Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, IFT27 and parvalbumin

Am J Med Genet B Neuropsychiatr Genet. 2012 Dec;159B(8):941-50. doi: 10.1002/ajmg.b.32099. Epub 2012 Oct 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bipolar Disorder / genetics*
  • Calcium Channels / genetics
  • Case-Control Studies
  • Chromosome Mapping
  • Chromosomes, Human, Pair 22 / genetics*
  • Genetic Linkage
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes*
  • Humans
  • Microsatellite Repeats / genetics
  • Parvalbumins / genetics
  • Polymorphism, Single Nucleotide*


  • CACNG2 protein, human
  • Calcium Channels
  • Genetic Markers
  • Parvalbumins