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

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.

Fig 1. Comparison of number of associations and effect sizes of measured height (A) and genetically-predicted height (B) between non-Hispanic White and non-Hispanic Black individuals.

Associations of measured and genetically-predicted height with phecodes represented as odds ratios (OR) in non-Hispanic Black (AA) and non-Hispanic White (EA) MVP participants. Whether associations exceeded phenome-wide significance threshold in either or both race/ethnicity groups indicated by color. Venn diagrams providing pictorial representation of the same comparisons shown to the right of each plot.

Fig 2. Phenome-wide associations with genetically predicted height in non-Hispanic White individuals.

Plot of phecodes versus -log₁₀(p-value) for association with genetically-predicted height in non-Hispanic White participants in MVP. Phecodes were limited to single decimal place for clarity (e.g., 427.2 for atrial fibrillation or flutter is shown but 427.21 for atrial fibrillation is not). Associations with a negative beta coefficient (i.e., odds ratio < 1) are plotted below the x-axis, and those with a positive beta coefficient (i.e., odds ratio > 1) are plotted above the x-axis. Red dotted lines indicate race/ethnicity-specific phenome-wide significance thresholds (p < 3.6E-5 for non-Hispanic White). The top association (lowest p-value) within each phecode group is labeled.

Fig 3. Phenome-wide associations with genetically predicted height in non-Hispanic Black individuals.

Plot of phecodes versus -log₁₀(p-value) for association with genetically-predicted height in non-Hispanic Black participants in MVP. Phecodes were limited to single decimal place for clarity (e.g., 427.2 for atrial fibrillation or flutter is shown but 427.21 for atrial fibrillation is not). Associations with a negative beta coefficient (i.e., odds ratio < 1) are plotted below the x-axis, and those with a positive beta coefficient (i.e., odds ratio > 1) are plotted above the x-axis. Red dotted lines indicate race/ethnicity-specific phenome-wide significance thresholds (p < 5.0E-5 for non-Hispanic Black). The top association (lowest p-value) within each phecode group is labeled.

Fig 4. Associations of selected traits with genetically-predicted height after stratifying by coronary heart disease status.

Odds ratio (OR) and 95% confidence intervals shown for associations of the indicated traits with genetically-predicted height in all participants (purple), those without coronary heart disease (green) and those with coronary heart disease (yellow). P-values from test of heterogeneity between strata shown to the right.