Genome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia

V Bansal,H Ehrenreich,M Mitjans,C A Rietveld,M Begemann,P D Koellinger,S Ripke,C A P Burik,S Bonn,R De Vlaming,M G Nivard,A Okbay,R K Linnér

doi:10.1038/s41467-018-05510-z

Abstract

Higher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigate possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1169 controls; 1067 cases) with deeply phenotyped SZ patients. We find 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. Using EA as a proxy phenotype, we isolate FOXO6 and SLITRK1 as novel candidate genes for SZ. Our results reveal that current SZ diagnoses aggregate over at least two disease subtypes: one part resembles high intelligence and bipolar disorder (BIP), while the other part is a cognitive disorder that is independent of BIP.

Highlights

We focused on years of education, age at prodrome, age at disease onset, premorbid intelligence quotient (IQ), global assessment of functioning (GAF), the clinical global impression of severity (CGI-S) as well as positive and negative symptoms (PANSS positive and negative, respectively) among SZ patients (N ranges from 903 to 1039, see Supplementary Note 5)
We explored the genetic relationship between educational attainment (EA) and SZ using large, non-overlapping genomewide association study (GWAS) samples
Our results show that EA-associated single-nucleotide polymorphisms (SNPs) are much more likely to be associated with SZ than expected by chance, i.e. both traits are genetically dependent

Summary

Results

We compared the ratio of novel SNPs from ref.[28] included in our list of 132 loci that are jointly associated with EA and SZ (PEA < 10−5 and PSZ < 0.05, yielding 6 loci) with the ratio observed in all remaining approximately independent loci with PSZ < 0.05 in our SZ GWAS results. For the broad credibility set analyses (90%), we found 11 loci with a medium or high credibility to have direct causal effects on both EA and SZ (including one of the novel SNPs, rs7336518). Six of these loci have concordant effects on the two traits

SNPs novel for SZ

Discussion

Methods