MR-PheWAS: hypothesis prioritization among potential causal effects of body mass index on many outcomes, using Mendelian randomization

Abstract

Observational cohort studies can provide rich datasets with a diverse range of phenotypic variables. However, hypothesis-driven epidemiological analyses by definition only test particular hypotheses chosen by researchers. Furthermore, observational analyses may not provide robust evidence of causality, as they are susceptible to confounding, reverse causation and measurement error. Using body mass index (BMI) as an exemplar, we demonstrate a novel extension to the phenome-wide association study (pheWAS) approach, using automated screening with genotypic instruments to screen for causal associations amongst any number of phenotypic outcomes. We used a sample of 8,121 children from the ALSPAC dataset, and tested the linear association of a BMI-associated allele score with 172 phenotypic outcomes (with variable sample sizes). We also performed an instrumental variable analysis to estimate the causal effect of BMI on each phenotype. We found 21 of the 172 outcomes were associated with the allele score at an unadjusted p < 0.05 threshold, and use Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed. The most strongly associated outcomes included leptin, lipid profile, and blood pressure. We also found novel evidence of effects of BMI on a global self-worth score.

The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study

“…Our findings provide strong support for undertaking RCTs in obese people to test the effect of triacylglycerol reduction and glycaemic control on CHD risk. Several MR studies have previously examined the association of BMI with CHD and CHD risk factors [11,12,14,24,25]. Our results are broadly consistent with those, including our finding of no evidence for the causal association between BMI and LDL-cholesterol [12,24,26].…”

Genetic Obesity and the Risk of Atrial Fibrillation

“…‘area under the BMI curve’) when compared to a one-time measure or even repeated measures of BMI recorded during cohort studies. 46 This might account for the numerically, albeit non-significantly, greater estimated causal effect of BMI on incident AF we obtained using genetic instruments compared to observational estimates. Similar discordance in instrumental and observational estimates has been reported for the association between BMI-increasing genetic variants and coronary disease risk.…”

“…40 Alternatively, pleiotropy – in which the selected genetic variants mediate AF risk through a non-BMI pathway – might account for some of the discordance in risk estimates. 46 The association between the genetic instruments and AF, however, remained significant after adjustment for several possible pleiotropic mediators including hypertension and coronary heart disease. In addition, our finding that adjustment for observed BMI nullified the statistical association between the genetic instruments and AF supports BMI as the causal mediator of the association between the genetic instruments and incident AF, and argues against a major contribution from pleiotropic effects.…”

Integrative variants, haplotypes and diplotypes of the CAPN3 and FRMD5 genes and several environmental exposures associate with serum lipid variables

“…A novel extension to the phenome-wide association study (pheWAS) approach20, using Bonferroni corrections, permutation testing and estimates of the false discovery rate to consider the strength of results given the number of tests performed demonstrated strongly associated outcomes included DBP and BMI with lipid profiles. They also found novel evidence of effects of BMI on a global self-worth score.…”