A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3

Abstract

In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.

Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12

“…16 Even with these improvements, conflicting reports and methodological uncertainties indicate that these are not confirmed, compelling findings. 3,17 In previous, more limited studies, we reported evidence of linkage to 21q 22 14,18,19 and nonreplication of proposed loci on 18p11 20 and Xq27-28. 21,22 Here, we report a comprehensive, whole-genome scan in a large series of pedigrees with high density of BP and other mood disorders.…”

“…For the dominant model, we used the same parameters described in previous publications. 14,18,19 This model assumes a disease allele frequency of 0.01, and a penetrance of 80% for gene carriers and 1% for noncarriers. A corresponding recessive model assumes the same penetrance in gene carriers and noncarriers but a disease allele frequency of 0.10.…”

An apparently dominant bipolar affective disorder (BPAD) locus on chromosome 20p11.2–q11.2 in a large Turkish pedigree

“…A series of studies has been performed using linkage analyses in mostly small and medium-size families with BPAD. One chromosomal region with the strongest evidence for a BPAD susceptibility gene was found on 13q32 with a maximum lod score of 3.5; 6 other regions with suggestive evidence for linkage were at 1q31-q32, 6 4p16, 7,8 4q35, 9 5p15.3, 10 6p24, 11 7q31, 6 16p13, 12,13 18p11.2 6,14 21q22.3, [15][16][17] 22q11-q13. 18 The ascertainment of occasional large families segregating a 'complex' trait such as BPAD is of considerable importance since it may reveal the existence of a single gene that in these families contributes considerably to the development of the phenotype.…”

“…However, their identification will undoubtedly contribute to the elucidation of the molecular pathophysiology of the disease. There are four examples of such families with positive linkage scores on 4p (θ = 4.1; marker D4S394), 19 21q22 (θ = 3.35, marker D12S1260), 15,20 18q22-q23 (θ = 4.06, marker D18S70), 21 and 12q23-q24 (θ = 3.37, marker D12S1639). 22 We studied a large Turkish BPAD pedigree, with an apparently autosomal dominant mode of inheritance.…”

The phenotypes of bipolar disorder: relevance for genetic investigations

“…In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation.…”