| 1. |
- 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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| 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. |
- 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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| 4. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 5. |
- 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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| 6. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 7. |
- Seshasai, Sreenivasa Rao Kondapally, et al.
(författare)
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Diabetes mellitus, fasting glucose, and risk of cause-specific death.
- 2011
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Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 364:9, s. 829-41
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.
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| 8. |
- Solazzo, Caroline, et al.
(författare)
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Modeling deamidation in sheep α-keratin peptides and application to archaeological wool textiles
- 2014
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 86:1, s. 567-575
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Tidskriftsartikel (refereegranskat)abstract
- Deamidation of glutamine (Q) and asparagine (N) has been recognized as a marker of degradation and aging in ancient proteins. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) to study deamidation in wool textiles, we identified eight peptides from α-keratin proteins in sheep wool that could potentially be used to assess the level of degradation. For each chosen peptide, the extent of deamidation was determined by comparing the calculated theoretical distribution with the measured distribution using a genetic algorithm that gives the best fit to the measured distribution. Variations in the levels of deamidation were observed between peptides and in modern wool samples buried for up to 8 years in which deamidation levels were relatively low under short-term burial. In contrast, deamidation was higher in archeological textile fragments from medieval sites ranging from the 9th to 13th century in York (United Kingdom) and Newcastle (United Kingdom) and from the 13th to 16th century in Reykholt (Iceland). Major differences were observed between the British and the Icelandic samples, showing a negative correlation between age of samples and levels of deamidation, but highlighting the effect of local environment. In addition, nanoscale liquid chromatography–electrospray ionization tandem mass spectrometry (nanoLC–ESI-MS/MS) data indicated that deamidation in wool’s α-keratin was influenced by primary and higher-order structures. Predominance of deamidation on glutamine rather than asparagine in the archeological samples was attributed to a higher abundance of Q in the α-helical core domain of keratins, neighboring residues and steric hindrance preventing deamidation of N.
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| 9. |
- Solazzo, Caroline, et al.
(författare)
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Proteomic evaluation of the biodegradation of wool fabrics in experimental burials
- 2013
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Ingår i: International Biodeterioration & Biodegradation. - : Elsevier BV. - 0964-8305. ; 80, s. 48-59
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Tidskriftsartikel (refereegranskat)abstract
- Woollen textiles recovered from archaeological excavations are usually fragile, discoloured, mineralised, or highly biodeteriorated fragmentary remains. The nature and extent of preservation is highly dependent on the site of burial and factors such as soil composition, pH, temperature, oxygen content, and contact with a wood coffin or metals. Understanding the particular biodegradation in archaeological sites is important for biomolecular studies of textiles, and to assist in the conservation of these finds. Wool fabrics dyed and buried for up to 8 yr in bog-type soils in Denmark (Lejre) and Norway (Rørmyra), and in marine sediments in Sweden (Marstrand) were evaluated by proteomics analysis. Wool degradation was found to occur through a range of differing mechanisms, mainly due to the complex nature of wool itself with its many families of proteins (keratin and keratin-associated proteins) and structures. Microbial activity was a large contributory factor to the physical deterioration of the wool fabrics at Lejre and Marstrand, and might result in faster loss of keratin-associated proteins over keratins. Additional hydrolysis took place at Marstrand, influenced by the environmental conditions of the sediment, and in particular the alkaline pH, contributing to the degradation of keratins. However, cross-linking was associated with the long-term preservation of the fabrics at Rørmyra, where pH, temperature, and vegetative composition of the bog prevented microbial activity, and sphagnum moss might preserve wool by binding with keratins.
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| 10. |
- von Holstein, I. C. C., et al.
(författare)
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Wet degradation of keratin proteins: linking amino acid, elemental and isotopic composition
- 2014
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Ingår i: Rapid Communications in Mass Spectrometry. - : Wiley. - 0951-4198. ; 28:19, s. 2121-2133
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Archaeological keratin samples are increasingly the subject of palaeodietary, provenancing and dating studies. Keratin samples from wet archaeological contexts are microbiologically and chemically degraded, causing differential diagenesis of protein structures in hair fibres. The effects of these processes on the analytical parameters of interest are currently unknown. METHODS: This study examined the impact of degradation of wool fibres on isotopic (delta C-13, delta N-15, un-exchangeable delta H-2 and delta O-18 values) composition. It compared two models of archaeological protein degradation in wet burial environments: (1) short term (up to 8 years) experimental burial in three contrasting soil environments; and (2) laboratory wet conditions, in which elevated temperature (80 degrees C, 110 degrees C, and 140 degrees C) and pressure simulated longer exposure. Elemental and amino acid (AA) composition were also measured. RESULTS: In experimentally soil-buried samples, AA, elemental and isotopic composition changes were small, despite extensive macroscopic alteration. Isothermally heated samples showed preferential loss of hydrophilic AAs (Asx, Glx, Ser, Gly) from wool residues, with depletion in H-2 and O-18 at higher temperatures (up to -73% change in delta H-2 and -2.6% in delta(18)Ovalues). The delta C-13 and delta(15)Nvalues showed little change except in densely pigmented samples at low temperatures only. Samples dyed with madder/alum were better preserved than undyed samples. CONCLUSIONS: Diagenesis in experimentally soil-buried wool textiles was consistent with microbiological, non-protein-selective activity, in contrast to highly AA-selective hydrolytic behaviour under laboratory wet conditions. Changes in delta H-2 and delta O-18 values were correlated with degree of AA change, but the delta C-13 and delta N-15 values were not. The results contribute to a baseline for interpreting analytical data from archaeological hair samples preserved by burial in wet environments. Copyright (C) 2014 John Wiley & Sons, Ltd.
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