Genome‐wide association study of schizophrenia in Ashkenazi Jews

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‐R2 ∼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. © 2015 Wiley Periodicals, Inc.

[1]  H. Ostrer,et al.  The population genetics of the Jewish people , 2012, Human Genetics.

[2]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

[3]  Christine Klein,et al.  LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. , 2006, The New England journal of medicine.

[4]  D. Conrad,et al.  Reciprocal Duplication of the Williams-Beuren Syndrome Deletion on Chromosome 7q11.23 Is Associated with Schizophrenia , 2014, Biological Psychiatry.

[5]  I. Pe’er,et al.  Length distributions of identity by descent reveal fine-scale demographic history. , 2012, American journal of human genetics.

[6]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[7]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[8]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[9]  J. Marchini,et al.  Genotype Imputation with Thousands of Genomes , 2011, G3: Genes | Genomes | Genetics.

[10]  J. Hirschhorn,et al.  Biological interpretation of genome-wide association studies using predicted gene functions , 2015, Nature Communications.

[11]  S. MacGregor,et al.  VEGAS2: Software for More Flexible Gene-Based Testing , 2014, Twin Research and Human Genetics.

[12]  S. Warren,et al.  Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population , 2010, Proceedings of the National Academy of Sciences.

[13]  H. Ostrer A genetic profile of contemporary Jewish populations , 2001, Nature Reviews Genetics.

[14]  M. King,et al.  Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. , 1995, American journal of human genetics.

[15]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[16]  J. Veijola,et al.  A systematic review and meta-analysis of recovery in schizophrenia. , 2013, Schizophrenia bulletin.

[17]  M. Owen,et al.  Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  N. Wray,et al.  Research review: Polygenic methods and their application to psychiatric traits. , 2014, Journal of child psychology and psychiatry, and allied disciplines.

[19]  Peter M Visscher,et al.  Explaining additional genetic variation in complex traits. , 2014, Trends in genetics : TIG.

[20]  A. Frances The Diagnostic Interview for Genetic Studies , 1994 .

[21]  Caroline A. Montojo,et al.  The 22q11.2 Deletion Syndrome as a Window into Complex Neuropsychiatric Disorders Over the Lifespan , 2014, Biological Psychiatry.

[22]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[23]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.

[24]  P. Mortensen,et al.  Excess early mortality in schizophrenia. , 2014, Annual review of clinical psychology.

[25]  Matthew E Ritchie,et al.  Using the R Package crlmm for Genotyping and Copy Number Estimation. , 2011, Journal of statistical software.

[26]  Jennifer Mulle,et al.  A Genome-Wide Scan of Ashkenazi Jewish Crohn's Disease Suggests Novel Susceptibility Loci , 2012, PLoS genetics.

[27]  Bernadette A. Thomas,et al.  Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010 , 2012, The Lancet.

[28]  D. Cutler,et al.  Microdeletions of 3q29 confer high risk for schizophrenia. , 2010, American journal of human genetics.

[29]  J. McGrath,et al.  Familiality of novel factorial dimensions of schizophrenia. , 2009, Archives of general psychiatry.

[30]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[31]  M. Kas,et al.  Contactins in the neurobiology of autism. , 2013, European journal of pharmacology.

[32]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[33]  P. Holmans,et al.  Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms , 2008, Molecular Psychiatry.

[34]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[35]  E M Wijsman,et al.  Meta-analysis of 32 genome-wide linkage studies of schizophrenia , 2009, Molecular Psychiatry.

[36]  M. Daly,et al.  Searching for missing heritability: Designing rare variant association studies , 2014, Proceedings of the National Academy of Sciences.

[37]  Saharon Rosset,et al.  The genome-wide structure of the Jewish people , 2010, Nature.

[38]  Stephan Ripke,et al.  Estimation of SNP heritability from dense genotype data. , 2013, American journal of human genetics.

[39]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[40]  A. Grunden,et al.  Prolidase function in proline metabolism and its medical and biotechnological applications , 2012, Journal of applied microbiology.

[41]  H. Mandel,et al.  A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability , 2009, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[42]  M. Schatz,et al.  Reducing INDEL calling errors in whole genome and exome sequencing data , 2014, Genome Medicine.

[43]  Patrick F. Sullivan,et al.  Genetic architectures of psychiatric disorders: the emerging picture and its implications , 2012, Nature Reviews Genetics.

[44]  Annette Lee,et al.  Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder , 2013, Nature Communications.