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

PLoS One. 2016 Apr 8;11(4):e0153224. doi: 10.1371/journal.pone.0153224. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Asian People / genetics
  • Autism Spectrum Disorder / genetics*
  • Cadherin Related Proteins
  • Cadherins / genetics*
  • Case-Control Studies
  • Child
  • Cohort Studies
  • Exons
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Schizophrenia / genetics*
  • Sequence Analysis, DNA
  • Young Adult

Substances

  • CDHR15, human
  • Cadherin Related Proteins
  • Cadherins

Grants and funding

The current research was supported by research grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Ministry of Health, Labour, and Welfare of Japan; “Integrated research on neuropsychiatric disorders” carried out under the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (AMED); the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) project of AMED; Grant-in-Aid for Scientific Research on Innovative Areas “Glial assembly: a new regulatory machinery of brain function and disorders”; and Innovative Areas “Comprehensive Brain Science Network.”