| 1. |
- Lindgren, Cecilia M, et al.
(författare)
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Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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| 2. |
- Aulchenko, Yurii S, et al.
(författare)
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Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:1, s. 47-55
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.
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| 3. |
- Willer, Cristen J., et al.
(författare)
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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
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Tidskriftsartikel (refereegranskat)abstract
- Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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| 4. |
- Johansson, Åsa, et al.
(författare)
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Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:2, s. 373-380
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Tidskriftsartikel (refereegranskat)abstract
- Genes for height has gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in approximately 4,000 individuals from five European populations. A total of 5 chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal p=7.0 x 10(-8) and p=9.6 x 10(-7) respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal p<1.6 x 10(-7)). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (N=31,077, N=1,268 and N=5,746) with overall meta p-values of 9.4x10(-10) and 5.3x10(-8). These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycaemia and growth retardation when knocked-out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height so far identified.
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| 5. |
- Vasan, Ramachandran S, et al.
(författare)
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Genetic variants associated with cardiac structure and function : a meta-analysis and replication of genome-wide association data
- 2009
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 302:2, s. 168-178
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
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