Association study of 83 candidate genes for bipolar disorder in chromosome 6q selected using an evidence-based prioritization algorithm

Authors

  • T. Bernard Bigdeli,

    1. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia
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  • Brion S. Maher,

    1. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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  • Zhongming Zhao,

    1. Departments of Psychiatry, Biomedical Informatics, and Cancer Biology, Vanderbilt University Medical Center, Vanderbilt, Tennessee
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  • Jingchun Sun,

    1. Departments of Psychiatry, Biomedical Informatics, and Cancer Biology, Vanderbilt University Medical Center, Vanderbilt, Tennessee
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  • Helena Medeiros,

    1. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California
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  • Nirmala Akula,

    1. Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland
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  • Francis J. McMahon,

    1. Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland
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  • Celia Carvalho,

    1. Department of Science Education, University of the Azores, Azores, Portugal
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  • Susana R. Ferreira,

    1. Department of Psychiatry, Sao Miguel, Azores, Portugal
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  • Maria H. Azevedo,

    1. Department of Psychiatry, University of Coimbra, Coimbra, Portugal
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  • James A. Knowles,

    1. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California
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  • Michele T. Pato,

    1. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California
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  • Carlos N. Pato,

    1. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California
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  • Ayman H. Fanous

    Corresponding author
    1. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia
    2. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California
    3. Mental Health Service Line, Washington VA Medical Center, Washington, District of Columbia
    4. Department of Psychiatry, Georgetown University School of Medicine, Washington, District of Columbia
    • Correspondence to:

      Ayman H. Fanous, M.D., Chief, Psychiatric Genetics Research Program, Washington, VA Medical Center, 50 Irving St. NW, Washington, DC 20422.

      E-mail: ayman.fanous@va.gov

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Abstract

Background

Prior genome-scans of bipolar disorder have revealed chromosome 6q22 as a promising candidate region. However, linkage disequilibrium (LD) mapping studies have yet to identify replicated susceptibility loci.

Methods

We analyzed 1,422 LD-tagging single nucleotide polymorphisms (SNPs) in 83 genes to test single-marker and locus-wide evidence of association with bipolar disorder in the NIMH Genetics Initiative bipolar pedigrees and the Portuguese Island Collection (PIC) (N = 1,093 in 528 informative pairs). Both studies previously demonstrated significant evidence of linkage to 6q. SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Evidence of single-marker association was assessed using the generalized disequilibrium test (GDT). Empirical estimates of gene-wide significance were obtained by permutation (via 100,000 gene-dropping simulations) of Fisher's combined test of P-values for each locus.

Results

No single variant yielded significant experiment-wide evidence of association, for either the combined sample or in each subsample. Our gene-dropping simulations identified nominally significant gene-wide associations with multiple loci, of which NT5DC1 in the NIMH subsample and CCNC in the PIC were the strongest candidates. However, no one gene consistently exceeded empirical significance criteria in both independent samples or survived Bonferroni correction for the number of genes tested.

Conclusions

Using a gene-based approach to family-based association, we identified gene-wide associations with several genes, though no single locus was significantly associated with bipolar disorder in both cohorts. This suggests that chromosome 6q may harbor multiple susceptibility loci or that complex patterns of LD in this region may confound approaches based on common SNPs. Published 2013. This article is a U.S. Government work and is in the public domain in the USA

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