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Sökning: WFRF:(Igl Wilmar)

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  • Allen, Hana Lango, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - 1476-4687. ; 467:7317, s. 832-8
  • 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(1), 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(2,3). 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.
  • Ameur, Adam, et al. (författare)
  • Genetic Adaptation of Fatty-Acid Metabolism : A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids
  • 2012
  • Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 90:5, s. 809-820
  • Tidskriftsartikel (refereegranskat)abstract
    • Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.
  • Chasman, Daniel I., et al. (författare)
  • Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
  • 2012
  • Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
  • Tidskriftsartikel (refereegranskat)abstract
    • In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
  • Demirkan, Ayse, et al. (författare)
  • Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations
  • 2012
  • Ingår i: PLoS Genetics. - 1553-7390. ; 8:2, s. e1002490
  • Tidskriftsartikel (refereegranskat)abstract
    • Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.
  • den Hoed, Marcel, et al. (författare)
  • Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
  • 2013
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 45:6, s. 621-
  • Tidskriftsartikel (refereegranskat)abstract
    • Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
  • Denkinger, Michael D., et al. (författare)
  • Does functional change predict the course of improvement in geriatric inpatient rehabilitation?
  • 2010
  • Ingår i: Clinical Rehabilitation. - 0269-2155 .- 1477-0873. ; 24:5, s. 463-470
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The evaluation of rehabilitation success as measured by different tools is becoming increasingly important in terms of time and money allocation. We wanted to know whether functional change in the first week predicts subsequent improvement in a geriatric inpatient rehabilitation clinic. Design: Observational longitudinal study. Setting: Geriatric inpatient rehabilitation clinic in Germany. Subjects: One hundred and sixty-one inpatients (117 women) with a median age of 82 years, capable of walking at baseline. Main measures: Weekly assessments of physical function were performed from admission until three weeks later. We used a self-rated tool (the function component of the Short Form - Late Life Function and Disability Index), a proxy-rated tool (the Barthel Index) and a performance-based tool (gait speed). We set up linear regression models to estimate the predictive capacity of change in physical function within the first week on change in physical function within the following two weeks. Results: Positive correlations were found between functional change within the first week and total change within three weeks. However, correlations of the same periods of change with subsequent change were negative. Correlations were highly significant for both analysis with P-values < 0.0001 when the same measures for prediction and outcome were used. Correlations were inconsistent when prediction and outcome were different. Conclusions: Improvement within the first week of inpatient rehabilitation is negatively correlated with subsequent functional change.
  • Denkinger, Michael D., et al. (författare)
  • Relationship Between Fear of Falling and Outcomes of an Inpatient Geriatric Rehabilitation Population : Fear of the Fear of Falling
  • 2010
  • Ingår i: Journal of The American Geriatrics Society. - 0002-8614 .- 1532-5415. ; 58:4, s. 664-673
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES To examine the effects of various risk factors on three functional outcomes during rehabilitation. SETTING Geriatric inpatient rehabilitation unit. DESIGN Observational longitudinal study. PARTICIPANTS One hundred sixty-one geriatric rehabilitation inpatients (men, women), mean age 82, who were capable of walking at baseline. MEASUREMENTS Functional status was assessed weekly between admission and discharge and at a follow-up 4 months later at home using the function component of the Short Form-Late Life Function and Disability Instrument, the Barthel Index, and Habitual Gait Speed. Various risk factors, such as falls-related self-efficacy (Falls Efficacy Scale-International), were measured. Associations between predictors and functional status at discharge and follow-up were analyzed using linear regression models and bivariate plots. RESULTS Fear of falling predicted functioning across all outcomes except for habitual gait speed at discharge and follow-up. Visual comparison of functional trajectories between subgroups confirmed these findings, with different levels of fear of falling across time in linear plots. Thus, superior ability of this measure to discriminate between functional status at baseline across all outcomes and to discriminate between functional change especially with regard to the performance-based outcome was demonstrated. CONCLUSION Falls-related self-efficacy is the only parameter that significantly predicts rehabilitation outcome at discharge and follow-up across all outcomes. Therefore, it should be routinely assessed in future studies in (geriatric) rehabilitation and considered to be an important treatment goal.
  • Ehret, Georg B., et al. (författare)
  • Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
  • 2011
  • Ingår i: Nature. - Nature Publishing Group. - 0028-0836. ; 478:7367, s. 103-109
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
  • Friedrichs, Bettina, et al. (författare)
  • Coexisting psychiatric problems and stressful life events in adults with symptoms of ADHD : a large Swedish population-based study of twins
  • 2012
  • Ingår i: Journal of Attention Disorders. - Sage Publications. - 1087-0547. ; 16:1, s. 13-22
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To explore the associations of subtypes of adult ADHD with other psychiatric problems, stressful life events, and sex differences.METHOD: Odds ratios were calculated using information from 17,899 participants from a population-based survey of adult twins born in Sweden between 1959 and 1985.RESULTS: Symptoms of attention deficit hyperactivity disorder (ADHD) were associated with an increased risk for symptoms of (odds ratio [95% confidence interval]): generalized anxiety disorder (5.6 [4.3; 6.5]), major depression (2.8 [2.4; 3.2]), bipolar disorder (8.0 [5.1; 12.6]), obsessive-compulsive disorder (3.9 [3.1; 4.9]), and alcohol dependence (2.6 [2.2; 3.1]). Symptoms of ADHD were found to be associated with an increased risk for stressful life events (1.8 [1.3; 2.4]). No significant difference in comorbidity was observed between the two sexes.CONCLUSION: Both women and men with ADHD are at increased risk for symptoms of other psychiatric disorders. They are also at increased risk for stressful life events.
  • Heid, Iris M, et al. (författare)
  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution.
  • 2010
  • Ingår i: Nature genetics. - 1546-1718. ; 42:11, s. 949-60
  • 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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