Depressive disorders represent a prevalent (1 to 2%) and major illness characterized by episodes of dysphoria that are associated with somatic symptoms. It may have a manic-depressive (bipolar) or purely depressive (unipolar) course. The most characteristic features of ... Depressive disorders represent a prevalent (1 to 2%) and major illness characterized by episodes of dysphoria that are associated with somatic symptoms. It may have a manic-depressive (bipolar) or purely depressive (unipolar) course. The most characteristic features of bipolar affective disorder (BPAD) are episodes of mania (bipolar I, BP I) or hypomania (bipolar II, BP II) interspersed with periods of depression (Goodwin and Jamison, 1990). If untreated, manic-depressive illness is associated with a suicide rate of approximately 20%.
- Association with the SLC6A3 Gene on Chromosome 5p15
Greenwood et al. (2001) reported evidence for an association between the DAT1 gene (SLC6A3; 126455) and bipolar disorder in a sample of 50 parent-proband trios. Using the ... - Association with the SLC6A3 Gene on Chromosome 5p15 Greenwood et al. (2001) reported evidence for an association between the DAT1 gene (SLC6A3; 126455) and bipolar disorder in a sample of 50 parent-proband trios. Using the transmission disequilibrium test (TDT), they showed an association between a haplotype comprised of 5 SNPs in the 3-prime region of the DAT1 gene, exon 9 through exon 15, and bipolar disorder (allele-wise TDT empirical P = 0.001; genotype-wise TDT empirical P = 0.0004). Greenwood et al. (2006) analyzed a total of 22 SNPs in the 50 previously studied parent-proband trios and an independent set of 70 parent-proband trios. Using TDT analysis, an intron 8 SNP and an intron 13 SNP were found to be moderately associated with bipolar disorder, each in 1 of the 2 independent samples. Analysis of haplotypes of all 22 SNPs in sliding windows of 5 adjacent SNPs revealed an association to the region near intron 7 and 8 in both samples (empirical P values of 0.002 and 0.001, respectively, for the same window). - Association with the HTR4 Gene on Chromosome 5q32 Ohtsuki et al. (2002) performed mutation and association analyses of the HTR4 gene (602164) on 5q32, which encodes the serotonin 5-HT4 receptor, in 96 Japanese patients, 48 with mood disorders and 48 with schizophrenia. Eight polymorphisms and 4 rare variants were identified. Four polymorphisms at or in close proximity to exon d showed significant association with bipolar disorder with odds ratios of 1.5 to 2; these included g.83097C/T (HTR4-SVR (splice variant region) SNP1), g.83159G/A (HTR4-SVRSNP2), g.83164(T)9-10 (HTR4-SVRSNP3), and g.83198A/G (HTR4-SVRSNP4). These polymorphisms were in linkage disequilibrium, and only 3 common haplotypes were observed. One haplotype (SVRSNP1, SVRSNP4 C-A) was significantly associated with bipolar disorder (p = 0.002). The genotypic and haplotypic associations with bipolar disorder were confirmed by the transmission disequilibrium test in the NIMH Genetics Initiative bipolar pedigrees with ratios of transmitted to not transmitted alleles of 1.5 to 2.0 (p = 0.01). The same haplotype that showed association with bipolar disorder was suggested to be associated with schizophrenia in the case-control analysis (p = 0.003) but was not confirmed when Japanese schizophrenia families were tested. The polymorphisms associated with mood disorder were located within the region that encodes the divergent C-terminal tails of the 5-HT4 receptor. - Association with the ABCA13 Gene on Chromosome 7p12.3 Knight et al. (2009) reported evidence that ABCA13 (607807) is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, Knight et al. (2009) resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including 1 nonsense and 9 missense mutations and compound heterozygosity/homozygosity in 6 cases. Variants were genotyped in more than 1,600 additional schizophrenia, bipolar, and depression cases and in more than 950 control cohorts, and the frequency of all rare variants combined was greater than controls in schizophrenia (odds ratio = 1.93, P = 0.0057) and bipolar disorder (odds ratio = 2.71, P = 0.00007). The population-attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a study of 21 families of mutation carriers, Knight et al. (2009) genotyped affected and unaffected relatives and found significant linkage (lod = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. Knight et al. (2009) concluded that their data identified a candidate gene (ABCA13), highlighted the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggested that rare coding variants may contribute significantly to risk of these disorders. - Association with the DRD4 Gene on Chromosome 11p15 Lopez Leon et al. (2005) conducted a metaanalysis to reevaluate the role of the 48-bp repeat polymorphism of the dopamine D4 receptor gene (DRD4; 126452) on chromosome 11p15 in mood disorders by studying 917 patients with unipolar or bipolar affective disorder and 1,164 control subjects from 12 samples using the Cockrane Review Manager. An association was found between all mood disorder groups and the DRD4 2-repeat 48-bp (2R) polymorphism. After correcting for multiple testing, the association between this repeat and bipolar affective disorder dropped to insignificance; however, the evidence for an association between the 2R allele and unipolar depression (p less than 0.001) and the combined group (p less than 0.001) remained. - Association with the BDNF Gene on Chromosome 11p13 Geller et al. (2004) noted