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Estimating the sensitivity of associations between risk factors and outcomes to shared genetic effects

By Jean-Baptiste Pingault, Frühling Rijsdijk, Tabea Schoeler, Shing Wan Choi, Saskia Selzam, Eva Krapohl, Paul O’Reilly, Frank Dudbridge

Posted 30 Mar 2019
bioRxiv DOI: 10.1101/592352

Objective: Countless associations between risk factors and outcomes are reported in epidemiological research, but often without estimating the contribution from genetics. However most outcomes and risk factors are substantially heritable, and genetic influences can confound these associations. Here we propose a two-stage approach for evaluating the role of shared genetic effects in explaining these observed associations. Method: Genotyped unrelated participants from the Twins Early Development Study are included (N from 3,663 to 4,693 depending on the outcome) in our analyses. As an example for our proposed approach, we focus on maternal educational attainment, a risk factor known to associate with a variety of offspring social and health outcomes, including child educational achievement, Body Mass Index, and Attention Deficit Hyperactivity Disorders (ADHD). In the first stage of our approach we estimate how much of the phenotypic associations between maternal education and child outcomes can be attributed to shared genetic effects via regressions controlling for increasingly powerful polygenic scores. In the second stage, we estimate shared genetic effects using heritability estimates and genetic correlations equal to those derived in both SNP-based and twin-based studies. Finally, evidence from the two stages are evaluated in conjunction to provide an overall assessment of the likelihood that the association is explained by genetics. Results: Associations between maternal education and the three developmental outcomes are highly significant. The magnitude of these associations decrease when using polygenic scores to account for shared genetic effects, explaining between 14.3% and 24.3% of the original associations. For the three outcomes, the magnitude of these associations further decrease under a SNP-based heritability scenario and are almost entirely or entirely explained by genetics under a twin-based heritability scenario. Conclusions: Observed association between maternal education and child educational attainment, BMI and ADHD symptoms may be largely explained by genetics. To the extent that available estimates of SNP-based and twin-based heritabilities are accurate, the present findings represent a call for caution when interpreting non-genetically informed epidemiology studies of the role of maternal education or other 'environmental' risk factors. The two-stage approach that we propose adds a new tool to probe the robustness of findings regarding the role of a range of risk factors. Our approach, akin to a genetically informed sensitivity analysis, only requires a genotyped cohort with adequate phenotypic measurements, and has the potential to be widely applied across the life and social sciences.

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