TY - JOUR
T1 - A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program
AU - Raghavan, Sridharan
AU - Huang, Jie
AU - Tcheandjieu, Catherine
AU - Huffman, Jennifer E.
AU - Litkowski, Elizabeth
AU - Liu, Chang
AU - Ho, Yuk Lam A.
AU - Hunter-Zinck, Haley
AU - Zhao, Hongyu
AU - Marouli, Eirini
AU - North, Kari E.
AU - Lange, Ethan
AU - Lange, Leslie A.
AU - Voight, Benjamin F.
AU - Michael Gaziano, J.
AU - Pyarajan, Saiju
AU - Hauser, Elizabeth R.
AU - Tsao, Philip S.
AU - Wilson, Peter W.F.
AU - Chang, Kyong Mi
AU - Cho, Kelly
AU - ODonnell, Christopher J.
AU - Sun, Yan V.
AU - Assimes, Themistocles L.
N1 - Publisher Copyright:
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2022/6/2
Y1 - 2022/6/2
N2 - Background 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. Methods and findings 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. Conclusions 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.
AB - Background 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. Methods and findings 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. Conclusions 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.
UR - http://www.scopus.com/inward/record.url?scp=85131258242&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1010193
DO - 10.1371/journal.pgen.1010193
M3 - Article
C2 - 35653334
AN - SCOPUS:85131258242
SN - 1553-7390
VL - 18
JO - PLoS Genetics
JF - PLoS Genetics
IS - 6
M1 - e1010193
ER -