Comprehensive Gene-Based Association Study of a Chromosome 20 Linked Region Implicates Novel Risk Loci for Depressive Symptoms in Psychotic Illness

Authors

T. Bernard Bigdeli, Virginia Commonwealth UniversityFollow
Brion S. Maher, Virginia Commonwealth UniversityFollow
Zhongming Zhao, Virginia Commonwealth UniversityFollow
Edwin J. C. G. van den Oord, Virginia Commonwealth University
Dawn L. Thiselton, Virginia Commonwealth University
Jingchun Sun, Vanderbilt University
Bradley T. Webb, Virginia Commonwealth UniversityFollow
Richard L. Amdur, Washington VA Medical Center
Brandon Wormley, Virginia Commonwealth University
Francis A. O'Neill, Queens University - Belfast
Dermot Walsh, The Health Research Board
Brien P. Riley, Virginia Commonwealth UniversityFollow
Kenneth S. Kendler, Virginia Commonwealth UniversityFollow
Ayman H. Fanous, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2011

Journal/Book/Conference Title

PLOS ONE

Volume

6

DOI of Original Publication

10.1371/journal.pone.0021440

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0021440

Date of Submission

November 2014

Abstract

Background

Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.

Methods

We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus.

Results

While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (PempP-value and truncated-product methods, respectively.

Conclusions

Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci.

Rights

Copyright: © 2011 Bigdeli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Human and Molecular Genetics Publications