SYNGR1 is associated with schizophrenia and bipolar disorder in southern India

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. We have previously identified a novel nonsense mutation in the SYNGR1 gene in a SCZ pedigree. In the present study, a detailed analysis of this gene was performed in a case–control cohort (198 BPAD, 193 SCZ and 107 controls from southern India) to test for association with SCZ and BPAD. Sequence analysis of all exonic and flanking intronic regions of the SYNGR1 gene in 198 BPAD and 193 SCZ cases 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. We also validated 9 out of 14 dbSNPs in our population. Case–control analysis revealed allelic (P=0.028–0.00007) association of five polymorphisms with SCZ and/or BPAD cases. Further, 3-SNP (with LD block 1 SNPs) and 2-SNP (with LD block 2 SNPs) haplotype analyses did not show any association with either SCZ or BPAD. Our results support SYNGR1 as a probable susceptibility gene for SCZ and BPAD. Also, the observed association of SYNGR1 with both SCZ and BPAD suggests the likely involvement of a common pathway in the etiology of these disorders.Electronic Supplementary Material Supplementary material is available for this article at     

Prevalence of migraine in bipolar disorder.

BACKGROUND: This study was undertaken to estimate the prevalence of migraine in people suffering from bipolar affective disorder. METHODS: a headache questionnaire incorporating the newly introduced International Headache Society (IHS) criteria was given to 117 patients on the Dunedin Bipolar Research Register. RESULTS: a total of 81 (69%) completed the questionnaire, out of which 21 (25.9%) reported migraine headaches. 25% of bipolar men and 27% of bipolar women suffered from migraine. CONCLUSIONS: these rates are higher than those reported in the general population with the rate for bipolar men being almost five-times higher than expected. An increased risk of suffering form migraine was particularly noted in bipolar patients with an early onset of the disorder. This may represent a more severe form of bipolar affective disorder.     

Endophenotypes in bipolar disorder

The search for genes in bipolar disorder has provided numerous genetic loci that have been linked to susceptibility to developing the disorder. However, because of the genetic heterogeneity inherent in bipolar disorder, additional strategies may need to be employed to fully dissect the genetic underpinnings. One such strategy involves reducing complex behaviors into their component parts (endophenotypes). Abnormal neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological findings are characteristics that often accompany psychiatric illness. It is possible that some of these may eventually be useful in subdefining complex genetic disorders, allowing for improvements in diagnostic assessment, genetic linkage studies, and development of animal models. Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells. Targeting circadian rhythm abnormalities may be a particularly useful strategy because circadian cycles appear to be an inherent evolutionarily conserved function in all organisms and have been implicated in the pathophysiology of bipolar disorder. Furthermore, lithium has been shown to regulate circadian cycles in diverse species, including humans, possibly through inhibition of glycogen synthase kinase 3-beta (GSK-3beta), a known target of lithium.     

Course sequences in bipolar disorder: Depressions preceding or following manias or hypomanias

Background

Inferior response to lithium treatment has been reported in bipolar disorder (BD) patients with mania or hypomania following episodes of major depression (DMI) versus preceding depression (MDI), with intervening euthymic periods. However, additional characteristics of BD course-patterns require further assessment.

Methods

We reviewed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences.

Results

Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals. Prevalent sequences included: major depression–hypomania (15.0%), mania–major depression (14.6%), major depression–mania (11.6%), and rapid-cycling (9.6%). Among subjects grouped by course-sequences (based on mania, mixed-states, or hypomania and major or minor depression), depression-before-[hypo]mania (DMI) cases were more likely to be women, diagnosed BD-II, have first-episodes of depressive or anxiety disorder, spend more time ill in depression, and benefit less with long-term mood-stabilizing treatments than with the opposite pattern (MDI). MDI patients were more likely to have substance-abuse and receive long-term mood-stabilizer treatments. Meta-analysis of 5 previous reports plus present findings found inferior treatment-response in DMI vs. MDI cases at a pooled risk-difference of 29% [CI: 18–40%] (p<0.0001).

Limitations

Some data were retrospective and subject to recall bias, and treatment was clinical (non-randomized).

Conclusions

The DMI course was strongly associated with first-episode depression or anxiety, excess depressive morbidity, and inferior treatment response, especially for depression.     

Genetic relationships of the populations in eastern India.

The genetic relationships for four sets of populations in eastern India have been studied by using gene frequency data available in the literature. The Caucasoid populations in Assam and West Bengal are genetically close but different from the Mongoloid populations in the neighbourhood. The genetic distance analysis shows that the Mongoloid populations in Assam and West Bengal cluster according to their states of residence, indicating a correlation between genetic and geographical distances.     

Genetics of bipolar disorder

Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed.     

