G2Cdb::Human Disease report

Disease id
D00000170
Name
Bipolar disorder
Nervous system disease
yes

Genes (8)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001807 MBP
myelin basic protein
Y (8723042) Translocation (T) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (12610658) Single nucleotide polymorphism (SNP) Y
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (16969270) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (16969270) Microsatellite polymorphism (MSP) N
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (15118355) Repeat polymorphism (RP) N
G00001821 SHANK2
SH3 and multiple ankyrin repeat domains 2
N (12895207) Repeat polymorphism (RP) N
G00002208 AKAP5
A kinase (PRKA) anchor protein 5
Y (16434481) Copy Number Polymorphism (CNP) Y
G00001420 GSK3B
glycogen synthase kinase 3 beta
Y (16289783) Polymorphism (P) N
G00001420 GSK3B
glycogen synthase kinase 3 beta
Y (16528748) Single nucleotide polymorphism (SNP) N
G00001420 GSK3B
glycogen synthase kinase 3 beta
Y (17357145) Copy Number Polymorphism (CNP) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (14681919) Single nucleotide polymorphism (SNP) N
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (16549338) Polymorphism (P) Y
G00001324 ATP1A1
ATPase, Na+/K+ transporting, alpha 1 polypeptide
Y (9646882) Dinucleotide polymorphism (DNP) Y

References

  • Increase in GSK3beta gene copy number variation in bipolar disorder.

    Lachman HM, Pedrosa E, Petruolo OA, Cockerham M, Papolos A, Novak T, Papolos DF and Stopkova P

    Department of Psychiatry and Behavioral Sciences, Division of Basic Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA. Lachman@aecom.yu.edu

    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. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. 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. We now 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.

    Funded by: Intramural NIH HHS; NHGRI NIH HHS: P50-HG00098, R01-HG00257; NIMH NIH HHS: R01MH073164, U01 MH46274, U01 MH46280, U01 MH46282

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;3;259-65

  • No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample.

    Georgi A, Jamra RA, Schumacher J, Becker T, Schmael C, Deschner M, Höfels S, Wulff M, Schwarz M, Klopp N, Illig T, Propping P, Cichon S, Nöthen MM, Rietschel M and Schulze TG

    Central Institute of Mental Health, Mannheim, Germany.

    Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.

    Psychiatric genetics 2006;16;5;183-4

  • N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels.

    Martucci L, Wong AH, De Luca V, Likhodi O, Wong GW, King N and Kennedy JL

    Neurogenetics Section, CAMH, Clarke Division, University of Toronto, R-31, 250 College Street, Toronto (ON), Canada M5T 1R8.

    The NR2B protein is a critical structural and functional subunit of the NMDA glutamate receptor. The glutamate neurotransmitter system has been implicated in psychosis and schizophrenia, and so we looked for genetic association and measured gene expression in human DNA and brain samples, respectively, of the GRIN2B gene that codes for the NR2B protein. We tested three genetic polymorphisms: G-200T (5'UTR), A5806C and T5988C (both 3'UTR) in 180 matched schizophrenia case-control pairs, 86 schizophrenia nuclear family trios, and 318 bipolar disorder trios (of which 158 probands had psychotic symptoms). We measured brain GRIN2B mRNA levels in schizophrenia, bipolar disorder and unaffected controls (n = 35 each). We detected genetic association between the G-200T marker and schizophrenia (p = 0.002), between T5988C and bipolar disorder (p = 0.02), and between A5806C and bipolar disorder with psychotic symptoms (p = 0.0038). The T-C-C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G-C-T haplotype was transmitted more often in schizophrenia. Significant differences were found in overall haplotype frequencies between schizophrenia cases and controls (p = 0.005). GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.

    Schizophrenia research 2006;84;2-3;214-21

  • Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

    Nievergelt CM, Kripke DF, Barrett TB, Burg E, Remick RA, Sadovnick AD, McElroy SL, Keck PE, Schork NJ and Kelsoe JR

    Department of Psychiatry, University of California, San Diego, La Jolla, California 92093-0603, USA.

    Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

    Funded by: Intramural NIH HHS; NCRR NIH HHS: M01 RR000827, M01 RR00827; NHLBI NIH HHS: HL054998-09, HL064777-06, HL069758-03, HL070137-01A1, HL071123, HL074730-02, HL61280, P50 HL054998, R01 HL070137, R01 HL071123, R01 HL074730, R56 HL071123, R56 HL071123-04, U01 HL064777, U01 HL069758; NIA NIH HHS: AG023122-01, AG12364, AG15763, R01 AG012364, R01 AG015763, U19 AG023122; NIDA NIH HHS: DA13769; NIMH NIH HHS: K08 MH067959, MH059567-05A2, MH067959, MH068503-01A1, MH47612, MH59567, MH68503, R01 MH059567, R01 MH068503, U01 MH46274, UO1 MH46280, UO1 MH46282; PHS HHS: HLMH065571-02

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2006;141B;3;234-41

  • DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling.

    Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG and Holt RA

    Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Suite 100, 570 West 7th Avenue, Vancouver, BC, Canada V5Z 4S6.

    Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 Mbp resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders.

    Human molecular genetics 2006;15;5;743-9

  • Association analysis of the glycogen synthase kinase-3beta gene in bipolar disorder.

    Nishiguchi N, Breen G, Russ C, St Clair D and Collier D

    Department of Psychological Medicine and Social, Genetic and Developmental Psychiatry Research Centre, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.

    Glycogen synthase kinase-3beta (GSK3beta) is a target of lithium as well as sodium valproate, both of which are effective mood stabilizing prophylatics/treatments for bipolar disorder, a highly heritable psychiatric disorder. Though it is not clear whether the mood stabilizing effects of these drugs act directly through GSK3beta, it is a good candidate for mediating at least part of lithium's action, and is an aetiological candidate gene for the disease itself. Recently, a potential locus for bipolar disorder was reported on chromosome 3q, close to 3q13.37 where GSK3beta maps. We conducted an association study to test the hypothesis that polymorphism of GSK3beta is involved in susceptibility to bipolar disorder by examining association between GSK3beta-gene polymorphisms and bipolar disorder. Of the five polymorphisms we examined, three were very rare in the study population and were not examined further. Neither of the remaining two polymorphisms we examined showed association with bipolar disorder. Thus, it is unlikely that the GSK3beta-gene is a risk factor for bipolar disorder in our sample, but we cannot exclude the gene completely as other unknown polymorphisms in the gene may increase susceptibility.

    Funded by: Medical Research Council: G90/106

    Neuroscience letters 2006;394;3;243-5

  • No association between a neuronal nitric oxide synthase (NOS1) gene polymorphism on chromosome 12q24 and bipolar disorder.

    Buttenschön HN, Mors O, Ewald H, McQuillin A, Kalsi G, Lawrence J, Gurling H and Kruse TA

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;124B;1;73-5

  • BanI polymorphism of the cytosolic phospholipase A2 gene and mood disorders in the Korean population.

    Pae CU, Yu HS, Kim JJ, Lee CU, Lee SJ, Lee KU, Jun TY, Paik IH, Serretti A and Lee C

    Department of Psychiatry, Kangnam St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea.

    Membrane phospholipid abnormalities have been proposed to be involved in the pathogenesis of mood disorders, and in signal transduction and neurotransmitter uptake. Cytosolic phospholipase A2 (cPLA2) is not only an essential enzyme in the metabolism of fatty acids but also in signaling process. Therefore, we examined the association between the BanI polymorphism of the cPLA2 gene and mood disorders. Sixty-two patients with major depressive disorder (MDD), 50 patients with bipolar I disorder (BID) and 117 healthy controls participated in this study. Genotyping was performed by using PCR-based methods. Genotype and allele distributions in MDD patients were significantly different from those of the controls. In particular, the A2 allele was associated with increased risk of MDD development (p = 0.007, odds ratio = 1.827; confidence interval = 1.141-2.927). However, the polymorphism was not different between BID patients and controls in genotype and allele distribution. This preliminary study indicates the need for further studies on the potential role of the cPLA2 gene polymorphism in the susceptibility to mood disorders.

    Neuropsychobiology 2004;49;4;185-8

  • Allelic association study between phospholipase A2 genes and bipolar affective disorder.

    Meira-Lima I, Jardim D, Junqueira R, Ikenaga E and Vallada H

    Laboratory of Neuroscience, Institute of Psychiatry, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil.

    Objectives: In vivo studies demonstrating that lithium is a powerful phospholipase A2 (PLA2) inhibitor suggest that PLA2 activation, and subsequent cell signaling overactivation by increased fatty acid release may be the primary abnormality in bipolar affective disorder (BPAD), thus making PLA2 genes attractive candidates for the susceptibility to BPAD. The present study investigates polymorphisms in cytosolic phospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2), and secretory phospholipase (sPLA2) genes in a Brazilian sample.

