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Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.

Genome-wide association study of schizophrenia in Ashkenazi Jews.

Author information

1
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
3
Department of Biostatistics, Bloomberg School of Public Health, Baltimore, Maryland.
4
The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, New York.
5
Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York.
6
Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York City, New York.
7
Center of Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York City, New York.
8
New York Genome Center, New York City, New York.
9
Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York.
10
Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, Manhasset, New York.
11
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.
12
Department of Psychiatry, Hofstra University School of Medicine, Hempstead, New York.
13
Department of Molecular Medicine, Hofstra University School of Medicine, Hempstead, New York.
14
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
15
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
16
Departments of Human Genetics, Pediatrics and Biochemistry, Emory University, Atlanta, Georgia.

Abstract

Schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ∼9.7%) and a SNP-heritability estimate of 0.39 (P = 0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P < 1 × 10(-4) ) was also found for several previously identified genome-wide significant findings, including the HLA region, CNTN4, IMMP2L, and GRIN2A. The meta-analysis of the U.S. sample with the PGC2 results provided initial genome-wide significant evidence for six new loci. Among the novel potential susceptibility genes is PEPD, a gene involved in proline metabolism, which is associated with a Mendelian disorder characterized by developmental delay and cognitive deficits.

KEYWORDS:

Ashkenazi; GWAS; genetics; polygenic; schizophrenia

PMID:
26198764
DOI:
10.1002/ajmg.b.32349
[Indexed for MEDLINE]

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