Cited by 84Schizophrenia research and treatmentGenetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and Animals

Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia

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Chen, Pei-Lung, Avramopoulos, Dimitrios, Lasseter, Virginia K., McGrath, John A., Fallin, M. Daniele, Liang, Kung-Yee, Nestadt, Gerald, Feng, Ningping +5 more·2009·The American Journal of Human Genetics

Abstract

Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.

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Crossref · 10.1016/j.ajhg.2008.12.005

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Authors
Chen, P.-L., Avramopoulos, D., Lasseter, V. K., McGrath, J. A., Fallin, M. D., Liang, K.-Y., Nestadt, G., Feng, N., Steel, G., Cutting, A. S., Wolyniec, P., Pulver, A. E., & Valle, D.
Affiliations
Johns Hopkins University (US)
Corresponding author
Valle, David
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2009-01
Volume
84
Issue
1
Pages
21-34
ISSN
0002-9297 (ISSN-L)
OpenAlex
W2020145862
Cited by
83
References
77
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2019: 2 · 2018: 4 · 2017: 9 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 10 · 2012: 6
FWCI
6.58
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Johns Hopkins University
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health (n01hg065403-000)
  • National Institute of Mental Health (R01MH057314, R01MH068406)
  • National Human Genome Research Institute (N01 HG065403)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
schizophrenia, NRG3, fine mapping, Ashkenazi Jewish population, family-based association, delusions
MeSH terms
Chromosome Mapping, Chromosomes, Human, Pair 10, Female, Humans, Genetic Linkage, Male, Schizophrenia, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Neuregulins, Intracellular Signaling Peptides and Proteins, Young Adult

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