title: Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, IFT27 and parvalbumin.
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.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla 92093, California.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nissen
authors.forename: Sherri
authors.initials: S
authors.lastname: Liang
authors.forename: Tatyana
authors.initials: T
authors.lastname: Shehktman
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nievergelt
authors.forename: Rebecca
authors.initials: R
authors.lastname: McKinney
authors.forename: Paul D
authors.initials: PD
authors.lastname: Shilling
authors.forename: Erin N
authors.initials: EN
authors.lastname: Smith
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Cinnamon S
authors.initials: CS
authors.lastname: Bloss
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.forename: Elliot S
authors.initials: ES
authors.lastname: Gershon
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.forename: William A
authors.initials: WA
authors.lastname: Scheftner
authors.forename: William B
authors.initials: WB
authors.lastname: Lawson
authors.forename: Evaristus A
authors.initials: EA
authors.lastname: Nwulia
authors.forename: Maria
authors.initials: M
authors.lastname: Hipolito
authors.forename: William
authors.initials: W
authors.lastname: Coryell
authors.forename: John
authors.initials: J
authors.lastname: Rice
authors.forename: William
authors.initials: W
authors.lastname: Byerley
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: Wade H
authors.initials: WH
authors.lastname: Berrettini
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Peter P
authors.initials: PP
authors.lastname: Zandi
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Mahon
authors.forename: Melvin G
authors.initials: MG
authors.lastname: McInnis
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zöllner
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Szabolics
authors.initials: S
authors.lastname: Szelinger
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Barrett
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D010320:Parvalbumins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: C491912:CACNG2 protein, human; D015220:Calcium Channels; D005819:Genetic Markers; D010320:Parvalbumins