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

Stephanie Nissen, Sherri Liang, Tatyana Shehktman, John R. Kelsoe, John R. Kelsoe, Tiffany A. Greenwood, Caroline M. Nievergelt, Rebecca McKinney, Paul D. Shilling, Erin N. Smith, Nicholas J. Schork, Cinnamon S. Bloss, John I. Nurnberger, Howard J. Edenberg, Tatiana Foroud, Daniel L. Koller, Elliot S. Gershon, Chunyu Liu, Judith A. Badner, William A. ScheftnerWilliam B. Lawson, Evaristus A. Nwulia, Maria Hipolito, William Coryell, John Rice, William Byerley, Francis J. McMahon, Wade H. Berrettini, James B. Potash, Peter P. Zandi, Pamela B. Mahon, Melvin G. McInnis, Sebastian Zöllner, Peng Zhang, David W. Craig, Szabolics Szelinger, Thomas B. Barrett, Thomas G. Schulze

Research output: Contribution to journalArticle

10 Scopus citations

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 5Mb 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.

Original languageEnglish
Pages (from-to)941-950
Number of pages10
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume159 B
Issue number8
DOIs
StatePublished - Dec 2012

Keywords

  • Bipolar disorder
  • Chromosome 22
  • Genetic association
  • Stargazin

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Nissen, S., Liang, S., Shehktman, T., Kelsoe, J. R., Kelsoe, J. R., Greenwood, T. A., Nievergelt, C. M., McKinney, R., Shilling, P. D., Smith, E. N., Schork, N. J., Bloss, C. S., Nurnberger, J. I., Edenberg, H. J., Foroud, T., Koller, D. L., Gershon, E. S., Liu, C., Badner, J. A., ... Schulze, T. G. (2012). Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin. American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 159 B(8), 941-950. https://doi.org/10.1002/ajmg.b.32099