title: Excess of homozygosity in the major histocompatibility complex in schizophrenia.
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.
authors.affiliation: 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.
authors.forename: Semanti
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: 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.
authors.forename: Saurav
authors.initials: S
authors.lastname: Guha
authors.affiliation: Fujita Health University School of Medicine, 1-98 Kutsukake-cho Dengakugakubo, Toyoake, Aichi 470-1192, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Fujita Health University School of Medicine, 1-98 Kutsukake-cho Dengakugakubo, Toyoake, Aichi 470-1192, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Malhotra
authors.affiliation: Department of Computer Science, Columbia University, New York, NY 10027, USA and.
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
authors.affiliation: 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.
authors.forename: Todd
authors.initials: T
authors.lastname: Lencz
mesh_terms: D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics*; D006649:Histocompatibility Antigens / Q000235:genetics; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007564:Japan; D008285:Major Histocompatibility Complex; D012559:Schizophrenia / Q000235:genetics*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D015234:HLA-A Antigens; D006649:Histocompatibility Antigens; D047908:Intracellular Signaling Peptides and Proteins; C108239:TRIM10 protein, human; D000070584:Tripartite Motif Proteins; C000597019:tripartite motif-containing protein 15, human; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases