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

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.

A multivariable Mendelian randomization to appraise the pleiotropy between intelligence, education, and bipolar disorder in relation to schizophrenia

“…This implies the pleiotropy between schooling years and schizophrenia is horizontal and likely confounded by a third trait also influencing Education Years. Further to this, bipolar disorder, associated observationally with both higher education and schizophrenia 3,12,13 , was investigated along with Education Years, using multivariable MR. The findings suggest that the increased risk of schizophrenia conferred by more schooling years is an artefact of bipolar disorder -not Education Years.…”

“…Educational attainment has been described as feature of bipolar disorder 12,13 . Bipolar disorder shares some cognitive deficits and genetic overlap with schizophrenia, but also predisposes to cognitive adeptness and creativity that distinguish it from the more neurodevelopmental aspects of schizophrenia 3 . This complex picture is reflected in the horizontal and confounding pleiotropy uncovered by the multivariate analyses here.…”

“…Schizophrenia is a heterogeneous neurological syndrome, typically presenting in early adolescence, and observationally associated with lower intelligence and lower educational attainment [1][2][3] .…”

“…Education is positively associated with many health outcomes 4,5 . Counterintuitively, more years of schooling is genetically associated with an increased risk for schizophrenia 3 . Intelligence and education are highly positively correlated both phenotypically (r = 0.8) 6 and genetically (r = 0.7) 7 .…”

A multivariable Mendelian randomization to appraise the pleiotropy between intelligence, education, and bipolar disorder in relation to schizophrenia

“…Counterintuitively, education, which is positively associated with many health outcomes 4,5 , is genetically associated with an increased risk for schizophrenia 3 . Intelligence and education are highly positively correlated both phenotypically (r=0.8) 6 and genetically (r=0.7) 7 .…”