A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.

A genome-wide search for risk genes using homozygosity mapping and microarrays with 1,494 single-nucleotide polymorphisms in 22 eastern Cuban families with bipolar disorder.

Homozygosity mapping is a very powerful method for finding rare recessive disease genes in monogenic disorders and may also be useful for locating risk genes in complex disorders, late onset disorders where parents often are not available, and for rare phenotypic subgroups. In the present study, homozygosity mapping was applied to 24 persons with bipolar disorder from 22 inbred families. The families were selected irrespective of whether other affected family members were present or not. A genome wide screen using genotypes from only a single affected person in each family was performed using the AFFYMETRIX GeneChip HuSNP Mapping Assay, which contains 1,494 single nucleotide polymorphisms. At chromosome 17q24-q25 a parametric multipoint LOD score of 1.96 was found at WIAF-2407 and WIAF-2405. When analyzing 19 additional microsatellite markers on chromosome 17q the maximum parametric multipoint LOD score was 2.08, 1.5 cM proximal to D17S668. The present study replicates a recent significant linkage finding.