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Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin

Authors

  • Stephanie Nissen,

    1. Department of Psychiatry, University of California San Diego, La Jolla, California
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  • Sherri Liang,

    1. Department of Psychiatry, University of California San Diego, La Jolla, California
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  • Tatyana Shehktman,

    1. Department of Psychiatry, University of California San Diego, La Jolla, California
    2. Department of Psychiatry, VA San Diego Healthcare System, La Jolla, California
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  • John R. Kelsoe,

    Corresponding author
    1. Department of Psychiatry, University of California San Diego, La Jolla, California
    2. Department of Psychiatry, VA San Diego Healthcare System, La Jolla, California
    3. Institute for Genomic Medicine, University of California San Diego, La Jolla, California
    • Department of Psychiatry, UCSD, La Jolla, CA 92093.
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  • the Bipolar Genome Study (BiGS)

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    • BiGS Consortium co-authors include: John R. Kelsoe, Tiffany A. Greenwood, Caroline M. Nievergelt, Rebecca McKinney, Paul D. Shilling, Erin N. Smith, University of California, San Diego, CA, USA; Nicholas J. Schork, Cinnamon S. Bloss, Scripps Translational Science Institute, La Jolla, CA, USA; John I. Nurnberger Jr, Howard J. Edenberg, Tatiana Foroud, Daniel L. Koller, Indiana University, Indianapolis, IN, USA; Elliot S. Gershon, Chunyu Liu, Judith A. Badner, University of Chicago, Chicago, IL, USA; William A. Scheftner, Rush University Medical Center, Chicago, IL, USA; William B. Lawson, Evaristus A. Nwulia, Maria Hipolito, Howard University, Washington, DC, USA; William Coryell, University of Iowa, Iowa City, IA, USA; John Rice, Washington University, St. Louis, MO, USA; William Byerley, University of California, San Francisco, CA, USA; Francis J. McMahon, National Institute of Mental Health Intramural Research Program, Bethesda, MD, USA; Wade H. Berrettini, University of Pennsylvania, Philadelphia, PA, USA; James B. Potash, Peter P. Zandi, Pamela B. Mahon, Johns Hopkins School of Medicine, Baltimore, MD, USA; Melvin G. McInnis, Sebastian Zöllner, Peng Zhang, University of Michigan, Ann Arbor, MI, USA; David W. Craig, Szabolics Szelinger, The Translational Genomics Research Institute, Phoenix, AZ, USA; Thomas B. Barrett, Portland Veterans Affairs Medical Center, Portland, OR, USA; Thomas G. Schulze, Georg-August-University Göttingen.


  • The authors have no conflicts of interest.

  • How to Cite this Article: Nissen S, Liang S, Shehktman T, Kelsoe JR, The Bipolar Genome Study (BiGS). 2012. Evidence for Association of Bipolar Disorder to Haplotypes in the 22q12.3 Region Near the Genes Stargazin, IFT27 and Parvalbumin. Am J Med Genet Part B 159B:941–950.

Abstract

We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case–control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5 Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P = 4.69 × 10−4). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P = 1.42 × 10−5). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P = 8.89 × 10−6). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P = 3.43 × 10−4). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P = 1.76 × 10−6). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region. © 2012 Wiley Periodicals, Inc.

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