The Heredity and Genetics of Bipolar Disorder

There are many genetic studies now coming out on bipolar disorder.  It is very likely that one day they will lead us to better treatment and prevention, but that day has not yet arrived.  The rate of bipolar disorders in first degree relatives of bipolar individuals (19%) is higher than in the general population (1%); monozygote twins have higher concordance rates for bipolar diseases (67%) than dizygote (19%). Many different genetic abnormalities have been implicated, but I haven't put very many here so far. One recent study, for instance, analyzed 4,000 different selected gene sites.  Someday in the not distant future, we will all have our genomes tested and complex computers programs will analyze the meaning.  The evidence is that hundreds, if not thousands of different genetics abnormalities at dozens of different gene sites each either cause or increase the risk of bipolar disorder.

Bipolar Disorder has Strong Heredity: Evidence from epidemiologic and twin studies strongly suggests that BPD is a familial illness, with heritability estimates at 59% to 87%. Kendler KS. Twin studies of psychiatric illness: current status and future directions. Arch Gen Psychiatry. 1993;50:905-915; There is a 10-fold increased risk over the general population that the child of a parent affected with BPD will also be affected.

Breakpoint Cluster Gene Abnormalities Linked to Bipolar and Major Depression: The breakpoint cluster region (BCR) gene is located on chromosome 22q11, one of the most significant susceptibility loci in bipolar disorder linkage studies. The BCR gene encodes a Rho GTPase activating protein, which play important roles in neurite growth and axonal guidance. In a study of Japanese patients with bipolar disorder (n = 171), major depressive disorder (n = 329) and controls (n = 351) testing eleven single nucleotide polymorphisms (SNPs), including a missense one (A2387G; N796S), in the genomic region of BCR, allelic associations with bipolar disorder were observed for three SNPs, and associations with bipolar II disorder were observed in ten SNPs including N796S SNP (bipolar disorder, p = .0054; bipolar II disorder p = .0014). There was an association with major depression in six SNPs. S796 allele carriers were 210% more common in bipolar II patients (p = .0046). Furthermore, we found a stronger evidence for association with bipolar II disorder in a multi-marker haplotype analysis (p = .0002). The Breakpoint Cluster Region Gene on Chromosome 22q11 is Associated with Bipolar Disorder. Hashimoto R, Okada T, et al. National Center of Neurology and Psychiatry, Kodaira. Biol Psychiatry. 2005 May 15;57(10):1097-102.

Calcium Channel Receptor Polymorphism Linked: Linkage analyses of bipolar families have confirmed that there is a susceptibility locus near the telomere on chromosome 21q. In 600 bipolar research subjects and 450 ancestrally matched supernormal controls, there was a significant allelic association with the microsatellite markers D21S171 (P=0.016) and two closely linked single-nucleotide polymorphisms, rs1556314 (P=0.008) and rs1785467 (P=0.025). A test of association with a three locus haplotype across the susceptibility region was significant with a permutation test of P=0.011. A two SNP haplotype was also significantly associated with bipolar disorder (P=0.01). Only two brain expressed genes, TRPM2 and C21ORF29 (TSPEAR), are present in the associated region. TRPM2 encodes a calcium channel receptor and TSPEAR encodes a peptide with repeats associated with epilepsy in the mouse. DNA from subjects who had inherited the associated marker alleles was sequenced. A base pair change (rs1556314) in exon 11 of TRPM2, which caused a change from an aspartic acid to a glutamic acid at peptide position 543 was found. This SNP showed the strongest association with bipolar disorder (P=0.008). Deletion of exon 11 of TRPM2 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress. A second nonconservative change from arginine to cysteine at position 755 in TRPM2 (ss48297761) was also detected. A third nonconservative change from histidine to glutamic acid was found in exon 8 of TSPEAR. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. McQuillin A, et al. University College London Medical School, UK. Molecular Psychiatry 4 October 2005

Chromogranin A Polymorphism Associated with Increased Risk: The CHGA gene is reduced in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia. Single-marker and haplotype analyses of SNPs within the CHGA gene of 633 schizophrenics and 589 healthy controls found an increase of one SNP marker, rs9658635 (p=0.0269), and with a 2 marker haplotype (p=0.0016). Significant association of rs9658635 was then replicated in a second independent cohort (377 schizophrenia and 338 control samples) (p=0.007).  Association between chromogranin A gene polymorphism and schizophrenia in the Japanese population. Takahashi N, et al. Nagoya University, Japan. Schiz Res 2006 Feb 24.

Dopamine Transporter Gene Defect E602G: Rare: Prevents DAT Protein From Getting to Cell Surface: The dopamine transporter (DAT) plays a crucial role in dopaminergic neurotransmission as it clears the extracellular space of dopamine (DA) and thus controls the concentration of active neurotransmitter. Genetic association studies have reported a variable number of tandem repeat polymorphisms in the 3'-noncoding region of the DAT gene implicating this protein in the development of various psychiatric disorders. In a sample of bipolar patients, two rare missense substitutions (A559V and E602G) have been identified, one of which (E602G) was inherited by the patient from her affected father. None of these mutations had been identified in any control subjects of this survey. Using a heterologous cellular expression system, researchers analysed possible consequences of these mutations on functional properties of the encoded DAT protein. DA transport measurements and antagonist binding revealed that the A559V mutant protein is fully functional, whereas the E602G mutant is not. Further analyses by confocal microscopy showed that the E602G protein is transcribed and translated but not delivered to the cell surface. A dopamine transporter mutation associated with bipolar affective disorder causes inhibition of transporter cell surface expression. Horschitz S, et al. Mannheim, Germany. Molecular Psychiatry, 16 August 2005.

DISC1 SNPs Linked to Bipolar and Schizophrenia in Scottish Women: The Translin-associated factor X/Disrupted in Schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a t(1;11) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. In a new study of linkage disequilibrium in a representative sample of the Scottish population across the 510 kb of TRAX and DISC1, SNPs representing each haplotype block were selected for case-control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 was detected in a region of DISC1. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Thomson PA, Wray NR, et al. University of Edinburgh, UK. Molecular Psychiatry 19 April 2005

GABA Receptor-5 Polymorphisms May Influence Bipolar Risk: Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) is located. GABA is one of the major neurotransmitters. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in Japan adults. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with controls. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57). The GABA type A receptor alpha5 subunit gene is associated with bipolar I disorder. Otani K, Ujike H, et al. Okayama University, Japan. Neurosci Lett. 2005 Jun;381(1-2):108-13.

GSK3beta: Copy Number Polymorphisms Appear Important to Risk: The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of schizophrenia and bipolar candidate genes have their coding elements disrupted by polymorphic CNVs. One such gene is GSK3beta, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3beta locus at chromosome 3q13.3 appears to disrupt the gene's 3'-coding elements. The CNV also affects two other annotated genes. Researchers report that patients with BD have an increased frequency of this CNV-primarily the duplication variant-compared with controls (P = 0.002). The finding suggests that GSK3beta may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants. Increase in GSK3beta gene copy number variation in bipolar disorder. Lachman HM, et al. Albert Einstein College of Medicine, Bronx, New York. Am J Med Genetics 2007 Mar 13.

