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.

Isolated populations and complex disease gene identification

“…Studies of type 2 diabetes and obesity have used Pima Indians [ 26 ], as well as other genetic isolates, such as Finland and Sardinia [ 27 , 28 ]. Genes contributing to neuropsychiatric disorders are sought, and previous gene discoveries are confirmed, in studies of special populations, such as people from the Antioquia in Colombia and the Central Valley of Costa Rica [ 29 ], Basques from Spain [ 30 ], the Micronesian population of the islands of Kosrae [ 31 ] and Palau [ 32 ], Bulgarian Gypsies [ 33 ], and sub-isolates from Sweden [ 34 ] and Israel [ 35 ]. Other special populations utilized in recent genetic studies of complex diseases include French Canadians [ 36 ], Ashkenazi Jews [ 37 ], Mennonites [ 38 ], Newfoundlanders [ 39 ], sub-isolates from the Netherlands [ 40 ] and the Amish [ 41 ].…”

A linkage and exome study implicates rare variants of KANK4 and CAP2 in bipolar disorder in a multiplex family

“…9 Several BD genetic loci have been identified using large-family studies and a few among these map to chromosomes 4p, 4q35, 16p13, 13q14, 20p11.2-q11.2 and Xq24-27.1. [10][11][12][13][14][15] There are instances where unexpected genetic heterogeneity has been observed within single large families, [16][17][18][19][20][21][22] suggesting that even in apparently monogenic families, the phenotypic manifestation may not be entirely due to a straight forward effect of a single major locus or gene.…”

Tests of linkage and allelic association between markers in the 1p36 PRKCZ (Protein Kinase C Zeta) gene region and bipolar affective disorder

“…A nonparametric LOD linkage score of 3.97 was found in a Spanish sample of bipolar affective disorder at 1p34‐36 with 52 families of Spanish, Romanian and Bulgarian descent [Schumacher et al, 2005]. The 1p34‐36 region has also been implicated with nominally significant LODs in linkage studies of bipolar disorder and related affective disorders in Gypsy families [Kaneva et al, 2009]. Thus, there is considerable evidence from family linkage studies that an affective disorder susceptibility locus exists in the 1p36 region.…”