Genetic Instrumental Variable (GIV) Regression: Explaining Socioeconomic and Health Outcomes in Non-Experimental Data

We introduce Genetic Instrumental Variables (GIV) regression – a method to estimate causal effects in non-experimental data with many possible applications in the social sciences and epidemiology. In non-experimental data, genetic correlation between the outcome and the exposure of interest is a source of bias. Instrumental variable (IV) regression is a potential solution, but valid instruments are scarce. Existing literature proposes to use genes related to the exposure as instruments (i.e. Mendelian Randomization – MR), but this approach is problematic due to possible pleiotropic effects of genes that can violate the assumptions of IV regression. In contrast, GIV regression provides accurate estimates for the causal effect of the exposure and gene-environment interactions involving the exposure under less restrictive assumptions than for MR. 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 exposure and the outcome of interest, both of 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. In two empirical applications, we demonstrate that our approach produces reasonable estimates of the chip heritability of educational attainment (EA) and, unlike the results using MR, GIV regression estimates find that the positive relationship between body height and EA is primarily due to genetic confounds that have pleiotropic effects on both traits.

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