A genome screen of 13 bipolar affective disorder pedigrees provides evidence for susceptibility loci on chromosome 3 as well as chromosomes 9, 13 and 19

Abstract

Bipolar affective disorder is a severe mood disorder that afflicts approximately 1% of the population worldwide. Twin and adoption studies have indicated that genetic factors contribute to the disorder and while many chromosomal regions have been implicated, no susceptibility genes have been identified. We undertook a combined analysis of 10 cM genome screen data from a single large bipolar affective disorder pedigree, for which we have previously reported linkage to chromosome 13q14 (Badenhop et al, 2001) and 12 pedigrees independently screened using the same 400 microsatellite markers. This 13 pedigree cohort consisted of 231 individuals, including 69 affected members. Two-point LOD score analysis was carried out under heterogeneity for three diagnostic and four genetic models. Non-parametric multipoint analysis was carried out on regions of interest. Two-point heterogeneity LOD scores (HLODs) greater than 1.5 were obtained for 11 markers across the genome, with HLODs greater than 2.0 obtained for four of these markers. The strongest evidence for linkage was at 3q25-26 with a genome-wide maximum score of 2.49 at D3S1279. Six markers across a 50 cM region at 3q25-26 gave HLODs greater than 1.5, with three of these markers producing scores greater than 2.0. Multipoint analysis indicated a 20 cM peak between markers D3S1569 and D3S1614 with a maximum NPL of 2.8 (P = 0.004). Three other chromosomal regions yielded evidence for linkage: 9q31-q33, 13q14 and 19q12-q13. The regions on chromosomes 3q and 13q have previously been implicated in other bipolar and schizophrenia studies. In addition, several individual pedigrees gave LOD scores greater than 1.5 for previously reported bipolar susceptibility loci on chromosomes 18p11, 18q12, 22q11 and 8p22-23.

A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

“…These regions include the following cytobands: murine 4qE, homologous to human 1p36, implicated in BPD in two studies with linkage scores of 3.97 [60] and 3.1 [61] and a region in which SNPs predict BPD susceptibility [62]; murine 5qF, homologous to human 12q24, implicated in BPD in multiple studies with linkage scores of 4.91 [63], 3.63 [64], 3.37 [65], 2.8 [61], and 2.08 [66] and a region in which SNPs and allele variants predict BPD susceptibility [44], [46], [67]; 8qE1, homologous to human 16q24, implicated in BPD in two studies with linkage scores of 3.51 [68] and 2.29 [69]; murine 11qE2, homologous to human 17q25, implicated in BPD in five studies with linkage scores of 3.11 [70], 2.4 [71], 2.4 [72], 2.1 [73], and 2.08 [74]; murine 13qA3 and 17qA3-17qB1, two cytobands with homology to human 6p21–22, implicated in BPD in multiple studies with linkage scores of 3.19 [68], 2.60 [75], 2.26 [72], and 1.91 [69]; murine 14qA1, homologous to human 3p14, implicated in BPD in two studies with linkage scores of 3.51 [76] and 2.31 [77]; and murine 16qB2–B3, homologous to human 3q29, implicated in BPD in two studies with linkage scores of 3.74 [78] and 2.0 [61]. Additional enriched genome regions showing weaker previous relationships to BPD included: murine 2qE, homologous to human 11p13, implicated in BPD in one study with a linkage score of 1.95 [79] and a region in which SNPs and allele variants predict BPD susceptibility [80], [81]; murine 8qB2–B3.1, homologous to human 4q34, implicated in BPD in a study with a linkage score of 3.28 [82]; murine 8qB3.3 and 9qA3, homologous to human 19p13, implicated in BPD in three studies with linkage scores of 2.37 [83], 1.8 [66], and 1.55 [84]; and 15qE3, homologous to 22q13, implicated in BPD in one study with a linkage score of 2.22 [85]. One cluster at murine cytoband 13qD1 shared synteny with human 5q13–14, a region with no significant linkage to BPD in any human literature we could find, but implicated in schizophrenia in a study with a linkage score of 3.20 [86] and implicated in ADHD in a study with a linkage score of 4.16 [87].…”

Neuropsychological performance as endophenotypes in extended schizophrenia families from the Central Valley of Costa Rica

“…A meta-analysis shows modest association of schizophrenia and G72 (Shi et al , 2007). No previously implicated schizophrenia or cognition candidates in the other two regions (10p13 and 3q25), although evidence for linkage of the 3p25 region and the 10p13 region to bipolar disorder has been demonstrated (Badenhop et al , 2002; Maziade et al , 2005). …”

Associations between LSAMP gene polymorphisms and major depressive disorder and panic disorder

“…11 Proteomic assessment has strongly implicated LSAMP in schizophrenia and bipolar disorder, 12 demonstrating its increased level in the dorsolateral prefrontal cortex. Furthermore, stronger or weaker linkages have been shown in the long arm of chromosome 3 with recurrent early-onset MDD or anxiety, 13 agoraphobia, 14 schizophrenia, 15, 16, 17, 18 bipolar disorder 19, 20 and autism-spectrum disorders. 21 A number of genome-wide association studies of depression have mainly given results that did not meet a genome-wide threshold for significance, but there were associations between depression and LSAMP or adjacent gene loci in top findings of all publications.…”