that Sklar et al. (2002) and Neves-Pereira et al. (2002), using family-based methods, had found that the BDNF val66 allele (113505.0002) was preferentially transmitted to predominantly Caucasian adult probands with bipolar disorder. Geller et al. (2004) reported that the val66 allele was also preferentially transmitted in children with bipolar disorder. Lohoff et al. (2005) studied the BDNF val66 allele in 621 European patients with bipolar I disorder and positive family histories of affective disorder and 998 European controls. The frequency of the val66 allele was significantly increased in the bipolar I patients when compared to controls (P = 0.028; OR of 1.22). Rybakowski et al. (2006) studied 111 patients with bipolar disorder, 129 schizophrenia patients, and 92 healthy controls utilizing the Wisconsin Card Sorting Test in the context of the BDNF V66M polymorphism. They found that bipolar patients with the val/val genotype made significantly fewer perseverative errors, had more correctly completed categories and conceptual level responses compared to bipolar patients with the val/met or met/met genotypes. No differences were observed in schizophrenia patients and controls. - Association with the CUX2 Gene on Chromosome 12q Glaser et al. (2005) performed linkage disequilibrium mapping with 17 microsatellite markers across a 1.6-Mb segment forming the central part of the chromosome 12q23-q24 region implicated in several linkage studies for bipolar affective disorder. In a U.K. Caucasian case-control sample of 347 cases and 374 controls, a significant signal was identified (p = 0.0016) for the microsatellite marker M19 at 12q24. Genes, including regulatory elements, around this marker were screened for mutations and the linkage disequilibrium structure of the region determined by genotyping 22 SNPs and insertion/deletion polymorphisms in 94 individuals. Eleven haplotypes and SNPs were genotyped and 3, an insertion/deletion and a SNP within GENBANK FLJ32356 (dbSNP rs3840795 and dbSNP rs933399) and a SNP within CUX2 (dbSNP rs3847953), showed significant or nearly significant association with bipolar disorder after Bonferroni-correction (p values from 0.002-0.005). - Association with the SLC6A4 Gene on Chromosome 17q11 Lasky-Su et al. (2005) conducted a metaanalysis on case-control studies of the association between 2 polymorphisms of the SLC6A4 gene (a 17-bp VNTR in intron 2, and a 44-bp insertion/deletion in the promoter region; see 182138.0001) and affective disorders (bipolar disorder and unipolar depression) resulting in 4 metaanalyses. For each polymorphism, the authors assessed the evidence for allelic association, heterogeneity among studies, the influence of individual studies, and the potential for publication bias. The short alleles of the 44-bp insertion/deletion polymorphism showed a significant association with bipolar disorder (OR = 1.13, p = 0.001) but not unipolar disorder. The VNTR had no association with either disorder. Cho et al. (2005) performed 2 metaanalyses of published studies involving the SLC4A4 gene as a candidate for bipolar disorder. The studies were population-based and family-based studies investigating the association with the promoter polymorphism (5-HTTLPR) and the intron 2 VNTR. Seventeen population-based studies comprising 1,712 cases and 2,583 controls and 6 family-based studies comprising 587 trios were included in the 5-HTTLPR metaanalysis. Sixteen population-based studies comprising 1,764 cases and 2,703 controls as well as for family-based studies comprising 382 trios were included in the intron 2 VNTR metaanalysis. Meta-regression showed that neither study type nor ethnic sample significantly contributed to heterogeneity of the metaanalyses. Overall, odds ratios suggested a very small but detectable effect of the serotonin transporter in susceptibility to bipolar disorder. - Association with the BCR Gene on Chromosome 22q11 Hashimoto et al. (2005) studied 171 patients with bipolar disorder, 329 with major depressive disorder, and 351 controls, all of whom were Japanese, for genetic association using 11 single nucleotide polymorphisms, including a missense polymorphism (N796S; dbSNP rs140504) in the region of the breakpoint cluster region gene (BCR; 151410) on chromosome 22q11. Significant allelic associations with bipolar disorder were observed for 3 single nucleotide polymorphisms and associations with bipolar II disorder were observed for 10 polymorphisms including N796S (bipolar disorder, p = 0.0054; bipolar II disorder, p = 0.0014). There was a significant association with major depression for 6 polymorphisms. S796 allele carriers were in excess in bipolar II patients (p = 0.0046; OR = 3.1, 95% CI, 1.53-8.76). - Association with the COMT Gene on Chromosome 22q11 Comorbid panic disorder may define a subtype of bipolar disorder and may influence the strength of association between bipolar disorder and candidate genes involved in monoamine neurotransmission. Rotondo et al. (2002) studied the frequency of the V158M polymorphism of catechol-O-methyltransferase (COMT; 116790.0001), the 5-HTTLPR polymorphism of the serotonin transporter SLC6A4 (182138.0001), and a splice site polymorphism (IVS7+218C-A) of tryptophan hydroxylase (TPH; 191060) in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. They compared results from DNA extracted from blood leukocytes of 111 unrelated subjects of Italian descent meeting DSM-III-R criteria for bipolar disorder, including 49 with and 62 without comorbid lifetime panic disorder, with those of 127 healthy subjects. Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT met158 and the short 5-HTTLPR alleles. No statistical significance was found between the bipolar disorder groups and the TPH polymorphism. Rotondo et al. (2002) concluded that bipolar disorder without panic disorder may represent a more homogeneous form of illness and that variants of the COMT and SLC6A4 genes may influence clinical features of bipolar disorder. - Association with the XBP1 Gene on Chromosome 22q12 See 194355 for discussion of an association between susceptibility to bipolar disorder and a polymorphism in the XBP1 gene. - Association with the TRPM2 Gene on Chromosome 21q22 McQuillin et al. (2006) fine mapped chromosome 21q22.3 using 30 genetic markers in 600 bipolar subjects and 450 ancestrally matched supernormal controls. Allelic association with D21S171 (p = 0.016), dbSNP rs1556314 (p = 0.008), and dbSNP rs1785467 (p = 0.025) was observed. A test of association with a 3-locus haplotype across a susceptibility region was significant with a permutation test (p = 0.011), and a 2-SNP haplotype was also significantly associated with bipolar disorder (p = 0.01). The 2 brain-expressed genes present in the associated region, TRPM2 (603749) and C21ORF29 (612920), were sequenced from subjects who had inherited the associated marker alleles. The dbSNP rs1556314 polymorphism in exon 11 of TRPM2, which causes an asp543-to-glu (D543E) change, showed the strongest association with bipolar disorder (p = 0.008). McQuillin et al. (2006) noted that deletion of exon 11 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. - Association with Repeat Expansions Del-Favero et al. (2002) studied the CTG repeat in the third intron of the SEF2-1B gene (602272) located at 18q21.1 and the CAG repeat at the ERDA1 locus (603279) located at 17q21.3 in a large combined European case-control sample of bipolar affective disorder. The sample consisted of 403 patients and 486 controls matched for age, gender, and ethnicity. The patients were consecutively recruited from 5 participating centers in Belgium, Croatia, Denmark, Scotland, and Sweden. Dichotomous analysis of the combined sample did not show a significant difference in expansion frequency between cases and controls at either of the 2 loci. Secondary analysis after stratification for family history of affective disorder in first-degree relatives and disease severity revealed a borderline significant difference (p = 0.03) with a relative risk of 2.43 of developing bipolar disorder in familial cases homozygous for the expanded SEF2-1B allele. This finding rendered further support to the hypothesis that SEF2-1B cannot be excluded as a susceptibility gene for bipolar disorder or that SEF2-1B is in linkage disequilibrium with a causal gene for bipolar disorder. Tsutsumi et al. (2004) used a repeat expansion detection assay to examine genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. They found that 28% of probands with schizophrenia and 38% of probands with bipolar disorder had a CAG/CTG repeat in the expanded range. Each expansion could be explained by 1 of 3 nonpathogenic repeat expansions known to exist in the general population. Thus, a novel CAG/CTG repeat expansion was not a common genetic risk factor for bipolar disorder or schizophrenia in this study. - Association with the Mitochondrial MTND1 Gene Munakata et al. (2004) reported an association between bipolar disorder and a polymorphism in the mitochondrial MTND1 gene (516000). - Gene Interaction and Locus Heterogeneity Jamra et al. (2007) presented the first genomewide interaction and locus heterogeneity linkage scan in bipolar affective disorder, using a large linkage dataset (52 families of European descent; 448 participants and 259 affected individuals). The results provided the strongest evidence of interaction between BPAD genes on chromosome 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions; nonparametric lod (NPL) scores of 7.55 on 2q and 7.63 on 6q; P less than 0.0001 and P = 0.0001, respectively, after a genomewide permutation procedure. The second-best BPAD interaction evidence was observed between 2q22-q24 and 15q26. Here, Jamra et al. (2007) also observed a symmetric interaction. Heterogeneity analysis revealed locus heterogeneity at 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. - Epigenetic Theory of Major Psychosis As a test of the hypothesis that epigenetic misregulation is consistent with various nonmendelian features of schizophrenia (181500) and bipolar disorder, Mill et al. (2008) used CpG island microarrays to identify DNA methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex they found evidence for psychosis-associated DNA methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA methylation changes in a significant proportion of these loci corresponded to reported changes of steady-state mRNA levels associated with psychosis. Gene ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Changes in both the brain and the germline of affected individuals suggested that systemic epigenetic dysfunction may be associated with major psychosis. Mill et al. (2008) observed that frontal cortex DNA methylation in the BDNF gene (113505) is correlated with genotype at a nearby nonsynonymous SNP (V66M) that had been associated with major psychosis. - Reviews See Kato (2007) for a review of molecular genetic findings on bipolar disorder and major depression from 2004 to 2007. Also see the review on the genetics of bipolar disorder by Craddock and Sklar (2009).