Proceedings of the National Academy of Sciences | 2021
Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies
Abstract
Significance It has been shown that human genomes can affect phenotype both directly (through inherited genetic variants) and indirectly (through parents and the family environment they create). Due to the correlation between parental and offspring genotypes, a standard genome-wide association study (GWAS) captures both the direct and indirect genetic effects. In this study, we introduce a statistical framework named DONUTS to estimate direct and indirect effects using summary statistics from GWAS conducted on own and offspring phenotypes. It requires only GWAS summary statistics as input, allows differential paternal and maternal effects, and accounts for sample overlap and assortative mating. DONUTS provides deeper etiological insights for complex traits and has practical guidance on future study designs. Marginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic, and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower body mass index, less-active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. A polygenic transmission disequilibrium test showed a significant overtransmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.