Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder
Open accessAbstract
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. Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3in severe psychiatric disease.
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- Authors
- Lencz, T., Guha, S., Liu, C., Rosenfeld, J., Mukherjee, S., DeRosse, P., John, M., Cheng, L., Zhang, C., Badner, J. A., Ikeda, M., Iwata, N., Cichon, S., Rietschel, M., Nöthen, M. M., Cheng, A. T. A., Hodgkinson, C., Yuan, Q., Kane, J. M., Lee, A. T., Pisanté, A., Gregersen, P. K., Pe’er, I., Malhotra, A. K., Goldman, D., & Darvasi, A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Northwell Health (US)
- University of Illinois Chicago (US)
- University of Chicago (US)
- Fujita Health University (JP)
- University of Bonn (DE)
- University of Mannheim (DE)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- National Institutes of Health (US)
- Feinstein Institute for Medical Research (US)
- Hebrew University of Jerusalem (IL)
- Columbia University (US)
- Corresponding author
- Lencz, Todd
- Darvasi, Ariel
- ORCID
- Lencz, Todd
- Guha, Saurav
- Liu, Chunyu
- Rosenfeld, Jeffrey
- Mukherjee, Semanti
- DeRosse, Pamela
- John, Majnu
- Cheng, Lijun
- Zhang, Chunling
- Ikeda, Masashi
- Iwata, Nakao
- Cichon, Sven
- Rietschel, Marcella
- Nöthen, Markus M.
- Cheng, A.T.A.
- Hodgkinson, Colin
- Yuan, Qiaoping
- Kane, John M.
- Gregersen, Peter K.
- Pe’er, Itsik
- Malhotra, Anil K.
- Goldman, David
- Venue
- Nature Communications
- Published
- 2013-11-19
- Volume
- 4
- Issue
- 1
- Pages
- 2739-2739
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3905728
- OpenAlex
- W2088042334
- Cited by
- 111
- References
- 49
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 7 · 2017: 13 · 2016: 14 · 2015: 13 · 2014: 15
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health (MH080173)
- Japan Society for the Promotion of Science (24689046)
- National Institute of Mental Health (R01MH095458, RC2MH089964, R01MH080425, P50MH080173, P30MH090590, R01MH084098)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- schizophrenia, bipolar disorder, genetic susceptibility loci, Ashkenazi Jewish population, founder populations, psychiatric genetics
- MeSH terms
- Bipolar Disorder, Gene Expression Regulation, Humans, Jews, Schizophrenia, Sulfotransferases, Genome, Human, Odds Ratio, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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