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Hum Mol Genet. 2014 Nov 15;23(22):6088-95. doi: 10.1093/hmg/ddu308. Epub 2014 Jun 18.

Excess of homozygosity in the major histocompatibility complex in schizophrenia.

Author information

1
The Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USA, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA, smukherje1@nshs.edu tlencz@nshs.edu.
2
The Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USA, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
3
Fujita Health University School of Medicine, 1-98 Kutsukake-cho Dengakugakubo, Toyoake, Aichi 470-1192, Japan.
4
The Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USA, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA, Hofstra University School of Medicine, 500 Hofstra University, Hempstead, NY 11549, USA.
5
Department of Computer Science, Columbia University, New York, NY 10027, USA and.
6
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
7
The Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USA, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA, Hofstra University School of Medicine, 500 Hofstra University, Hempstead, NY 11549, USA, smukherje1@nshs.edu tlencz@nshs.edu.

Abstract

Genome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 × 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease.

PMID:
24943592
PMCID:
PMC4204767
DOI:
10.1093/hmg/ddu308
[Indexed for MEDLINE]
Free PMC Article

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