Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort
Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort
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DOI：
10.1136/jmedgenet-2018-105437
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发表时间：
2018-11-01
影响因子：
4
通讯作者：
de Cid, Rafael
中科院分区：
文献类型：
--
作者：
Galvan-Femenia, Ivan;Obon-Santacana, Mireia;de Cid, Rafael
背景遗传力估计揭示了SNP变异对大多数常见性状的重要贡献；然而，单性状全基因组关联研究(GWAS)的SNP分析未能揭示它们的影响。方法我们分析了205个性状，包括GCAT队列(生命基因组-加泰罗尼亚基因组研究)(n=4988)中基线确定的疾病。GCAT队列研究是一项来自欧洲南部的地中海成年人群队列研究。我们估计了1500万个SNP变异中所有性状的SNP遗传力贡献和单性状遗传效应。然后，我们应用多性状相关的方法，在与英国生物库队列(n=336107)的两阶段荟萃分析中，研究了全基因组与人体测量指标的关联。结果遗传度估计(例如，肤色、饮酒、吸烟习惯、体重指数、教育水平或身高)揭示了单核苷酸多态性变异的重要贡献，范围在18%到77%之间。单性状分析确定了1785个具有全基因组显著阈值的SNP。其中，在我们的样本中证实了几个先前报道的单性状命中，LINC01432(p=1.9x10(-9))变异与男性秃顶有关，LDLR变异与高脂血症(ICD-9：272)(p=9.4x10(-10))以及IRF4(p=2.8x10(-57))，SLC45A2(p=2.2x10(-130))，HERC2(p=2.8x10(-176))，OCA2(p=2.4x10(-121))和MC1R(p=7.7x10(-22))变异与头发、皮肤颜色、雀斑、雀斑有关晒黑能力、日晒敏感度和菲茨帕特里克照相得分，都是高度相关的交叉表型。人体测量变异的多性状荟萃分析在一个大型英国血统队列的两阶段荟萃分析中验证了27个基因座，其中6个是这里新报告的(p值阈值
Background Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact. In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation.Methods We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe. We estimated SNP heritability contribution and single-trait GWAS for all traits from 15million SNP variants. Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336107).Results Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77%. Single-trait analysis identified 1785 SNPs with genome-wide significance threshold. From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=1.9x10(-9)) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=9.4x10(-10)) and variants in IRF4 (p=2.8x10(-57)), SLC45A2 (p=2.2x10(-130)), HERC2 (p=2.8x10(-176)), OCA2 (p= 2.4x10(-121)) and MC1R (p=7.7x10(-22)) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes. Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold