Bipolar disorder (BPD) has been shown to have genetic links that may cause the mood fluctuations and related symptoms experienced by manic and/or depressed patients. Bipolar Disorder is considered one of the most highly heritable disorders, implied by the high concordance rates amongst relatives[1] . This is specifically shown through adoption and twin studies taking into account the environment influences [1]. Although there is no evidence to suggest a single mutation or gene that underlies or causes the disorder [1], candidate gene association studies and genome wide association studies have proposed different susceptibility genes and target proteins.

Table 1: Summary of the Genetics of BPD
Population Risk
1-2 %
Risk for 1st degree relatives
Recurrence risk ratio
MZ twin concordance
Heritability
Cytogenetic/CNV-associated region
Leading linked regions
Leading candidate genes[b]
Genes implicated by GWAS
9%
7–10
40%–45%
80%–85%
22q11[a]
6q, 8q, 13q, 22q
BDNF, DAOA, DISC1, TPH2,SLC6A4
DGKH, CACNA1C, ANK3
a Velocardiofacial/DiGeorge’s syndrome microdeletion.
b Supported in independent studies or meta-analysis.


1 Family/Twin Studies

1.1 Familial Concordance

The heritability of bipolar disorder has been suggested by the significantly higher concordance rates of monozygotic twins than dizygotic twins and first degree relatives, suggesting a strong genetic component1. In specific studies, the concordance was highest for the heritability of bipolar I than bipolar II and unipolar disorder. The findings by Both Kendler et al. and Cardno et al. indicate the concordance of monozygotic twins to be 0.80 and 0.82[2] while the rates for dizygotic twins are 0.28 and 0.31[2]. These studies noted that the AE model, which explains variance by common environmental factors constrained to zero[2], with heritability estimates of 0.79 and 0.84, respectively[2].

1.2 Determining Factors within Families

Many studies of bipolar disorder have shown that the condition aggregates within families and relatives are at higher risks than the general population[3] . The increased risks and familial concordance has been shown to be related to many other phenotypic subtypes. The age of onset differs amongst patients diagnosed with BPD, suggesting that early-onset is associated with the prevalence of either bipolar I disorder or recurrent MDD being as high as 46.5%[1] among first-degree relatives of prepubertal/early-adolescent onset BPD study participants. Additionally, other factors that may influence the likelihood of the concordance within a family vary, for example, the polarity of illness onset (mania vs. depression)[1], mood episode frequency[1], psychosis[1][4] , lithium-responsiveness[1][4], suicidality[1][4], rapid-cycling[1], and co-morbid alcohol use disorders and panic disorder[4].

2 Shared Genetics with Schizophrenia

Many studies on the genetics of bipolar disorder have limitations with the genetic overlap with other psychiatric disorders such as schizophrenia[2][5] , unipolar disorder[2] and cyclothymia[2], all of which can occur in combination with bipolar disorder I or II[2]. Concordance rates amongst family members are higher for specific disorders, specifically in monozygotic twins, suggesting a genetic basis for the disorder[1][4].

schizo.jpg
Fig 1. Genetic overlap and variance between bipolar disorder and schizophrenia
Researchers have studied the genetic overlap between bipolar disorder and schizophrenia[5][6] to determine a possible cause and the sources for the overlap. However, it is difficult to assess whether the substantial overlap is due to genetic effects or purely by chance[5]. Studies on the genetic association with schizophrenia have suggested the genetic correlation (ie, the correlation between the genetic effects that determine the liabilities for the two disorders) is 0.60[5]. Meta-analyses of both schizophrenia and bipolar disorder estimate higher heritability rates as twin studies are less sensitive to non-additive genetic effects[5] and age[5], but it can still be concluded that the heritability of both disorders is between 60-80%.

Schizophrenia is generally considered to be a separate diagnosis from bipolar disorder, but patients who exhibit multiple symptoms of both disorders are often given the mixed diagnosis of schizoaffective disorder[6]. This suggests in accordance with the argument that schizophrenia and bipolar disorder are variant expressions of a diathesis, partially because of the similar frequencies of both conditions, age of onset, and absence of sex bias between the two disorders[6].








