Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder

Todd Lencz (), Saurav Guha, Chunyu Liu, Jeffrey Rosenfeld, Semanti Mukherjee, Pamela DeRosse, Majnu John, Lijun Cheng, Chunling Zhang, Judith A. Badner, Masashi Ikeda, Nakao Iwata, Sven Cichon, Marcella Rietschel, Markus M. Nöthen, A.T.A. Cheng, Colin Hodgkinson, Qiaoping Yuan, John M. Kane, Annette T. Lee, Anne Pisanté, Peter K. Gregersen, Itsik Pe’er, Anil K. Malhotra, David Goldman and Ariel Darvasi ()
Additional contact information
Todd Lencz: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Saurav Guha: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Chunyu Liu: University of Illinois at Chicago
Jeffrey Rosenfeld: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Semanti Mukherjee: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Pamela DeRosse: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Majnu John: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Lijun Cheng: University of Chicago
Chunling Zhang: University of Chicago
Judith A. Badner: University of Chicago
Masashi Ikeda: School of Medicine, Fujita Health University
Nakao Iwata: School of Medicine, Fujita Health University
Sven Cichon: Institute of Human Genetics, University of Bonn
Marcella Rietschel: Central Institute of Mental Health, University of Mannheim
Markus M. Nöthen: Institute of Human Genetics, University of Bonn
A.T.A. Cheng: Institute of Biomedical Sciences, Academia Sinica
Colin Hodgkinson: Laboratory of Neurogenetics, NIAAA
Qiaoping Yuan: Laboratory of Neurogenetics, NIAAA
John M. Kane: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
Annette T. Lee: Robert S. Boas Center for Human Genetics and Genomics, The Feinstein Institute for Medical Research
Anne Pisanté: The Institute of Life Sciences, The Hebrew University of Jerusalem
Peter K. Gregersen: Robert S. Boas Center for Human Genetics and Genomics, The Feinstein Institute for Medical Research
Itsik Pe’er: Columbia University
Anil K. Malhotra: Division of Research, Department of Psychiatry, The Zucker Hillside Hospital Division of the North Shore—Long Island Jewish Health System
David Goldman: Laboratory of Neurogenetics, NIAAA
Ariel Darvasi: The Institute of Life Sciences, The Hebrew University of Jerusalem

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: Abstract Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10−12 (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08–1.17) across both disorders and Pmeta=2.67 × 10−8 (OR=1.15, 95% CI: 1.08–1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders.

Date: 2013
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DOI: 10.1038/ncomms3739

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