GWAS results for educational attainment aid in identifying genetic heterogeneity of schizophrenia

Higher educational attainment (EA) is known to have a protective effect on the severity of schizophrenia (SZ). However, recent studies have found a small positive genetic correlation between EA and SZ. We investigated possible... [ view full abstract ]

Higher educational attainment (EA) is known to have a protective effect on the severity of schizophrenia (SZ). However, recent studies have found a small positive genetic correlation between EA and SZ. We investigated possible causes of this counterintuitive finding using genome-wide association (GWAS) results for EA and SZ (N = 443,581) and a replication cohort (1,169 controls and 1,067 cases) with high-quality SZ phenotypes. 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 in both phenotypes is the most likely explanation of this finding. This insight can be exploited by using a combination of EA and SZ GWAS results to improve the polygenic prediction of clinical symptoms and disease severity of SZ. In particular, although a polygenic score for SZ is robustly associated with case-control status, it does not predict any of the SZ symptoms or disease severity. In contrast, co-dependent polygenic scores that split the SZ score into two parts based on the sign concordance of SNPs for SZ and EA predict symptoms and disease severity in patients to some extent. Furthermore, using EA as a proxy-phenotype for SZ, we isolate FOXO6 and SLITRK1 as additional statistically plausible candidate genes for SZ.