Genome-Wide Association Analysis with Gray Matter Volume as a Quantitative Phenotype in First-Episode Treatment-Naïve Patients with Schizophrenia

Qiang Wang,Pak C Sham,Xun Hu,Xiaohong Ma,Siew E Chua,Tao Li,Lijun Jiang,Yingcheng Wang,Grainne Mcalonan,Mingli Li,Junyao Wu,Bo Xiang,Wei Deng,Yong-Gang Yao

doi:10.1371/journal.pone.0075083

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 left hOC3v in the collateral sulcus of visual cortex (hOC3vL), left cerebellar vermis lobule 10 (vermisL10) and right cerebellar vermis lobule 10 (vermisR10) were found in patients with schizophrenia. 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.

Highlights

Schizophrenia is one of the leading causes of mental disability, which affects about 1% of the population worldwide [1]
The aim of the present study is to identify the common genetic variants that underlie the deficits of Gray matter (GM) volume in schizophrenia
Reduced GM volume in patients with schizophrenia By using SPM Anatomy Toolbox, we found that GM volumes in three brain areas including left hOC3v in the collateral sulcus of visual cortex, left cerebellar vermis lobule 10 and right cerebellar vermis lobule 10 were significantly reduced in patients with schizophrenia (See Figure S1)

Summary

Introduction

Schizophrenia is one of the leading causes of mental disability, which affects about 1% of the population worldwide [1]. It is challenging to identify genes involved in the pathogenesis of schizophrenia due to its complex model of inheritance and the unknown pathophysiology of the disorder. Phenotypic heterogeneity, such as various clinical presentation and duration of illness, complicated the genetic study in schizophrenia. A number of large-scale genome-wide association studies (GWAs) using the case–control design have identified some genetic variants associated with schizophrenia Of these previous studies, the latest Psychiatric Genomics Consortium (PGC) identified 61 common variants in liability to schizophrenia. Endophenotypes have been considered to be more proximal to the biological etiology of the disorder [8], and may provide an alternative strategy to explore the pathogenesis of complex genetic diseases such as schizophrenia

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