Linkage Studies Of Bipolar Disorder Research Articles

Association analysis between polymorphisms in the myo-inositol monophosphatase 2 ( IMPA2) gene and bipolar disorder

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The myo-inositol monophosphatase 2 gene ( IMPA2) maps to this genomic region. Myo-inositol monophosphatase dephosphorylates inositol monophosphate, regenerating free inositol. Lithium, a common treatment for BPD, has been shown to inhibit IMPA2 activity and decrease levels of inositol. It is hypothesized that lithium conveys its therapeutic effect for BPD patients partially through inositol regulation. Hence, dysfunction of inositol caused by IMPA2 irregularity may contribute to the pathophysiology of BPD. In this study, we hypothesize that genetic variations in the IMPA2 gene contributes to increased susceptibility to BPD. We tested this hypothesis by genotyping 9 SNPs (rs1787984; rs585247; rs3974759; rs650727; rs589247; rs669838; rs636173; rs3786285; rs613993) in BPD patients ( n = 556) and controls ( n = 735). Genotype and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed several associations between IMPA2 variations and BPD, which were subsequently rendered non-significant after correction for multiple testing. Although our study did not show strong support for an association between the tested IMPA2 polymorphisms and susceptibility to BPD, additional larger studies are necessary to comprehensively investigate a role of the IMPA2 gene in the pathophysiology of BPD.

Comorbid Bipolar Disorder and Usher Syndrome

To the Editor: Co-occurrence of psychiatric disorder and rare syndromes with known gene loci can facilitate critical pathophysiologic insights and might have important therapeutic implications as well.1 Usher syndrome is the most common type of deaf-blindness. It is a group of genetically distinct disorders phenotypically associated with dual sensory impairments as a result of congenital sensorineural hearing loss and progressive visual impairment from retinitis pigmentosa. Rarely, Usher syndrome may be associated with mental subnormality and infertility. Twenty-three percent of these patients have a psychiatric illness, mainly schizophrenia.1,2 Pathogenic Usher protein complex is a group of proteins that are neurosensory receptors at the outer hair cells of the inner ear and the retinal photoreceptor cells and are encoded by different genes present on the chromosomes 1, 8, and 14.3,4 Mutation of any one of the multiple genes in these chromosomes leads to the symptom complex of Usher syndrome. Although co-occurrence of psychosis with Usher syndrome has been reported,5–7 co-occurrence of bipolar disorder has not been reported. For the first time, we report a patient with bipolar disorder and Usher syndrome and the treatment implications. Case report. Mr A, a 25-year-old man, presented to our hospital in December 2007 with a history of elated mood, overactivity, overtalkativeness, overfamiliarity, delusions of grandiosity, decreased need for sleep, and decreased appetite for the past 3 months. In the past, Mr A had experienced 2 episodes of mania that responded to treatment with haloperidol, with complete remission of symptoms. He also had a history of congenital hearing impairment and night blindness. There was a family history suggestive of congenital deafness and night blindness in a first-degree relative. Results of investigations, namely, hemogram, liver function tests, kidney function tests, and serum electrolytes, were normal. Magnetic resonance imaging did not reveal structural abnormalities. He was evaluated using the Mini International Neuropsychiatric Inventory8 and diagnosed as having bipolar affective disorder with psychotic symptoms (ICD-10). He had a score of 16 on the Young Mania Rating Scale (YMRS).9 Audiometry showed sensorineural hearing loss for 4–8 kHz, and ophthalmic examination revealed retinitis pigmentosa, suggestive of Usher syndrome. Mr A was started on treatment with lithium 600 mg/d for management of bipolar disorder. Subsequently, he developed hyperpigmented papular and pustular lesions involving the skin and buccal mucosa. Dermatologic opinion was sought, resulting in a diagnosis of pemphigus vulgaris, and treatment with prednisolone 30 mg/d was advised. In view of this, lithium treatment was stopped and treatment with risperidone 4 mg/d and valproate 1000 mg/d was started. He improved with this medication and at the end of 2 weeks had a score of 4 on the YMRS. Mr A had no new skin lesion, and he maintained euthymia at the end of 1 year. To the best of our knowledge, this is the first report of the co-occurrence of Usher syndrome and bipolar disorder. Our patient had high-frequency sensory neural hearing loss and atypical retinitis pigmentosa suggestive of Usher syndrome. He developed significant side effects when lithium treatment was started. One should be cautious of dermatologic side effects when starting lithium treatment in patients with comorbid Usher syndrome. This report exemplifies the need for systematic assessment of patients with bipolar disorder in liaison with other specialties for comorbid conditions whenever indicated. Interestingly, chromosomes 8 and 14 are also implicated in linkage studies of bipolar disorder.10 Further molecular biologic studies of such patients with comorbid bipolar disorder might facilitate better understanding of the pathogenesis of bipolar disorder.