    Methods: A cross-sectional study was performed with 181 unrelated DSM-IIIR BPAD subjects and 312 controls. A polymerase chain reaction-restriction fragment length polymorphism assay for BanI cPLA2 and AvrII iPLA2 polymorphisms was performed, and an ATT repeat in sPLA2 was assessed using a semiautomated genetic analyzer (ALFexpress).

    Results: There was no significant difference observed in the allelic and genotypic distribution between the BPAD and control groups for cPLA2 (genotype: chi2 = 0.8, 2df, p = 0.6; allele chi2 = 0, 1df, p = 0.9), iPLA2 (genotype: chi2 = 1.7, 2df, p = 0.4; allele: chi2 = 0.3, 1df, p = 0.6), and sPLA2 (allele: chi2 = 3.6, 6df, p = 0.8).

    Conclusion: Our results failed to demonstrate that the studied PLA2 polymorphisms were associated with an increased risk for BPAD in our sample.

    Bipolar disorders 2003;5;4;295-9

  • Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.

    Mundo E, Tharmalingham S, Neves-Pereira M, Dalton EJ, Macciardi F, Parikh SV, Bolonna A, Kerwin RW, Arranz MJ, Makoff AJ and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), Department of Psychiatry, University of Toronto, Clarke Site R-31, Toronto, Ontario, Canada M5T 1R8.

    There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

    Molecular psychiatry 2003;8;2;241-5

  • Evidence for an allelic association between bipolar disorder and a Na+, K+ adenosine triphosphatase alpha subunit gene (ATP1A3).

    Mynett-Johnson L, Murphy V, McCormack J, Shields DC, Claffey E, Manley P and McKeon P

    Department of Genetics, Trinity College Dublin, Ireland.

    Background: Disturbances in central nervous system Na+, K+ adenosine triphosphatase (ATPase) activity have previously been proposed as being involved in the pathophysiology of bipolar mood disorder.

    Methods: We have examined one particular alpha subunit of this enzyme for allelic association in a sample of 85 Irish bipolar patients and 85 matched controls.

    Results: There was evidence for an overall allelic association between the disease and a dinucleotide polymorphism within the ATP1A3 gene (p = .022). Subjects were then analyzed on the basis of a number of criteria, and the significance of the association increased when cases were divided based on the nature of the first episode. Patients who presented with a depressive episode first showed a significant association (p = .001) with this polymorphism.

    Conclusions: The results presented here provide preliminary evidence of an association between bipolar disorder and an alpha subunit of Na+, K+ ATPase, the expression of which predominates in the brain.

    Funded by: Wellcome Trust

    Biological psychiatry 1998;44;1;47-51

  • Psychiatric disorder in a familial 15;18 translocation and sublocalization of myelin basic protein of 18q22.3.

    Calzolari E, Aiello V, Palazzi P, Sensi A, Calzolari S, Orrico D, Calliari L, Holler H, Marzi C, Belli S, Bernardi F and Patracchini P

    Istituto di Genetica Medica, Universitá Ferrara, Universitá Ferrara, Italy.

    Two related patients with similar clinical features consisting of a few dysmorphic signs and psychiatric disturbance were reported to have a partial trisomy of chromosomes 15(pter-q13.3) and 18(q23-qter) deriving from a familial translocation t(15;18). One patient is affected by bipolar disorder and the other by schizoaffective disorder. Both cases have a predominantly affective course; nevertheless, a clear diagnosis is difficult in the first patient, who is 15 years of age, and only a longitudinal course will allow us to establish a definite diagnosis. The possibility that these two pathologies belong to a single category is discussed, and the presence of a susceptibility locus on chromosome 18 is hypothesized. Cytogenetic data, FISH, and DNA studies indicate that the myelin basic protein (MPB) gene is not involved in the translocation, and localize it centromeric to the breakpoint on chromosome 18(q22.3). Thus, it is unlikely to be involved in the disease.

    American journal of medical genetics 1996;67;2;154-61

Literature (12)

Pubmed - human_disease

  • Increase in GSK3beta gene copy number variation in bipolar disorder.

    Lachman HM, Pedrosa E, Petruolo OA, Cockerham M, Papolos A, Novak T, Papolos DF and Stopkova P

    Department of Psychiatry and Behavioral Sciences, Division of Basic Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA. Lachman@aecom.yu.edu

    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. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. 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. We now 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.