GTP Cyclohydrolase I Polymorphism Lowers Tetrahydrolase and Associated with Bipolar Disorder: Using a collection of Irish sib-pair nuclear families, researchers have found modest evidence of linkage implicating 14q22-24 in bipolar disorder (BPD). In an extended linkage analysis was performed which employed thirteen microsatellite markers, spanning a total distance of 85 cM on 14q, P-values <0.05 were observed for a region extending over 41.88 cM, with the marker D14S281 displaying a peak multipoint non-parametric lod (NPL) score of 2.72 (p= 0.003). A web-based candidate gene search of 14q22-24 resulted in the selection of GTP cyclohydrolase I (GCHI), located 200 kb 3' of D14S281, as the best plausible candidate gene for involvement in BPD. GCHI is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH(4)), a natural cofactor for tyrosine and tryptophan hydroxylases. These enzymes play an essential role in the biosynthesis of various hormones and neurotransmitters such as dopamine, noradrenaline, adrenaline, and serotonin. Numerous studies have also suggested that the clinical symptoms of depression might be related to a deficiency of BH(4). An association study between BPD and a novel single nucleotide polymorphism (SNP) in GCHI (G to A at position -959 bp, upstream of the ATG codon) was found. The variant A allele is preferentially transmitted to BPD probands (p = 0.033). Linkage and candidate gene analysis of 14q22-24 in bipolar disorder: support for GCHI as a novel susceptibility gene. Kealey C, Roche S, et al. University of Pennsylvania. Am J Med Genet B Neuropsychiatr Genet. 2005 May 20

Methylenetetrahydrofolate Reductase  Polymorphism 677C>T Doubles Bipolar and 80% Schizophrenia: In a study of the genotype and allelic frequencies of MTHFR 677C>T polymorphism in the 200 patients with bipolar disorder type I and 200 with schizophrenia and 300 control, the odds ratio for bipolar was 1.988; P=0.0003 and for schizophrenia 1.796; P=0.0020. Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Kempisty B, et al. University of Medical Sciences, Poznan, Poland. Ed: Give folic acid as a supplement 800 mcg per day.

Mitochondrial Gene Defects Appear Involved: Phosphorus magnetic resonance spectroscopic studies in bipolar disorder revealed altered brain energy metabolism resembling that of chronic progressive external ophthalmoplegia (CPEO). Mood disorder is one characteristic symptom in several families of CPEO caused by mutations of three genes, ANT1, Twinkle, and POLG. Molecular genetic analysis revealed association of bipolar disorder with mitochondrial DNA (mtDNA) 10398A polymorphism, 3644C mutation, and FDUFV2. In the postmortem brains, increased levels of mtDNA 4977bp deletion and 3243G mutation, and altered expression of mitochondria-related genes were reported. Mitochondria play an important role in neuroplasticity and apoptotic signaling via regulating intracellular calcium homeostasis. Thus, mitochondrial dysfunction may cause altered calcium homeostasis and neuroplasticity, resulting in bipolar disorder. Most molecular genetic findings in bipolar disorder regarding mitochondria and endoplasmic reticulum stress signaling are common to Parkinson's disease and diabetes mellitus. Thus, it is possible that bipolar disorder is also a disease caused by the progressive loss of some neuronal cells. Mitochondrial dysfunction in bipolar disorder. Kato T. RIKEN Brain Science Institute, Japan. . Nihon Shinkei Seishin Yakurigaku Zasshi. 2005 Apr;25(2):61-72. Similar: More genetic mitochondrial variants found. Eur J Hum Genetics 2006 Mar 15

Mitochondrial Gene Defect Associated with Some Bipolar Disease: In a study of 104 parents and children of NIMH pedigrees and of Japanese patients, polymorphisms in the promoter region of NDUFV2 are a genetic risk factor for bipolar disorder by affecting promoter activity. NDUFV2 at 18p11 encodes a subunit of the complex I, reduced nicotinamide adenine dinucleotide (NADH) ubiquinone oxidoreductase. Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees. Washizuka S, Iwamoto K, et al. Saitama, Japan. Biol Psychiatry. 2004 Oct 1;56(7):483-9