Association between polymorphisms in the metallophosphoesterase (MPPE1) gene and bipolar disorder

Genetic linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The metallophosphoesterase (MPPE1) gene maps to this region. Dysregulation of protein phosphorylation and subsequent abnormal cellular signaling has been postulated to be involved in neuropsychiatric disorders thus making MPPE1 a plausible biological candidate gene for BPD. In this study, we hypothesized that genetic variation in the MPPE1 gene contributes to BPD. We tested this hypothesis by genotyping four SNPs (rs871044; rs3974590; rs593713; rs602201) in BPD patients (n = 570) and healthy controls (n = 725). Genotypes and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs3974590 with BPD (P = 0.009; permutation corrected P = 0.046). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide evidence of an association between a polymorphism in the MPPE1 gene and BPD. Additional studies are necessary to confirm and elucidate the role of MPPE1 as a susceptibility gene for BPD on chromosome 18p.

A genome-wide linkage study of bipolar disorder and co-morbid migraine: Replication of migraine linkage on chromosome 4q24, and suggestion of an overlapping susceptibility region for both disorders on chromosome 20p11

Migraine and Bipolar Disorder (BPAD) are clinically heterogeneous disorders of the brain with a significant, but complex, genetic component. Epidemiological and clinical studies have demonstrated a high degree of co-morbidity between migraine and BPAD. Several genome-wide linkage studies in BPAD and migraine have shown overlapping regions of linkage on chromosomes, and two functionally similar voltage-dependent calcium channels CACNA1A and CACNA1C have been identified in familial hemiplegic migraine and recently implicated in two whole genome BPAD association studies, respectively. We hypothesized that using migraine co-morbidity to look at subsets of BPAD families in a genetic linkage analysis would prove useful in identifying genetic susceptibility regions in both of these disorders. We used BPAD with co-morbid migraine as an alternative phenotype definition in a re-analysis of the NIMH Bipolar Genetics Initiative wave 4 data set. In this analysis we selected only those families in which at least two members were diagnosed with migraine by a doctor according to patients' reports. Nonparametric linkage analysis performed on 31 families segregating both BPAD and migraine identified a linkage signal on chromosome 4q24 for migraine (but not BPAD) with a peak LOD of 2.26. This region has previously been implicated in two independent migraine linkage studies. In addition we identified a locus on chromosome 20p11 with overlapping elevated LOD scores for both migraine (LOD = 1.95) and BPAD (LOD = 1.67) phenotypes. This region has previously been implicated in two BPAD linkage studies, and, interestingly, it harbors a known potassium dependant sodium/calcium exchanger gene, SLC24A3, that plays a critical role in neuronal calcium homeostasis. Our findings replicate a previously identified migraine linkage locus on chromosome 4 (not co-segregating with BPAD) in a sample of BPAD families with co-morbid migraine, and suggest a susceptibility locus on chromosome 20, harboring a gene for the migraine/BPAD phenotype. Together these data suggest that some genes may predispose to both bipolar disorder and migraine.

Association between polymorphisms in the vesicle-associated membrane protein-associated protein A (VAPA) gene on chromosome 18p and bipolar disorder

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The vesicle-associated membrane protein-associated protein A (VAPA) gene maps to this region. VAPA interacts with presynaptic proteins and is necessary for vesicular neurotransmission. Dysregulation of synaptic neurotransmission might contribute to the pathophysiology of BPD. In this study, we hypothesize that genetic variations in the VAPA gene contribute to BPD. We tested this hypothesis by genotyping 6 SNPs (rs494015; rs29193; rs29162; rs29145; rs29067; rs29066) in BPD patients (n = 570) and healthy controls (n = 730). Genotype and allele frequencies were compared between groups using Chi square contingency analysis. Linkage disequilibrium (LD) between markers was calculated and estimated haplotype frequencies were compared between groups. Single marker analysis revealed an association of rs29067 and rs29066 with BPD; however, after permutation correction, only rs29066 showed a trend towards an allelic association (P = 0.066). Haplotype analysis did not show any significant association with disease after permutation correction. Our results provide suggestive evidence of an association between SNPs in the 3'UTR of the VAPA gene and BPD. Interestingly, these SNPs are in close proximity to the microsatellite marker D18S464, which showed significant signals in previous linkage studies of BPD. Additional studies are necessary to confirm and elucidate the role of VAPA as a susceptibility gene for BPD on chromosome 18p.

