A survey of rare coding variants in candidate genes in schizophrenia by deep sequencing

W He,A Power,R Kleiman,B Zhang,W Liu,A M Mcintosh,S M Lawrie,D Blackwood,T A Lanz,D St Clair,N J Brandon,X Hu,B Dougherty,S L John,S K Hall,S Paciga

doi:10.1038/mp.2013.131

Abstract

The genetic architecture of schizophrenia is likely contributed by both common and rare variants.1 Recent genome-wide studies have revealed that common variants in the major histocompatibility complex (MHC) region, TCF4 and other genes are associated with schizophrenia.1 In addition, rare copy-number variation (CNV) regions in broad regions like 1q21.1, 15q13.3, 15q11.2, 22q111 as well as individual genes such as Neurexin2, 3 have been identified. Unbiased exome or whole genome scanning procedures have the potential to identify novel loci while likely requiring large sample sets to reach a genome-wide significance level. It is possible that the previously identified genes/regions from high-throughput single-nucleotide polymorphisms (SNP) chip genome-wide scanning techniques, in contrast to some ‘classical' candidate genes,4 may harbor rare coding variants that have a role in disease risk. We selected a total of 101 genes from within the 1q21.1, 15q13.3, 22q11 and 15q11.2 regions and a number of other candidate genes, with either a priori knowledge for association with schizophrenia, for example, TCF4/CCDC68, NRXN1, or interesting for drug-discovery efforts, for example, cyclic nucleotide phosphodiesterase genes, and surveyed rare variants in their coding regions through deep sequencing.

Highlights

The genetic architecture of schizophrenia is likely contributed by both common and rare variants.[1]
Recent genome-wide studies have revealed that common variants in the major histocompatibility complex (MHC) region, TCF4 and other genes are associated with schizophrenia.[1]
It is possible that the previously identified genes/regions from high-throughput single-nucleotide polymorphisms (SNP) chip genome-wide scanning techniques, in contrast to some ‘classical’ candidate genes,[4] may harbor rare coding variants that have a role in disease risk

Summary

Introduction

The genetic architecture of schizophrenia is likely contributed by both common and rare variants.[1]. Our discovery set included 525 schizophrenia cases (68% male cases, 69 cases were diagnosed with schizophrenia before 18 years of age) and 619 controls (62% male cases) without any neurological and psychiatric disorders and were primarily collected during Pfizer clinical trials.

Results

Conclusion