Mitochondrial DNA 3644T-->C Mutation Associated with Bipolar Disorder: A mitochondrial SNP 3644C was found in 5 of 199 patients with bipolar disorder but in none of 258 controls (p = 0.015). The association was significant in the extended samples [bipolar disorder, 9/630 (1.43%); controls, 1/734 (0.14%); p = 0.007]. Also, 5 of 25 family members with this mutation developed bipolar disorder, of which 4 had comorbid physical symptoms. The 3644T-->C mutation converts amino acid 113, valine, to alanine in the NADH-ubiquinone dehydrogenase subunit I, a subunit of complex I, and 113 valine is well conserved from Drosophila to 61 mammalian species. The abnormality decreases mitochondrial membrane potential and complex I activity. In other studies, 3644C was not found in centenarians but was found in 3% of patients with Alzheimer disease and 2% with Parkinson disease. The result of modest functional impairment caused by 3644T-->C suggests that this mutation could increase the risk for bipolar disorder. Mitochondrial DNA 3644T-->C mutation associated with bipolar disorder. Munakata K, Tanaka M, et al. RIKEN Brain Science Institute, Saitama, Japan. Genomics. 2004 Dec;84(6):1041-50.

Multiple Copies Cause Some Schizophrenia, Bipolar, Early-Onset Alzheimers, and Charcot-Marie-Tooth Disease: Literally everyone inherits genetics duplications or deletions covering entire genes with one study finding 11 in the average person.  Duplications or deletions covering less than an entire gene are even more common and as genetic tools improve, variation appears even more frequent. Charcot-Maorie-Tooth syndrome, a common hereditary disease affecting the nervous system, is entirely due to having an extra copy of one section of chromosome 17.  Genetic deletions cause the Rh negative blood types and some forms of color blindness. New Scientist 4/8/06.

Neurological Changes: Many studies have found atrophy/cell loss in mood disorders^. These show a loss of volume in the basal ganglia, frontal lobes, temporal lobes, and the amygdala/hippocampal region with volumetric increases in the lateral and third ventricles. Autopsies show a decrease in cortical thickness, number of neurons, and glial density in patients with mood disorders. 

Potassium Chloride Co-Transporter 3 Gene Variants Linked to Schizophrenia and Bipolar: R

SYNGR1 Presynaptic Vesicle Gene Appears Involved in Schizophrenia and Bipolar: Chromosome 22q11-13 is one of the most consistent linkage regions for schizophrenia (SCZ) and bipolar disorder (BPAD). The SYNGR1 gene, which is associated with presynaptic vesicles in neuronal cells, is located on 22q13.1. An earlier study identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. This case control study of 98 BPAD, 193 SCZ and 107 controls revealed a novel mutation Lsy99Glu (in one BPAD patient) and two other novel common polymorphisms [synonymous single nucleotide polymorphism (SNP-Ser97Ser) and an Asn ins/del] in the SYNGR1 gene. Researchers also validated 9 out of 14 dbSNPs. Case-control analysis revealed allelic (P=0.028-0.00007) association of five polymorphisms with SCZ and/or BPAD cases. SYNGR1 is associated with schizophrenia and bipolar disorder in southern India. Verma R, et al. Delhi University, India, . J Hum Genet. 2005 Oct 8

Wolfram Gene SNPs Increase Mood Disorders: Wolfram syndrome is an extremely rare autosomal-recessive disorder that predisposes the development of type 1 diabetes and progressive optic atrophy. The WFS1 gene encodes a transmembrane protein called wolframin, which may serve as an endoplasmic reticulum calcium channel in pancreatic beta-cells and neurons. Researchers found a 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers. In another study of 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects, five SNPs were associated with major depressive disorder, and three SNPs with bipolar disorder. The GTA haplotype, formed by SNPs 684CG, 1185CT and 1832GA, confers a risk for major depression with an OR of 1.59 (p=0.01) and for bipolar disorder an OR of 1.89 (p=0.03). Polymorphisms in the wolframin (WFS1) gene are possibly related to increased risk for mood disorders. Koido K, Kks S, et al. University of Tartu, Estonia. Int J Neuropsychopharmacol. 2004 Oct 11:1-10. Ed: This is a minor, but apparently real increase. It shows the extreme complexity and diversity of human genetics.

Thomas E. Radecki, M.D., J.D.

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