    Funded by: Intramural NIH HHS; NHGRI NIH HHS: P50-HG00098, R01-HG00257; NIMH NIH HHS: R01MH073164, U01 MH46274, U01 MH46280, U01 MH46282

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2007;144B;3;259-65

  • No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample.

    Georgi A, Jamra RA, Schumacher J, Becker T, Schmael C, Deschner M, Höfels S, Wulff M, Schwarz M, Klopp N, Illig T, Propping P, Cichon S, Nöthen MM, Rietschel M and Schulze TG

    Central Institute of Mental Health, Mannheim, Germany.

    Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.

    Psychiatric genetics 2006;16;5;183-4

  • Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

    Nievergelt CM, Kripke DF, Barrett TB, Burg E, Remick RA, Sadovnick AD, McElroy SL, Keck PE, Schork NJ and Kelsoe JR

    Department of Psychiatry, University of California, San Diego, La Jolla, California 92093-0603, USA.

    Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1epsilon, DBP, GSK3beta, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1epsilon. This finding was not substantiated in the association study. Fifty-two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single-gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni-corrected P-value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

    Funded by: Intramural NIH HHS; NCRR NIH HHS: M01 RR000827, M01 RR00827; NHLBI NIH HHS: HL054998-09, HL064777-06, HL069758-03, HL070137-01A1, HL071123, HL074730-02, HL61280, P50 HL054998, R01 HL070137, R01 HL071123, R01 HL074730, R56 HL071123, R56 HL071123-04, U01 HL064777, U01 HL069758; NIA NIH HHS: AG023122-01, AG12364, AG15763, R01 AG012364, R01 AG015763, U19 AG023122; NIDA NIH HHS: DA13769; NIMH NIH HHS: K08 MH067959, MH059567-05A2, MH067959, MH068503-01A1, MH47612, MH59567, MH68503, R01 MH059567, R01 MH068503, U01 MH46274, UO1 MH46280, UO1 MH46282; PHS HHS: HLMH065571-02

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2006;141B;3;234-41

  • DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling.

    Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG and Holt RA

    Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Suite 100, 570 West 7th Avenue, Vancouver, BC, Canada V5Z 4S6.

    Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 Mbp resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders.

    Human molecular genetics 2006;15;5;743-9

  • Association analysis of the glycogen synthase kinase-3beta gene in bipolar disorder.

    Nishiguchi N, Breen G, Russ C, St Clair D and Collier D

    Department of Psychological Medicine and Social, Genetic and Developmental Psychiatry Research Centre, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.

    Glycogen synthase kinase-3beta (GSK3beta) is a target of lithium as well as sodium valproate, both of which are effective mood stabilizing prophylatics/treatments for bipolar disorder, a highly heritable psychiatric disorder. Though it is not clear whether the mood stabilizing effects of these drugs act directly through GSK3beta, it is a good candidate for mediating at least part of lithium's action, and is an aetiological candidate gene for the disease itself. Recently, a potential locus for bipolar disorder was reported on chromosome 3q, close to 3q13.37 where GSK3beta maps. We conducted an association study to test the hypothesis that polymorphism of GSK3beta is involved in susceptibility to bipolar disorder by examining association between GSK3beta-gene polymorphisms and bipolar disorder. Of the five polymorphisms we examined, three were very rare in the study population and were not examined further. Neither of the remaining two polymorphisms we examined showed association with bipolar disorder. Thus, it is unlikely that the GSK3beta-gene is a risk factor for bipolar disorder in our sample, but we cannot exclude the gene completely as other unknown polymorphisms in the gene may increase susceptibility.

    Funded by: Medical Research Council: G90/106

    Neuroscience letters 2006;394;3;243-5

  • No association between a neuronal nitric oxide synthase (NOS1) gene polymorphism on chromosome 12q24 and bipolar disorder.

    Buttenschön HN, Mors O, Ewald H, McQuillin A, Kalsi G, Lawrence J, Gurling H and Kruse TA

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;124B;1;73-5

  • BanI polymorphism of the cytosolic phospholipase A2 gene and mood disorders in the Korean population.

    Pae CU, Yu HS, Kim JJ, Lee CU, Lee SJ, Lee KU, Jun TY, Paik IH, Serretti A and Lee C

    Department of Psychiatry, Kangnam St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea.

