title: Bipolar disorder in the Bulgarian Gypsies: genetic heterogeneity in a young founder population.
abstract: We report the results of follow-up analyses of 12 genomic regions showing evidence of linkage in a genome-wide scan (GWS) of Gypsy families with bipolar affective disorder (BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong founder effect and limited genetic diversity. The BPAD families belong to a single sub-isolate and are connected by numerous inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and search for evidence of a founder susceptibility allele after the addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage analysis was conducted with SimWalk2, accommodating the full complexity of pedigree structure and using a conservative narrow phenotype definition (BPAD only). Six regions were rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31 produced nominally significant results in both the individual families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region was a 12 cM interval on 4q31, also implicated in previous studies, where we obtained significant results in the super-pedigree using both SimWalk2 (P = 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium (P = 0.000056). The size of the region and the characteristics of the Gypsy population make it suitable for LD mapping.
authors.affiliation: Medical University of Sofia, Bulgaria.
authors.forename: Radka
authors.initials: R
authors.lastname: Kaneva
authors.forename: Vihra
authors.initials: V
authors.lastname: Milanova
authors.forename: Dora
authors.initials: D
authors.lastname: Angelicheva
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.forename: Christian
authors.initials: C
authors.lastname: Kostov
authors.forename: Rositza
authors.initials: R
authors.lastname: Vladimirova
authors.forename: Spiridon
authors.initials: S
authors.lastname: Aleksiev
authors.forename: Mina
authors.initials: M
authors.lastname: Angelova
authors.forename: Vessela
authors.initials: V
authors.lastname: Stoyanova
authors.forename: Angeline
authors.initials: A
authors.lastname: Loh
authors.forename: Joachim
authors.initials: J
authors.lastname: Hallmayer
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.forename: Assen
authors.initials: A
authors.lastname: Jablensky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D002031:Bulgaria; D005260:Female; D018703:Founder Effect; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D006178:Romani People / Q000235:genetics*; D055815:Young Adult