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

Abstract

Bipolar affective disorder (BPAD), also known as manic-depressive illness, is a common complex, polygenic disorder characterised by recurrent cyclic episodes of mania and depression. Family, twin, and adoption studies strongly suggest a genetic predisposition/susceptibility to BPAD, but no genes have yet been identified. We studied a large Turkish pedigree, with an apparently autosomal dominant BPAD, which contained 13 affected individuals. The age of onset ranged from 15-40 with a mean of 25 years. The phenotypes consisted of recurrent manic and major depressive episodes, including suicidal attempts; there was usually full remission with lithium treatment. A genome-wide linkage analysis using a dominant mode of inheritance showed strong evidence for a BPAD susceptibility locus on chromosome 20p11.2-q11.2. The highest 2-point lod score of 4.34 at θ = 0 was obtained with markers D20S604, D20S470, D20S836 and D20S838 using a dominant model with full penetrance. Haplotype analysis enabled the mapping of the BPAD locus in this family between markers D20S186 and D20S109, to a region of approximately 42 cM.

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

“…The 3p14 region, detected here, has been reported in several other genome scans (McInnes et al, 1996;Cichon et al, 2001;Kelsoe et al, 2001;Radhakrishna et al, 2001;Ewald et al, 2003;Fallin et al, 2004).…”

Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14

“…Regions 3p14, 7q36, 10q23 and 20p12 are particularly interesting as they were detected in our sample and in at least two of the previously published scans in BPAD using a significance threshold of P < 0.01 (see Table 4). Chromosomal regions 2p21, 38,39 3p14, [40][41][42] 7q36 43,44 and 20p12 45,46 were previously identified in three independent studies, reinforcing the hypothesis of linkage. Some of these regions (2p21, 7q36 and 20p12) were also detected in a previous genome scan.…”

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

“…These results are consistent with those of our previous genomewide scan for early-onset BD, 8 and strengthened by three other genome-wide scans reporting linkage on chromosome 20p12. [9][10][11] The SNP, for which the highest significant association was observed (SNP4), is located in a CpG island, spanning the promoter region of the gene, and may affect the transcription level of SNAP25. Using quantitative RT-PCR analysis on brain samples, we showed that individuals with 'CC' genotype showed a significant increase in mRNA level of the major isoform of SNAP25 in adult (SNAP25b) in prefrontal cortex.…”

“…8 These regions included the 20p12 region, already reported by three independent studies to contain a gene conferring susceptibility to BD. [9][10][11] The gene encoding the synaptosomal-associated protein of 25 kDa (SNAP25) is located in this region.…”