    Membrane phospholipid abnormalities have been proposed to be involved in the pathogenesis of mood disorders, and in signal transduction and neurotransmitter uptake. Cytosolic phospholipase A2 (cPLA2) is not only an essential enzyme in the metabolism of fatty acids but also in signaling process. Therefore, we examined the association between the BanI polymorphism of the cPLA2 gene and mood disorders. Sixty-two patients with major depressive disorder (MDD), 50 patients with bipolar I disorder (BID) and 117 healthy controls participated in this study. Genotyping was performed by using PCR-based methods. Genotype and allele distributions in MDD patients were significantly different from those of the controls. In particular, the A2 allele was associated with increased risk of MDD development (p = 0.007, odds ratio = 1.827; confidence interval = 1.141-2.927). However, the polymorphism was not different between BID patients and controls in genotype and allele distribution. This preliminary study indicates the need for further studies on the potential role of the cPLA2 gene polymorphism in the susceptibility to mood disorders.

    Neuropsychobiology 2004;49;4;185-8

  • Allelic association study between phospholipase A2 genes and bipolar affective disorder.

    Meira-Lima I, Jardim D, Junqueira R, Ikenaga E and Vallada H

    Laboratory of Neuroscience, Institute of Psychiatry, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil.

    Objectives: In vivo studies demonstrating that lithium is a powerful phospholipase A2 (PLA2) inhibitor suggest that PLA2 activation, and subsequent cell signaling overactivation by increased fatty acid release may be the primary abnormality in bipolar affective disorder (BPAD), thus making PLA2 genes attractive candidates for the susceptibility to BPAD. The present study investigates polymorphisms in cytosolic phospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2), and secretory phospholipase (sPLA2) genes in a Brazilian sample.

    Methods: A cross-sectional study was performed with 181 unrelated DSM-IIIR BPAD subjects and 312 controls. A polymerase chain reaction-restriction fragment length polymorphism assay for BanI cPLA2 and AvrII iPLA2 polymorphisms was performed, and an ATT repeat in sPLA2 was assessed using a semiautomated genetic analyzer (ALFexpress).

    Results: There was no significant difference observed in the allelic and genotypic distribution between the BPAD and control groups for cPLA2 (genotype: chi2 = 0.8, 2df, p = 0.6; allele chi2 = 0, 1df, p = 0.9), iPLA2 (genotype: chi2 = 1.7, 2df, p = 0.4; allele: chi2 = 0.3, 1df, p = 0.6), and sPLA2 (allele: chi2 = 3.6, 6df, p = 0.8).

    Conclusion: Our results failed to demonstrate that the studied PLA2 polymorphisms were associated with an increased risk for BPAD in our sample.

    Bipolar disorders 2003;5;4;295-9

  • Evidence for an allelic association between bipolar disorder and a Na+, K+ adenosine triphosphatase alpha subunit gene (ATP1A3).

    Mynett-Johnson L, Murphy V, McCormack J, Shields DC, Claffey E, Manley P and McKeon P

    Department of Genetics, Trinity College Dublin, Ireland.

    Background: Disturbances in central nervous system Na+, K+ adenosine triphosphatase (ATPase) activity have previously been proposed as being involved in the pathophysiology of bipolar mood disorder.

    Methods: We have examined one particular alpha subunit of this enzyme for allelic association in a sample of 85 Irish bipolar patients and 85 matched controls.

    Results: There was evidence for an overall allelic association between the disease and a dinucleotide polymorphism within the ATP1A3 gene (p = .022). Subjects were then analyzed on the basis of a number of criteria, and the significance of the association increased when cases were divided based on the nature of the first episode. Patients who presented with a depressive episode first showed a significant association (p = .001) with this polymorphism.

    Conclusions: The results presented here provide preliminary evidence of an association between bipolar disorder and an alpha subunit of Na+, K+ ATPase, the expression of which predominates in the brain.

    Funded by: Wellcome Trust

    Biological psychiatry 1998;44;1;47-51

  • Psychiatric disorder in a familial 15;18 translocation and sublocalization of myelin basic protein of 18q22.3.

    Calzolari E, Aiello V, Palazzi P, Sensi A, Calzolari S, Orrico D, Calliari L, Holler H, Marzi C, Belli S, Bernardi F and Patracchini P

    Istituto di Genetica Medica, Universitá Ferrara, Universitá Ferrara, Italy.

