Investigating brain structural differences and the impact of common genetic variation across the psychosis spectrum

Abstract

BACKGROUND: Abnormalities in glutamate transmission have been implicated in schizophrenia (SZ). A genome-wide association study (GWAS) associated single nucleotide polymorphisms (SNPs) in glutamate-related genes with the disorder. To elucidate a pathologic role of these variants, this study aims to examine the effects of these SNPs on hippocampal volume. METHOD: Six SNPs from five glutamate-related genes identified by the Psychiatric Genetics Consortium were selected in 279 controls and 284 probands recruited from the B-SNIP study. Hippocampal subfield volumes were extracted from T1 weighted images via the MAGeT pipeline. A mixed model analysis was conducted using SPSS to evaluate a diagnosis by SNP effect on volumes, with site as a random factor, age, sex, and principal component analysis values as fixed factors. P values were adjusted for multiple corrections. RESULTS: rs10520163 (CLCN3), rs2973155 (GRIA1), and rs9922678 (GRIN2A) displayed a significant main effect (p< .01) on bilateral total hippocampal volume. Post hoc comparison revealed individuals homozygous for the risk allele (HZ-Risk) had significantly smaller volumes than those who were homozygous for the non-risk allele (HZ-NoRisk) (p<.01). For the same SNPs, a significant diagnosis-by-genotype interaction (p<.01) was found for bilateral total hippocampal volume. Significant main effects (p<.01) for the same SNPs were found in subfield volumes bilaterally for the CA1, subiculum, and stratum, with HZ-Risk having smaller volumes. CONCLUSION: Our findings suggest CLCN3, GRIA1, and GRIN2A appear to be associated with reductions in bilateral hippocampal total volume and subfield regions, indicating a potential mechanism by which these genes may confer risk for the disorder.