Estimating direct and indirect genetic effects on offspring phenotypes using genome-wide summary results data: a comparison of multivariate methods

Estimation of the direct genetic effect of an individuals’ own genotype on their phenotype, independent of any contaminating indirect parental genetic effects is becoming increasingly important. These conditional estimates are of interest in their own right, but are also useful for downstream analyses such as intergenerational Mendelian randomization. We compare several available multivariate methods that utilize summary results statistics from genome-wide association studies to determine how well they estimate conditional direct and indirect genetic effects, while accounting for sample overlap. Using robustly associated birth weight variants and data from the UK Biobank, we contrasted the point estimates and their standard errors at each of the individual loci compared to those obtained using individual level genotype data, in addition to comparing the computational time, inflation of the test statistics and number of genome-wide significant SNPs identified by each of the methods. We show that Genomic SEM outperforms the other methods in accurately estimating conditional genetic effects and their standard errors. We subsequently applied Genomic SEM to fertility data in the UK Biobank and partitioned the genetic effect into female and male fertility in addition to a sibling specific effect. This analysis identified one novel locus for fertility and replicated seven previously identified loci. We also identified genetic correlations between fertility and educational attainment, risk taking behaviour, autism and subjective well-being. We therefore recommend Genomic SEM to be used to partition genetic effects across the genome into direct and indirect components.