    Two related patients with similar clinical features consisting of a few dysmorphic signs and psychiatric disturbance were reported to have a partial trisomy of chromosomes 15(pter-q13.3) and 18(q23-qter) deriving from a familial translocation t(15;18). One patient is affected by bipolar disorder and the other by schizoaffective disorder. Both cases have a predominantly affective course; nevertheless, a clear diagnosis is difficult in the first patient, who is 15 years of age, and only a longitudinal course will allow us to establish a definite diagnosis. The possibility that these two pathologies belong to a single category is discussed, and the presence of a susceptibility locus on chromosome 18 is hypothesized. Cytogenetic data, FISH, and DNA studies indicate that the myelin basic protein (MPB) gene is not involved in the translocation, and localize it centromeric to the breakpoint on chromosome 18(q22.3). Thus, it is unlikely to be involved in the disease.

    American journal of medical genetics 1996;67;2;154-61

Pubmed - other

  • N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels.

    Martucci L, Wong AH, De Luca V, Likhodi O, Wong GW, King N and Kennedy JL

    Neurogenetics Section, CAMH, Clarke Division, University of Toronto, R-31, 250 College Street, Toronto (ON), Canada M5T 1R8.

    The NR2B protein is a critical structural and functional subunit of the NMDA glutamate receptor. The glutamate neurotransmitter system has been implicated in psychosis and schizophrenia, and so we looked for genetic association and measured gene expression in human DNA and brain samples, respectively, of the GRIN2B gene that codes for the NR2B protein. We tested three genetic polymorphisms: G-200T (5'UTR), A5806C and T5988C (both 3'UTR) in 180 matched schizophrenia case-control pairs, 86 schizophrenia nuclear family trios, and 318 bipolar disorder trios (of which 158 probands had psychotic symptoms). We measured brain GRIN2B mRNA levels in schizophrenia, bipolar disorder and unaffected controls (n = 35 each). We detected genetic association between the G-200T marker and schizophrenia (p = 0.002), between T5988C and bipolar disorder (p = 0.02), and between A5806C and bipolar disorder with psychotic symptoms (p = 0.0038). The T-C-C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G-C-T haplotype was transmitted more often in schizophrenia. Significant differences were found in overall haplotype frequencies between schizophrenia cases and controls (p = 0.005). GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.

    Schizophrenia research 2006;84;2-3;214-21

  • Evidence that the N-methyl-D-aspartate subunit 1 receptor gene (GRIN1) confers susceptibility to bipolar disorder.

    Mundo E, Tharmalingham S, Neves-Pereira M, Dalton EJ, Macciardi F, Parikh SV, Bolonna A, Kerwin RW, Arranz MJ, Makoff AJ and Kennedy JL

    Neurogenetics Section, Centre for Addiction and Mental Health (CAMH), Department of Psychiatry, University of Toronto, Clarke Site R-31, Toronto, Ontario, Canada M5T 1R8.

    There is evidence for the involvement of glutamatergic transmission in the pathogenesis of major psychoses. The two most commonly used mood stabilizers (ie lithium and valproate) have been found to act via the N-methyl-D-aspartate receptor (NMDAR), suggesting a specific role of NMDAR in the pathogenesis of bipolar disorder (BP). The key subunit of the NMDAR, named NMDA-1 receptor, is coded by a gene located on chromosome 9q34.3 (GRIN1). We tested for the presence of linkage disequilibrium between the GRIN1 (1001-G/C, 1970-A/G, and 6608-G/C polymorphisms) and BP. A total of 288 DSM-IV Bipolar I, Bipolar II, or schizoaffective disorder, manic type, probands with their living parents were studied. In all, 73 triads had heterozygous parents for the 1001-G/C polymorphism, 174 for the 1970-A/G, and 48 for the 6608-G/C. These triads were suitable for the final analyses, that is, the transmission disequilibrium test (TDT) and the haplotype-TDT. For the 1001-G/C and the 6608-G/C polymorphisms, we found a preferential transmission of the G allele to the affected individuals (chi(2)=4.765, df=1, P=0.030 and chi(2)= 8.395, df=1, P=0.004, respectively). The 1001G-1970A-6608A and the 1001G-1970A-6608G haplotypes showed the strongest association with BP (global chi(2)=14.12, df=4, P=0.007). If these results are replicated there could be important implications for the involvement of the GRIN1 in the pathogenesis of BP. The role of the gene variants in predicting the response to mood stabilizers in BP should also be investigated.

    Molecular psychiatry 2003;8;2;241-5

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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