Wood Andrew R, Tyrrell Jessica, Beaumont Robin, Jones Samuel E, Tuke Marcus A, Ruth Katherine S, Yaghootkar Hanieh, Freathy Rachel M, Murray Anna, Frayling Timothy M, Weedon Michael N
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
Diabetologia. 2016 Jun;59(6):1214-21. doi: 10.1007/s00125-016-3908-5. Epub 2016 Mar 10.
AIMS/HYPOTHESIS: Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.
We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity.
Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p DOMDEV = 3 × 10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p DOMDEV = 0.003; meta-analysis p DOMDEV = 1 × 10(-7)). For type 2 diabetes, we detected a recessive effect (p DOMDEV = 5 × 10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance.
CONCLUSIONS/INTERPRETATION: Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci.
Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.
目的/假设：全基因组关联（GWA）研究已鉴定出数百种与肥胖症和2型糖尿病相关的常见基因变异。这些研究通常集中在加性关联测试上。识别与加性的偏差可能会提供新的生物学见解，并解释这些疾病中一些缺失的遗传力。
我们使用显性偏差模型对英国生物银行研究中120286名英国血统个体的体重指数（BMI）、肥胖症（29925例）和2型糖尿病（4040例）进行了GWA研究。我们还研究了先前显示与这些性状相关的单核苷酸多态性是否显示出任何偏离加性的富集。
FTO基因中已知的肥胖相关变异通过与较高BMI相关的等位基因的隐性效应显示出强烈的偏离加性的证据（p DOMDEV = 3×10⁻⁵）。携带零个、一个或两个增加BMI等位基因的个体的平均BMI分别为27.27（95%CI 27.22，27.31）kg/m²、27.54（95%CI 27.50，27.58）kg/m²和28.07（95%CI 28.00，28.14）kg/m²。在来自GIANT联盟的105643名个体中观察到类似的效应（p DOMDEV = 0.003；荟萃分析p DOMDEV = 1×10⁻⁷）。对于2型糖尿病，我们在CDKAL1基因处检测到隐性效应（p DOMDEV = 5×10⁻⁴）。相对于纯合非风险等位基因携带者，纯合风险等位基因携带者的比值比为1.48（95%CI 1.32，1.65），而异合子组的比值比为1.06（95%CI 0.99，1.14），这一结果与先前的一项研究一致。我们没有在全基因组显著性水平上发现任何新的关联。
结论/解读：尽管我们没有发现广泛的非加性基因效应导致肥胖症和2型糖尿病风险的证据，但我们确实在FTO和CDKAL1基因座发现了隐性效应的确凿例子。
汇总统计数据可在www.t2diabetesgenes.org上获取，也可通过请求获取（a.r.wood@exeter.ac.uk）。所有基础数据可通过向英国生物银行申请获得。
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