ABSTRACTHigher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigated possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1,169 controls; 1,067 cases) with deeply phenotyped SZ patients. We found strong genetic dependence between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, several genes seem to have pleiotropic effects on EA and SZ, but without a clear pattern of sign concordance. Genetic heterogeneity of SZ contributes to this finding. We demonstrate this by showing that the polygenic prediction of clinical SZ symptoms can be improved by taking the sign concordance of loci for EA and SZ into account. Furthermore, using EA as a proxy phenotype, we isolate FOXO6 and SLITRK1 as novel candidate genes for SZ.
Comparing Genome-Wide Association Study Results from Different Measurements of an Underlying Phenotype
