Genetic Instrumental Variable (GIV) regression: Explaining socioeconomic and health outcomes in non-experimental data

Abstract

Identifying causal effects in non-experimental data is an enduring challenge. One proposed solution that recently gained popularity is the idea to use genes as instrumental variables (i.e. Mendelian Randomization - MR). However, this approach is problematic because many variables of interest are genetically correlated, which implies the possibility that many genes could affect both the exposure and the outcome directly or via unobserved confounding factors. Thus, pleiotropic effects of genes are themselves a source of bias in non-experimental data that would also undermine the ability of MR to correct for endogeneity bias from non-genetic sources. Here, we propose an alternative approach, GIV regression, that provides estimates for the effect of an exposure on an outcome in the presence of pleiotropy. As a valuable byproduct, GIV regression also provides accurate estimates of the chip heritability of the outcome variable. GIV regression uses polygenic scores (PGS) for the outcome of interest which can be constructed from genome-wide association study (GWAS) results. By splitting the GWAS sample for the outcome into non-overlapping subsamples, we obtain multiple indicators of the outcome PGS that can be used as instruments for each other, and, in combination with other methods such as sibling fixed effects, can address endogeneity bias from both pleiotropy and the environment. In two empirical applications, we demonstrate that our approach produces reasonable estimates of the chip heritability of educational attainment (EA) and show that standard regression and MR provide upwardly biased estimates of the effect of body height on EA.