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. LeeAnne Pisanté, Peter K. Gregersen, Itsik Pe'er, Anil K. Malhotra, David Goldman, Ariel Darvasi

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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.

Original languageEnglish
Article number2739
JournalNature Communications
Volume4
DOIs
Publication statusPublished - 01-12-2013

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    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., ... Darvasi, A. (2013). Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder. Nature Communications, 4, [2739]. https://doi.org/10.1038/ncomms3739