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

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  • Raghavan, S.
    • Other Affiliation: University of Colorado Anschutz Medical Campus
  • Huang, J.
    • Other Affiliation: Southern University of Science and Technology
  • Tcheandjieu, C.
    • Other Affiliation: Stanford University
  • Huffman, J.E.
    • Other Affiliation: Veterans Affairs Boston Healthcare System
  • Litkowski, E.
    • Other Affiliation: Veterans Affairs Eastern Colorado Health Care System
  • Liu, C.
    • Other Affiliation: Emory University
  • Ho, Y.-L.A.
    • Other Affiliation: Veterans Affairs Boston Healthcare System
  • Hunter-Zinck, H.
    • Other Affiliation: Veterans Affairs Boston Healthcare System
  • Zhao, H.
    • Other Affiliation: Veterans Affairs Connecticut Healthcare System
  • Marouli, E.
    • Other Affiliation: Queen Mary University of London
  • North, K.E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Lange, E.
    • Other Affiliation: University of Colorado Anschutz Medical Campus
  • Lange, L.A.
    • Other Affiliation: University of Colorado Anschutz Medical Campus
  • Voight, B.F.
    • Other Affiliation: University of Pennsylvania
  • Gaziano, J.M.
    • Other Affiliation: Brigham and Women’s Hospital
  • Pyarajan, S.
    • Other Affiliation: Brigham and Women’s Hospital
  • Hauser, E.R.
    • Other Affiliation: Stanford University
  • Tsao, P.S.
    • Other Affiliation: Duke University Medical Center
  • Wilson, P.W.F.
    • Other Affiliation: Emory University
  • Chang, K.-M.
    • Other Affiliation: University of Pennsylvania
  • Cho, K.
    • Other Affiliation: Brigham and Women's Hospital
  • O'Donnell, C.J.
    • Other Affiliation: Harvard Medical School
  • Sun, Y.V.
    • Other Affiliation: Emory University
  • Assimes, T.L.
    • Other Affiliation: Stanford University
Abstract
  • 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.
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  • Article
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  • In Copyright
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  • CC0 1.0 Universal
Journal title
  • PLoS Genetics
Journal volume
  • 18
Journal issue
  • 6
Language
  • English
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  • 1553-7390
Publisher
  • Public Library of Science

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