalescent simulations to test the mode of origin of 51 C. bursa-pastoris. Secondly we used Approximate Bayesian Computation to compare an 52 allopolyploid and an autopolyploid model. Both analyses led to the conclusion that C. 53 bursa-pastoris originated less than one million years ago by doubling of the C. 54 grandiflora genome.
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