3 Candidate Gene Association Studies

Gene Malfunctions and Chromosomal Abnormalities

Over recent years much of the research on bipolar disorder has focused on genetic association studies which examine whether specific alleles are more common in diagnosed patients than in matched controls (case-control studies)[1] or whether specific variants are transmitted within a family through familial concordance more often than expected by chance (family-based studies)[1]. Very few genes from these studies can be universally accepted as significant to the genetic etiology of bipolar disorder[1]. Chromosomal abnormalities and gene malfunctions are some of the leading areas of interest for candidate gene association studies[1], particularly in the genes coding the ionotropic glutamate receptor gene, GRIK4 [1][7] , NMDA receptor[1], the 5-HT transporter SLC6A4[1], peroxisome proliferators-activated receptor delta PPARD, catechol-omethyl transferase (COMT) [1] [8] [9] [10] [11] [12] [13] [14] ,
the dopamine transporter SLC6A3 [1],
disrupted in schizophrenia 1 DISC1[1][10], and
DISC_1.jpg
Figure 2. DISC1 regulation of dendritic growth.
tryptophan hydroxylase-2 (TPH2)[1] [12][15] [16] [17] .
DISC1 has been linked to schizophrenia[1][6][10] but has also been shown to associate with bipolar disorder and schizoaffective disorder. Researchers have narrowed the location of mutation to 13 exons, 39 SNP markers and 7 haplotype blocks on the DISC1 gene[6]. The mutations can range from that affect protein function, polymorphisms related to gene transcription or missense or nonsense mutations is expected to predispose individuals to disease[1][6].

Other genes such as, GRIK4/KA1, which is the kainate class ionotropic glutamate receptor gene is associated with bipolar disorder at the 3’UTR [7]. A deletion variant in the gene has shown significant alterations in risk by acting as a form of protection[7]. A 2-SNP haplotype (GC; SNPs rs2282586[7] and rsl944522[7]) expressing a deletion allele exhibits a protective effect, as lower frequencies are present in individuals with bipolar disorder [7].






4 Genome Wide Association Studies

GWAS technology specifically for research in bipolar disorder emerged in 2007 and has provided insight for future diagnosis and treatments. Itprovides researchers a new way of finding susceptibility genes since GWAS can agnostically generate new hypotheses, implicating novel biological systems that were not previously known, which could be the basis of new research in BPD[1].

Evidence for the CACNA1C gene, mentioned before, was strengthened, with the rs1006737 SNP now reaching genomewide levels of statistical significance (P=7×10−8)[1]. This SNP was shown to be significantly more common in the sets for bipolar disorder, schizophrenia and unipolar disorder. These data, not only show the association of alleles in rs1006737 being linked to bipolar disorder, but it also showed that there is some genetic and molecular commonality between unipolar depression, bipolar depression, and schizophrenia. [1]

In connection to CACNA1C [18] , a second, even stronger genomewide significant signal emerged for an intronic SNP (rs10994336) in the ANK3 gene on 10q21[1][19] . Ank3 is a component of the complex that localizes sodium channels to the axon initial segment of neurons, and these channels are responsible for action potential initiation and propagation.Other GWAS for psychiatric disorders, other SNPs have been associated to bipolar disorder. When included with just schizophrenia, the SNP in gene for a zinc finger protein, ZNF804, was not significant [19] . When bipolar disorder was included in the phenotype criteria, there was a very strong association [19].
Table 2. Representative SNPs with risk alleles linked to bipolar disorder.

Gene
SNP
Genome-Wide Significance
Bipolar Disorder link?
MDD link?
Schizophrenia link?
CACNA1C
ANK3
ZNF804A
rs1006737
rs1938526
Rs1344706
7.0×10−8
1.3×10−8
4.1×10−13
Y
Y
Y
Y
N
N
Y
N
Y

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