Genome-wide association analysis with gray matter volume as a quantitative phenotype in first-episode treatment-naïve patients with schizophrenia

Abstract

Reduced Gray matter (GM) volume is a core feature of schizophrenia. Mapping genes that is associated with the heritable disease-related phenotypes may be conducive to elucidate the pathogenesis of schizophrenia. This study aims to identify the common genetic variants that underlie the deficits of GM volume in schizophrenia. High-resolution T1 images and whole genome genotyping data were obtained from 74 first-episode treatment-naïve patients with schizophrenia and 51 healthy controls in the Mental Health Centre of the West China Hospital, Sichuan University. All participants were scanned using a 3T MR imaging system and were genotyped using the HumanHap660 Bead Array. Reduced GM volumes in three brain areas including right hOC3v in the collateral sulcus of visual cortex (hOC3vR), left cerebellar vermis lobule 10 (vermisL10) and right cerebellar vermis lobule 10 (vermisR10) were found in patients with schizophrenia [corrected].There was a group by genotype interaction when genotypes from genome-wide scan were subsequently considered in the case-control analyses. SNPs from three genes or chromosomal regions (TBXAS1, PIK3C2G and HS3ST5) were identified to predict the changes of GM volume in hOC3vL, vermisL10 and vermisR10. These results also highlighted the usefulness of endophenotype in exploring the pathogenesis of neuropsychiatric diseases such as schizophrenia although further independent replication studies are needed in the future.

Figure 1. Manhattan plot for the Han Chinese genome-wide association study (GWAS) on schizophrenia using brain structure measures as a quantitative phenotype (Note: the points with red mean their P values >5x10^-6).

Figure 2. Significance of GWAS Genotyped and imputed SNPs of the 400kb region in chromosomal region of TBXAS1, PIK3C2G and HS3ST5.

A, B, C and D are the results of association analysis of vermisL10, hOC3VL, vermisR10 as QT, respectively. Figure 2 was adapted from LocusZoom [49] output.

Figure 3. The comparison of the GM volume of hOC3vL of 3 genotypes in cases and controls, respectively.

The reduced volume of hOC3vl is associated with the interaction of diagnosis x rs10277664 (p<1.38×10^-7). And the significant difference was detected between the individuals with GG and AA only in case group only (p<0.03).