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

Publication ,  Journal Article
Raghavan, S; Huang, J; Tcheandjieu, C; Huffman, JE; Litkowski, E; Liu, C; Ho, Y-LA; Hunter-Zinck, H; Zhao, H; Marouli, E; North, KE; Lange, E ...
Published in: PLoS Genet
June 2022

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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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

June 2022

Volume

18

Issue

6

Start / End Page

e1010193

Location

United States

Related Subject Headings

  • Veterans
  • Polymorphism, Single Nucleotide
  • Hypertension
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Developmental Biology
  • Atrial Fibrillation
  • Adult
  • 3105 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Raghavan, S., Huang, J., Tcheandjieu, C., Huffman, J. E., Litkowski, E., Liu, C., … Assimes, T. L. (2022). A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program. PLoS Genet, 18(6), e1010193. https://doi.org/10.1371/journal.pgen.1010193
Raghavan, Sridharan, Jie Huang, Catherine Tcheandjieu, Jennifer E. Huffman, Elizabeth Litkowski, Chang Liu, Yuk-Lam A. Ho, et al. “A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.PLoS Genet 18, no. 6 (June 2022): e1010193. https://doi.org/10.1371/journal.pgen.1010193.
Raghavan S, Huang J, Tcheandjieu C, Huffman JE, Litkowski E, Liu C, et al. A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program. PLoS Genet. 2022 Jun;18(6):e1010193.
Raghavan, Sridharan, et al. “A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.PLoS Genet, vol. 18, no. 6, June 2022, p. e1010193. Pubmed, doi:10.1371/journal.pgen.1010193.
Raghavan S, Huang J, Tcheandjieu C, Huffman JE, Litkowski E, Liu C, Ho Y-LA, Hunter-Zinck H, Zhao H, Marouli E, North KE, VA Million Veteran Program, Lange E, Lange LA, Voight BF, Gaziano JM, Pyarajan S, Hauser ER, Tsao PS, Wilson PWF, Chang K-M, Cho K, O’Donnell CJ, Sun YV, Assimes TL. A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program. PLoS Genet. 2022 Jun;18(6):e1010193.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

June 2022

Volume

18

Issue

6

Start / End Page

e1010193

Location

United States

Related Subject Headings

  • Veterans
  • Polymorphism, Single Nucleotide
  • Hypertension
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Developmental Biology
  • Atrial Fibrillation
  • Adult
  • 3105 Genetics