Gene-Set Analysis of Gwas Data Identifies A Role For Satb2 and The Nurd Complex In Schizophrenia and Educational Attainment

Abstract

SATB2, BCL11B and GATAD2A map to genomic regions containing genome-wide significant SNPs for schizophrenia. These genes regulate key stages of neurodevelopment (e.g. axon guidance) via epigenetic mechanisms. SATB2, a DNA-binding protein, specifically mediates the projection of neurons across the cerebral hemispheres by regulating the activity of BCL11B via the NuRD nucleosome remodeling complex. GATAD2A is a core component of the NuRD complex. Given the schizophrenia association signals at SATB2, BCL11B and GATAD2A, we hypothesized that genes within the NuRD complex and genes regulated by SATB2 in the pre- and post-natal brain may also contribute to schizophrenia etiology. To test this, we developed three gene sets. 1) Genes reported in studies of SATB2 during cortical development (SATB2_Cortical, n=127 genes). 2) Genes mapping to SATB2 ChIP-seq peaks generated from mouse cortices at E15.5 (SATB2_Pre-natal, n=779). 3) Genes mapping to SATB2 ChIP-seq peaks generated from mouse P0 primary hippocampal neurons (SATB2_Post-natal, n=4,138). We performed competitive gene set analysis (GSA) using MAGMA to jointly analyse all SNPs within a gene set to test if those genes were more strongly associated with schizophrenia than other genes in the genome. We applied GSA to the largest available GWAS results dataset for schizophrenia (PGC2; 36,989 cases, 113,075 controls). Based on the genetic overlap between schizophrenia and cognition and the role for SATB2 in memory function, we also investigated these gene-sets for a genetic contribution to educational attainment (EA) using the largest available GWAS dataset (405,072 samples). After multiple test correction, we observed significant associations for (1) the SATB2_Cortical gene-set with schizophrenia (P=0.00012) and with EA (P=0.00049), (2) the SATB2_Pre-natal gene-set with EA (P=0.00675) and (3) the SATB2_Post-natal gene-set with EA (P=2.03x10-06). These data support a role for genes in the NuRD complex and genes regulated by SATB2 in the etiology of schizophrenia and EA.