Association analysis of the pituitary adenylate cyclase-activating polypeptide (PACAP/ADCYAP1) gene in bipolar disorder

Linkage studies in bipolar disorder (BPD) suggest that a susceptibility locus exists on chromosome 18p11. The pituitary adenylate cyclase-activating polypeptide/adenylate cyclase-activating polypeptide 1 (pituitary) (PACAP/ADCYAP1) gene maps to this region. PACAP is a neuropeptide involved in neurotransmission in both the peripheral nervous system and central nervous system and is required for catecholamine secretion. Animal models of PACAP mutations show remarkable behavioral defects, including hyperactivity and increased exploratory behavior. In this study we tested the hypothesis that genetic variations in the human PACAP gene contribute to BPD. Genotyping of seven single nucleotide polymorphisms (rs1893154; rs2846811; rs8192595; rs2856966; rs928978; rs2231187; rs1610037) was performed in BPD patients (n=570) and healthy controls (n=710). Genotypes and allele frequencies were compared between groups using chi contingency analysis. Linkage disequilibrium between markers was calculated and estimated haplotype frequencies were compared between groups. There were no significant differences between groups on the allele, genotype or haplotype level for any of the tested single nucleotide polymorphisms. Our results provide no evidence of an association of the PACAP gene with BPD in this group of patients and controls. Additional studies are necessary to elucidate the BPD susceptibility locus on chromosome 18p.

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

Three linkage studies of bipolar disorder have implicated chromosome 12q24.3 with lod scores of over 3.0 and several other linkage studies have found lods between 2 and 3. Fine mapping within the original chromosomal linkage regions has identified several loci that show association with bipolar disorder. One of these is the P2RX7 gene encoding a central nervous system-expressed purinergic receptor. A non-synonymous single nucleotide polymorphism, rs2230912 (P2RX7-E13A, G allele) and a microsatellite marker NBG6 were both previously found to be associated with bipolar disorder (P=0.00071 and 0.008, respectively). rs2230912 has also been found to show association with unipolar depression. The effect of the polymorphism is non-conservative and results in a glutamine to arginine change (Gln460Arg), which is likely to affect P2RX7 dimerization and protein-protein interactions. We have confirmed the allelic associations between bipolar disorder and the markers rs2230912 (P2RX7-E13A, G allele, P=0.043) and NBG6 (P=0.010) in a London-based sample of 604 bipolar cases and 560 controls. When we combined these data with the published case-control studies of P2RX7 and mood disorder (3586 individuals) the association between rs2230912 (Gln460Arg) and affective disorders became more robust (P=0.002). The increase in Gln460Arg was confined to heterozygotes rather than homozygotes suggesting a dominant effect (odds ratio 1.302, CI=1.129-1.503). Although further research is needed to prove that the Gln460Arg change has an aetiological role, it is so far the most convincing mutation to have been found with a role for increasing susceptibility to bipolar and genetically related unipolar disorders.

A Success at the End of an Era, and a Glimpse of Things to Come

A Success at the End of an Era, and a Glimpse of Things to Come

A Success at the End of an Era, and a Glimpse of Things to Come

A Success at the End of an Era, and a Glimpse of Things to Come

What Is Familial About Familial Bipolar Disorder?

Current diagnostic criteria for bipolar affective disorder define a phenotype that is highly heritable, yet clinically variable. A more homogeneous definition might facilitate genetic and other studies, but the best approach is unclear. Familial features of bipolar disorder should help define more homogeneous subtypes, but there are few data indicating which clinical features of bipolar disorder are the most familial. To study the familiality of phenotypic features in families ascertained through individuals with bipolar affective disorder. The study comprises 1246 individuals in 172 multiplex families ascertained for genetic linkage studies of bipolar disorder. The familiality of 40 diverse phenotypic features was studied using mixed-effects regression analysis. Substance abuse, alcoholism, psychosis, history of suicide attempt, and the level of social functioning were all strongly familial in this sample. Several other traits, including clinical subtype, earliest age at onset, and comorbid panic disorder, showed a suggestion of familiality that did not hold up to conservative correction for multiple testing. This is the largest and most comprehensive study to assess the familiality of phenotypic features in bipolar disorder. Our results suggest that comorbid conditions and social functioning should be considered along with other familial clinical features in formulating subtypes of bipolar disorder suitable for further studies. Familial variables may help reduce diagnostic heterogeneity in genetic and other biological studies.

