Mahajan Anubha, Sim Xueling, Ng Hui Jin, Manning Alisa, Rivas Manuel A, Highland Heather M, Locke Adam E, Grarup Niels, Im Hae Kyung, Cingolani Pablo, Flannick Jason, Fontanillas Pierre, Fuchsberger Christian, Gaulton Kyle J, Teslovich Tanya M, Rayner N William, Robertson Neil R, Beer Nicola L, Rundle Jana K, Bork-Jensen Jette, Ladenvall Claes, Blancher Christine, Buck David, Buck Gemma, Burtt Noël P, Gabriel Stacey, Gjesing Anette P, Groves Christopher J, Hollensted Mette, Huyghe Jeroen R, Jackson Anne U, Jun Goo, Justesen Johanne Marie, Mangino Massimo, Murphy Jacquelyn, Neville Matt, Onofrio Robert, Small Kerrin S, Stringham Heather M, Syvänen Ann-Christine, Trakalo Joseph, Abecasis Goncalo, Bell Graeme I, Blangero John, Cox Nancy J, Duggirala Ravindranath, Hanis Craig L, Seielstad Mark, Wilson James G, Christensen Cramer, Brandslund Ivan, Rauramaa Rainer, Surdulescu Gabriela L, Doney Alex S F, Lannfelt Lars, Linneberg Allan, Isomaa Bo, Tuomi Tiinamaija, Jørgensen Marit E, Jørgensen Torben, Kuusisto Johanna, Uusitupa Matti, Salomaa Veikko, Spector Timothy D, Morris Andrew D, Palmer Colin N A, Collins Francis S, Mohlke Karen L, Bergman Richard N, Ingelsson Erik, Lind Lars, Tuomilehto Jaakko, Hansen Torben, Watanabe Richard M, Prokopenko Inga, Dupuis Josee, Karpe Fredrik, Groop Leif, Laakso Markku, Pedersen Oluf, Florez Jose C, Morris Andrew P, Altshuler David, Meigs James B, Boehnke Michael, McCarthy Mark I, Lindgren Cecilia M, Gloyn Anna L
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS Genet. 2015 Jan 27;11(1):e1004876. doi: 10.1371/journal.pgen.1004876. eCollection 2015 Jan.
Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
空腹血糖（FG）和胰岛素（FI）的全基因组关联研究（GWAS）已经识别出常见变异信号，它们分别解释了4.8%和1.2%的性状变异。据推测，低频和罕见变异可能对无法解释的遗传变异有很大贡献。为了验证这一点，我们分析了多达33231名欧洲血统非糖尿病个体的外显子阵列数据。我们发现了两个常见变异GWAS之前未突出显示的位点存在全外显子显著（P<5×10-7）证据：影响FG水平的GLP1R（p.Ala316Thr，次要等位基因频率（MAF）=1.5%）和影响FI水平的URB2（p.Glu594Val，MAF = 0.1%）。编码变异关联可以在（非编码）GWAS信号处突出潜在的效应基因。在G6PC2/ABCB11位点，我们在G6PC2中鉴定出多个影响FG水平的编码变异（p.Val219Leu、p.His177Tyr和p.Tyr207Ser），它们相互之间以及与非编码GWAS信号有条件地独立。体外试验表明，这些相关的编码等位基因通过蛋白酶体降解导致蛋白质丰度降低，确立了G6PC2作为该位点的效应基因。只有在考虑单倍型相位时，单变异关联和功能效应的协调才有可能。与早期报告相反，早期报告表明，矛盾的是，该位点的升糖等位基因对2型糖尿病（T2D）有保护作用，p.Val219Leu G6PC2变异与T2D风险呈适度但方向一致的关联。GWAS信号中血糖性状的编码变异关联突出了PCSK1、RREB1和ZHX3作为可能的效应转录本。这些编码变异关联信号对解释的性状变异没有重大影响，但它们确实提供了有价值的生物学见解。
