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

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.