Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Apr 23. pii: 201707388. doi: 10.1073/pnas.1707388115. [Epub ahead of print]

Genetic instrumental variable regression: Explaining socioeconomic and health outcomes in nonexperimental data.

Author information

Department of Sociology, Columbia University, New York, NY 10027;
Department of Economics, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
Department of Economics, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands


Identifying causal effects in nonexperimental 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 nonexperimental data that would also undermine the ability of MR to correct for endogeneity bias from nongenetic sources. Here, we propose an alternative approach, genetic instrumental variable (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 (PGSs) 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 nonoverlapping subsamples, we obtain multiple indicators of the outcome PGSs 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.


causal effects; genetic instrumental variables; genome-wide association studies; pleiotropy; polygenic scores

Free full text

Conflict of interest statement

The authors declare no conflict of interest.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center