Exome sequencing in 53 sporadic cases of schizophrenia identifies 18 putative candidate genes.

Michel Guipponi,David P Siderovski,Dan Rujescu,Dimitris Dikeos,Corinne Gehrig,Stéphane Jamain,Logos Curtis,Vincent Setola,Olivier Guillin,Stylianos E Antonarakis,Marion Leboyer,Alexandre Méary,Franck Schürhoff,Dominique Campion,Macarena Cuenca,Georgios Georgantopoulos,Dimitri Avramopoulos,Maud Rothärmel ,Federico Santoni ,Ann E Pulver ,George N Papadimitriou

doi:10.1371/journal.pone.0112745

Abstract

Schizophrenia (SCZ) is a severe, debilitating mental illness which has a significant genetic component. The identification of genetic factors related to SCZ has been challenging and these factors remain largely unknown. To evaluate the contribution of de novo variants (DNVs) to SCZ, we sequenced the exomes of 53 individuals with sporadic SCZ and of their non-affected parents. We identified 49 DNVs, 18 of which were predicted to alter gene function, including 13 damaging missense mutations, 2 conserved splice site mutations, 2 nonsense mutations, and 1 frameshift deletion. The average number of exonic DNV per proband was 0.88, which corresponds to an exonic point mutation rate of 1.7×10−8 per nucleotide per generation. The non-synonymous-to-synonymous mutation ratio of 2.06 did not differ from neutral expectations. Overall, this study provides a list of 18 putative candidate genes for sporadic SCZ, and when combined with the results of similar reports, identifies a second proband carrying a non-synonymous DNV in the RGS12 gene.

Highlights

Schizophrenia (SCZ) is a severe mental illness that has a population prevalence of 0.4 to 0.8% [1]
Similar to other studies [19, 20, 21, 22, 23], we used whole-exome sequencing to estimate the contribution of protein-altering de novo mutations to sporadic SCZ and to identify susceptibility genes
Our study reveals that 34% of the sporadic cases analyzed (18 out of 53 cases) carried a predicted damaging de novo variant, and our results provide a list of 18 putative candidate genes

Summary

Introduction

Schizophrenia (SCZ) is a severe mental illness that has a population prevalence of 0.4 to 0.8% [1]. Individuals with SCZ experience psychosis, poor social functioning, and cognitive impairments. SCZ is a highly heritable disorder encouraging research into the genetic component of the disorder [2]. Rare copy number variants (CNVs) have been shown to contribute to SCZ risk [7, 8, 9, 10]. Despite these encouraging advances, many of the genetic components of the disease await identification.

Methods

Results

Conclusion