Identification of the Slynar Gene (AY070435) and Related Brain Expressed Sequences as a Candidate Gene for Susceptibility to Affective Disorders Through Allelic and Haplotypic Association With Bipolar Disorder on Chromosome 12q24

Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant lod scores of over 3.00. Several other linkage studies have found lod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene. DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies. Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations. These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder.

Identification of the Slynar Gene (AY070435) and Related Brain Expressed Sequences as a Candidate Gene for Susceptibility to Affective Disorders Through Allelic and Haplotypic Association With Bipolar Disorder on Chromosome 12q24

Objective: Three linkage studies of bipolar disorder have implicated chromosome 12q24.3, with significant lod scores of over 3.00. Several other linkage studies have found lod scores between 2.00 and 3.00. In order to identify which gene on this chromosome is responsible, the authors carried out tests of allelic association with bipolar disorder in order to fine map an affective disorder susceptibility gene. Method: DNA samples from 681 bipolar disorder patients and 570 comparison subjects from Denmark and the United Kingdom were genotyped with markers close to the region at which the authors had found maximum linkage in previous studies. Results: Single marker allelic association was found with four markers in the Danish cohort. Seven markers in exactly the same region were then found to show significant allelic association in the U.K. cohort. Tests of haplotypic association were also significant, confirming the single marker allelic associations. Conclusions: These positive fine mapping results validate earlier linkage studies and implicate a 278-kilobase region of chromosome 12 that contributes to the etiology of bipolar disorder. Several brain transcripts are transcribed from sequences in the region. The main candidate gene has no known function but is found in human brain cDNA and is homologous to a Macaque brain cDNA. Sequencing of expressed sequences and control regions in the area should identify etiological base pair changes that increase susceptibility to bipolar disorder.

Lymphocyte G-protein receptor kinase (GRK)3 mRNA levels in bipolar disorder

Linkage studies in bipolar disorder were positive for markers in the region of chromosome 22q12.1 including the gene coding for G-protein receptor kinase (GRK)3. Two of six variants of the GRK3 5'-UTR/promoter were reported to be associated with bipolar disorder. GRK3 protein levels in lymphoblastoid cell lines derived from bipolar patients originating from families with linkage to chromosome 22q11 were reported to be decreased compared to those of control subjects and correlated with disease severity. We compared GRK3 mRNA levels in fresh lymphocytes from 31 bipolar patients vs. 26 control subjects, using real-time RT-PCR. No overall difference was found between patients and controls. However, GRK3 mRNA levels were markedly and significantly reduced in the subgroup of patients with no family history of a major psychiatric disorder compared with patients with family history.

Characterization of CTG/CAG repeats on chromosome 18: a study of bipolar disorder

Anticipation has been frequently found in bipolar families ascertained for linkage studies. An association of polymorphic triplet repeats with the bipolar phenotype in some pedigrees has been proposed. We have previously found linkage to chromosome 18 in a set of families with evidence of anticipation. As part of a search for CAG/CTG motifs on chromosome 18, we screened a genomic chromosome 18 cosmid library and identified 65 loci with trinucleotide repeats. Eleven of 33 genotyped loci were polymorphic, though none of these showed any evidence of instability. We performed genetic analysis of six loci in the Hopkins/Dana bipolar pedigrees ascertained for a genetic linkage study of bipolar disorder and found that the CAG repeat within the AD4D2 clone on 18q21.1 showed nominally significant over-transmission of the rare CAG23 allele (P=0.034). We have characterized all 65 trinucleotide repeats and flanking sequences with GENSCAN analysis and find that 29 were predicted to be in coding regions. These 29 trinucleotide-repeat-containing genes may be involved in functional modulation of their respective proteins, and may be candidates for other diseases or disease mechanisms that map to this region.

Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications.

