Estimating indirect parental genetic effects on offspring phenotypes using virtual parental genotypes derived from sibling and half sibling pairs

Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to their children. However, given the relative paucity of large-scale family-based cohorts around the world, it is difficult to demonstrate parental genetic effects on human traits, particularly at individual loci. In this manuscript, we illustrate how parental genetic effects on offspring phenotypes, including late onset conditions, can be estimated at individual loci in principle using large-scale genome-wide association study (GWAS) data, even in the absence of parental genotypes. Our strategy involves creating “virtual” mothers and fathers by estimating the genotypic dosages of parental genotypes using physically genotyped data from relative pairs. We then utilize the expected dosages of the parents, and the actual genotypes of the offspring relative pairs, to perform conditional genetic association analyses to obtain asymptotically unbiased estimates of maternal, paternal and offspring genetic effects. We apply our approach to 19066 sibling pairs from the UK Biobank and show that a polygenic score consisting of imputed parental educational attainment SNP dosages is strongly related to offspring educational attainment even after correcting for offspring genotype at the same loci. We develop a freely available web application that quantifies the power of our approach using closed form asymptotic solutions. We implement our methods in a user-friendly software package IMPISH (IMputing Parental genotypes In Siblings and Half Siblings) which allows users to quickly and efficiently impute parental genotypes across the genome in large genome-wide datasets, and then use these estimated dosages in downstream linear mixed model association analyses. We conclude that imputing parental genotypes from relative pairs may provide a useful adjunct to existing large-scale genetic studies of parents and their offspring.Author summary: Indirect parental genetic effects may be defined as the influence of parental genotypes on offspring phenotypes over and above that which results from the transmission of genes from parents to children. Estimating indirect parental genetic effects on offspring outcomes at the genotype level has been challenging because it requires large-scale, individual level genotypes from both parents and their offspring, and there is a paucity of cohorts around the world with this information. Here we present a new approach to estimate indirect parental genetic effects without the requirement of physically genotyped parents. Our method creates virtual parental genotypes based on the genotypes of offspring pairs, and then uses these virtual genotypes in downstream genetic association analyses. We developed a software package “IMPISH” that allows users to impute virtual parental genotypes in their own genome-wide datasets and then use these in downstream genome-wide association analyses, as well a series of power calculators to estimate the power to detect indirect parental genetic effects on offspring phenotypes. We apply our method to educational attainment data from the UK Biobank and show that indirect parental genetic effects are related to offspring educational attainment even after correcting for offspring genotype at the same loci.