Investigation of Rare Single-Nucleotide PCDH15 Variants in Schizophrenia and Autism Spectrum Disorders.

Kanako Ishizuka,Yuko Arioka,Yota Uno,Hiroki Kimura,Tomoko Oya-Ito,Daisuke Mori,Chenyao Wang,Jingrui Xing,Takashi Okada,Branko Aleksic,Itaru Kushima,Norio Ozaki,Ryota Hashimoto

doi:10.1371/journal.pone.0153224

Abstract

Both schizophrenia (SCZ) and autism spectrum disorders (ASD) are neuropsychiatric disorders with overlapping genetic etiology. Protocadherin 15 (PCDH15), which encodes a member of the cadherin super family that contributes to neural development and function, has been cited as a risk gene for neuropsychiatric disorders. Recently, rare variants of large effect have been paid attention to understand the etiopathology of these complex disorders. Thus, we evaluated the impacts of rare, single-nucleotide variants (SNVs) in PCDH15 on SCZ or ASD. First, we conducted coding exon-targeted resequencing of PCDH15 with next-generation sequencing technology in 562 Japanese patients (370 SCZ and 192 ASD) and detected 16 heterozygous SNVs. We then performed association analyses on 2,096 cases (1,714 SCZ and 382 ASD) and 1,917 controls with six novel variants of these 16 SNVs. Of these six variants, four (p.R219K, p.T281A, p.D642N, c.3010-1G>C) were ultra-rare variants (minor allele frequency < 0.0005) that may increase disease susceptibility. Finally, no statistically significant association between any of these rare, heterozygous PCDH15 point variants and SCZ or ASD was found. Our results suggest that a larger sample size of resequencing subjects is necessary to detect associations between rare PCDH15 variants and neuropsychiatric disorders.

Highlights

Schizophrenia (SCZ) and autism spectrum disorders (ASD) are neurodevelopmental in origin
Exonic copy-number variants (CNVs) in Protocadherin 15 (PCDH15) were recently identified in ASD [26] and bipolar disorder (BD) patients [27,28]. These findings strongly suggest that PCDH15 is a promising candidate risk gene for neuropsychiatric disorders because several neuropsychiatric disorders including SCZ, ASD, and BD share genetic risk factors [3,4,5,6,13,27,29,30]
Of 17 single-nucleotide variants (SNVs) and three indels detected by the Ion Torrent PGMTM, one SNV and three indels were not validated by Sanger sequencing

Summary

Introduction

Schizophrenia (SCZ) and autism spectrum disorders (ASD) are neurodevelopmental in origin. While SCZ and ASD are regarded as separate clinical entities, etiological, clinical, and genetic overlap between them have been discovered [1,2]. Genetic factors make substantial contributions to the etiology of both conditions; heritability is estimated to be a minimum of 80% for each [3]. Thousands of trait- and disease-associated common genetic variants confer increased risk of developing either condition [4,5,6], they may explain less than half of the total variation in risk of SCZ [7,8] and ASD [9]. Recent studies suggest that rare copy-number variants (CNVs) and rare single-nucleotide variants (SNVs) may explain additional disease risk or PLOS ONE | DOI:10.1371/journal.pone.0153224. Recent studies suggest that rare copy-number variants (CNVs) and rare single-nucleotide variants (SNVs) may explain additional disease risk or PLOS ONE | DOI:10.1371/journal.pone.0153224 April 8, 2016

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