Brain-derived neurotrophic factor (BDNF) plays an important role in promoting and modifying growth, development, and survival of neuronal populations, and, in the mature nervous system, is involved in activity-dependent neuronal plasticity. Based on several lines of evidence, BDNF has been hypothesized to play an important role in the pathogenesis of mood disorder and the therapeutic action of at least some effective treatments. The gene encoding BDNF lies on the short arm of chromosome 11 in a region where some linkage studies of bipolar disorder have reported evidence for a susceptibility gene. BDNF can, thus, be considered as an attractive candidate gene for involvement in the pathogenesis of bipolar disorder, and two recent family-based association studies have provided evidence that one or more sequence variants within or near the BDNF gene show an association with disease susceptibility. These findings are of great interest and may open up a new chapter in the understanding of the causation and treatment of bipolar disorder. However, it is still early in the genetic investigation of BDNF in bipolar disorder, and it is important that these findings are replicated in large independent samples and that functional studies can confirm and characterize the pathogenic relevance of this genetic variation.

Self-reported schizotypy and bipolar disorder: demonstration of a lack of specificity of the Kings Schizotypy Questionnaire

Previous studies have demonstrated that schizophrenia patients score highly on self-reported measures of schizotypy such as the Kings Schizotypy Questionnaire (KSQ), but relatively little is known about the specificity of these self-reported features to schizophrenia. We aimed to explore the specificity of schizotypal features to schizophrenia by measuring their prevalence in subjects with bipolar disorder. The Kings Schizotypy Questionnaire (KSQ) was administered to participants ( n=92) in a sibling–pair genetic linkage study of bipolar disorder. Scores were compared with those of participants in a similarly designed, concurrent family study of schizophrenia ( n=135) and psychiatrically well controls ( n=263). The bipolar group had significantly more schizotypal features than controls but significantly less than schizophrenia patients. Whether a bipolar subject had experienced positive psychosis had no effect on his/her schizotypy score. We conclude that elevated self-reported schizotypy as measured by the KSQ is not specific to schizophrenia, and may be associated with functional psychosis in general.

Genetic analysis of the (CTG)n NOTCH4 polymorphism in 65 multiplex bipolar pedigrees

A strong genetic association between the NOTCH4 locus on chromosome 6 and schizophrenia was recently reported. Based on the data suggesting overlapping susceptibility for schizophrenia and bipolar disorder, we genotyped the polymorphic (CTG)n encoding polyleucine repeat in exon 1 of NOTCH4 in 65 pedigrees ascertained for a genetic linkage study of bipolar disorder. In addition, we analyzed a subset of our pedigrees with psychotic features at this locus. We failed to find any association between the (CTG)n NOTCH4 polymorphism and either the bipolar or the psychotic bipolar phenotype in our 65 pedigrees.

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Abstracts for the IXth World Congress of Psychiatric Genetics, Saint Louis, Missouri

Genetic studies of bipolar affective disorder in large families

Background Genetic factors are known to be important in the aetiology of bipolar disorder. Aims To review linkage studies in extended families multiply affected with bipolar disorder. Method Selective review of linkage studies of bipolar disorder emphasising the gains and drawbacks of studying large multiply-affected families and comparing the statistical methods used for data analysis. Results Linkage of bipolar disorder to several chromosome regions including 4p, 4q, 10p, 12q, 16p, 18q, 21q and Xq has first been reported in extended families. In other families chromosomal rearrangements associated with affective illnesses provide signposts to the location of disease-related genes. Statistical analyses using variance component methods can be applied to extended families, require no prior knowledge of the disease inheritance, and can test multilocus models. Conclusion Studying single large pedigrees combined with variance component analysis is an efficient and effective strategy likely to lead to further insights into the genetic basis of bipolar disorders.

Linkage studies of bipolar disorder with chromosome 18 markers

Evidence consistent with the existence of genetic linkage between bipolar disorder and three regions on chromosome 18, the pericentromeric region, 18q21, and 18q22-q23 have been reported. Some analyses indicated greater evidence for linkage in pedigrees in which paternal transmission of disease occurs. We have undertaken linkage analyses using 12 highly polymorphic markers spanning these three regions of interest in a sample of 48 U.K. bipolar pedigrees. The sample comprises predominantly nuclear families and includes 118 subjects with Diagnostic and Statistical Manual of Mental Disorders (DSM IV) bipolar I disorder and 147 subjects with broadly defined phenotype. Our data do not provide support for linkage using either parametric or nonparametric analyses. Evidence for linkage was not significantly increased by analyses that allowed for heterogeneity nor by analysing the subset of pedigrees consistent with paternal transmission.