A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

现象 孟德尔随机化 全基因组关联研究 生物 混淆 人口 人口学 遗传关联 遗传谱系 肥胖 体质指数 医学 遗传流行病学 疾病 内科学 遗传学 单核苷酸多态性 环境卫生 基因型 基因组 社会学 遗传变异 基因
作者
Sridharan Raghavan,Jie Huang,Catherine Tcheandjieu,Jennifer E. Huffman,Elizabeth Litkowski,Chang Liu,Yuk‐Lam Ho,Haley Hunter-Zinck,Hongyu Zhao,Eirini Marouli,Kari E. North,Ethan M. Lange,Leslie A. Lange,Benjamin F. Voight,J. Michael Gaziano,Saiju Pyarajan,Elizabeth R. Hauser,Philip S. Tsao,Peter W.F. Wilson,Kyong‐Mi Chang,Kelly Cho,Christopher J. O’Donnell,Yan V. Sun,Themistocles L. Assimes
出处
期刊:PLOS Genetics 卷期号:18 (6): e1010193-e1010193 被引量:10
标识
DOI:10.1371/journal.pgen.1010193
摘要

Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
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