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; Ariel Darvasi

doi:10.1038/ncomms3739

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

Psychiatry

Research output: Contribution to journal › Article › peer-review

96 Citations (Scopus)

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 P_meta = 9.49 × 10^-12 (odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.08-1.17) across both disorders and P_meta = 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 language	English
Article number	2739
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3739
Publication status	Published - 2013

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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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, Article 2739. https://doi.org/10.1038/ncomms3739

@article{e69376bf12294881920c798b340f55e9,

title = "Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder",

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.",

author = "Todd Lencz and Saurav Guha and Chunyu Liu and Jeffrey Rosenfeld and Semanti Mukherjee and Pamela DeRosse and Majnu John and Lijun Cheng and Chunling Zhang and Badner, {Judith A.} and Masashi Ikeda and Nakao Iwata and Sven Cichon and Marcella Rietschel and N{\"o}then, {Markus M.} and Cheng, {A. T.A.} and Colin Hodgkinson and Qiaoping Yuan and Kane, {John M.} and Lee, {Annette T.} and Anne Pisant{\'e} and Gregersen, {Peter K.} and Itsik Pe'er and Malhotra, {Anil K.} and David Goldman and Ariel Darvasi",

note = "Funding Information: We thank Michael Ryan of the Feinstein Institute Biorepository for assistance with sample handling and preparation. This work was supported by the North Shore-LIJ Health System Foundation and the National Institutes of Health (RC2 MH089964, R01 MH095458 and R01 MH084098 to T.L.; P50 MH080173 to A.K.M.; P30 MH090590 to J.M.K.; and R01 MH080425 to C.L.). We thank David B. Goldstein for providing summary data from the Aberdeen and Munich cohorts. We are extremely grateful to investigators, including Pablo Gejman, John Kelsoe and Nick Craddock, who have made their genotype data publicly available through dbGAP and the Wellcome Trust Case– Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of these data sets is available from www.wtccc.org.uk as well as the following studies within dbGAP (http://www.ncbi.nlm.nih.gov/projects/gap): /cgi-bin/study.cgi?study_id = phs000167.v1.p1; /cgi-bin/study.cgi?study_id = phs000021.v2.p1; /cgi-bin/study.cgi?study_id = phs000017.v3.p1.",

year = "2013",

doi = "10.1038/ncomms3739",

language = "English",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Lencz, T, Guha, S, Liu, C, Rosenfeld, J, Mukherjee, S, DeRosse, P, John, M, Cheng, L, Zhang, C, Badner, JA, Ikeda, M, Iwata, N, Cichon, S, Rietschel, M, Nöthen, MM, Cheng, ATA, Hodgkinson, C, Yuan, Q, Kane, JM, Lee, AT, Pisanté, A, Gregersen, PK, Pe'er, I, Malhotra, AK, Goldman, D & Darvasi, A 2013, 'Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder', Nature communications, vol. 4, 2739. https://doi.org/10.1038/ncomms3739

TY - JOUR

T1 - Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder

AU - Lencz, Todd

AU - Guha, Saurav

AU - Liu, Chunyu

AU - Rosenfeld, Jeffrey

AU - Mukherjee, Semanti

AU - DeRosse, Pamela

AU - John, Majnu

AU - Cheng, Lijun

AU - Zhang, Chunling

AU - Badner, Judith A.

AU - Ikeda, Masashi

AU - Iwata, Nakao

AU - Cichon, Sven

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

AU - Cheng, A. T.A.

AU - Hodgkinson, Colin

AU - Yuan, Qiaoping

AU - Kane, John M.

AU - Lee, Annette T.

AU - Pisanté, Anne

AU - Gregersen, Peter K.

AU - Pe'er, Itsik

AU - Malhotra, Anil K.

AU - Goldman, David

AU - Darvasi, Ariel

N1 - Funding Information: We thank Michael Ryan of the Feinstein Institute Biorepository for assistance with sample handling and preparation. This work was supported by the North Shore-LIJ Health System Foundation and the National Institutes of Health (RC2 MH089964, R01 MH095458 and R01 MH084098 to T.L.; P50 MH080173 to A.K.M.; P30 MH090590 to J.M.K.; and R01 MH080425 to C.L.). We thank David B. Goldstein for providing summary data from the Aberdeen and Munich cohorts. We are extremely grateful to investigators, including Pablo Gejman, John Kelsoe and Nick Craddock, who have made their genotype data publicly available through dbGAP and the Wellcome Trust Case– Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of these data sets is available from www.wtccc.org.uk as well as the following studies within dbGAP (http://www.ncbi.nlm.nih.gov/projects/gap): /cgi-bin/study.cgi?study_id = phs000167.v1.p1; /cgi-bin/study.cgi?study_id = phs000021.v2.p1; /cgi-bin/study.cgi?study_id = phs000017.v3.p1.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84893361550&partnerID=8YFLogxK

U2 - 10.1038/ncomms3739

DO - 10.1038/ncomms3739

M3 - Article

C2 - 24253340

AN - SCOPUS:84893361550

SN - 2041-1723

VL - 4

JO - Nature communications

JF - Nature communications

M1 - 2739

ER -

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

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