Mexiletine in treatment-resistant bipolar disorder

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of mexiletine, a medication with antiarrhythmic, anticonvulsant and analgesic properties, in treatment-resistant bipolar disorder patients. METHODS: Twenty subjects with rapid-cycling bipolar disorder who had failed to respond or were intolerant to lithium, valproic acid and carbamazepine were entered into the 6-week, open label study. Subjects were followed on a weekly basis for dosing of mexiletine, blood levels, and completion of the Hamilton Depression Rating Scale (HAM-D) and the Manic State Rating Scale (MSRS). "Burden of Mood Symptoms" (BMS) was calculated by combining scores for the HAM-D and MSRS. RESULTS: Thirteen subjects (10 female, 3 male), mean age 41 years (S.D.=7.6), and mean duration of illness 20 years (S.D.=7.7) completed the study. The dose range of mexiletine was 200-1200 mg/day. Full response (>/=50% reduction in BMS) was seen in 46% of the subjects, and a partial response (25-49% reduction in BMS) in 15%. Of note, 5/5 subjects with a mixed or manic state demonstrated a full or partial response. LIMITATIONS: This study has an open label design, and a small number of subjects. CONCLUSIONS: Mexiletine may be effective and safe in patients with highly treatment-resistant, chronic bipolar disorder. Randomized, controlled trials are required to confirm the current results.     

Gabapentin as an adjunctive treatment in bipolar disorder.

OBJECTIVE: To evaluate the efficacy of gabapentin as an adjunctive treatment for bipolar disorder in both depressed and manic phases. METHOD: Thirty seven patients with bipolar type I or II with or without a rapid cycling course were openly treated with gabapentin added to current treatment for up to six months. Mood symptoms were rated weekly for 12 weeks then monthly for 3 months utilizing the HamD and YMS. RESULTS: Participants experienced a significant reduction in both depressive and manic symptoms. CONCLUSIONS: These findings are consistent with others in establishing the efficacy of gabapentin in both phases of bipolar disorder. LIMITATIONS: Small sample size and the use of an open uncontrolled design limit interpretation of results.     

Dysfunctional assumptions in bipolar disorder

BACKGROUND: Despite the initial encouraging outcome in developing CBT for bipolar affective disorder [Arch. Gen. Psychiatry 2002 (in press); Psychol. Med. 31 (2001) 459-467], very little is known about whether there are any differences in dysfunctional attitudes between unipolar and bipolar patients. Both the behavioural activation system theory [J. Pers. Soc. Psychol. 67 (1994) 488-498; Major Theories of Personality Disorder, Guilford Press, New York, 1996; Psychol. Bull. 117 (1995) 434-449] and the cognitive model for bipolar affective disorder [Cognitive Therapy for Bipolar Disorder: A Therapist's Guide to Concepts, Methods and Practise, Wiley, New York, 1999] postulate high goal striving as a risk factor for bipolar disorder. However, the existing subscales in the dysfunctional attitude scale (DAS) were derived from patients and relatives of patients suffering from unipolar depression, patients with a mixed psychiatric diagnosis or normal controls. None of the existing subscales reflects high goal striving beliefs. Using a sample of bipolar patients may yield different factors. METHODS: A total of 143 bipolar 1 patients filled in the short version of DAS 24. Principal component analysis was carried out to derive factors. The scores of these factors were compared with those of 109 unipolar patients to investigate if these factors distinguish bipolar patients from unipolar patients. RESULTS: Three factors were derived: factor 1 'Goal-attainment' accounted for 25.0% of the total variance. Factor 2 'Dependency' accounted for 11.0% of the total variance. Factor 3 'Achievement' accounted for 8.2% of the total variance. However, factor 1 appeared to consist of items that made a coherent theoretical construct. No significant differences were found when the validation sample was compared with 109 patients suffering from unipolar depression in any of the three factors. When subjects who were likely to be in a major depressive episode were excluded, the scores of bipolar patients (n=49) were significantly higher than euthymic unipolar patients (n=25) in factor 1 'Goal attainment'. Goal-attainment also correlated with the number of past hospitalisations due to manic episodes and to bipolar episodes as a whole. CONCLUSIONS: The Goal-attainment subscale captures the risky attitudes described by the behavioural activation system theory and the cognitive model for bipolar affective disorder. It is postulated that these beliefs may interact with the illness and predispose bipolar patients to have a more severe course of the illness.     

Anticipation in Swedish families with bipolar affective disorder.

Anticipation describes an inheritance pattern within a pedigree with an increase in disease severity or decrease in age at onset or both in successive generations. The phenomenon of anticipation has recently been shown to be correlated with the expansion of trinucleotide repeat sequences in different disorders. We have studied differences of age at onset and disease severity between two generations in 14 families with unilinear inheritance of bipolar affective disorder (BPAD). There was a significant difference in age at onset (p < 0.008), in episodes per year with (p < 0.006) and without (p < 0.03) lithium treatment, and in total episodes per year (p < 0.002) between generations I and II. Furthermore, there was a highly significant correlation (p < 0.001) in age at onset between generations I and II. No evidence for specific paternal or maternal inheritance was found. We found evidence of anticipation and could rule out ascertainment bias or some other artefact. Anticipation is thus an inheritance pattern in BPAD which suggests that the expansion of trinucleotide repeat sequences is a possible mode of inheritance in BPAD.     

Life events and relapse in bipolar affective disorder.

In a 2 year study of life events and relapse in a cohort of 62 patients with bipolar affective disorder, an excess of events was found during the month immediately preceding relapse. Of 52 relapses 19% were preceded by a severe event in the previous month, compared to a background rate of 5% of patients experiencing a severe event each month at other times. The rate of life events prior to relapse was not apparently different between manic and depressive relapse, though the number of depressive episodes was small.     

Heritability of cognitive functions in families with bipolar disorder.

Bipolar disorder is highly heritable. Cognitive dysfunctions often observed in bipolar patients and their unaffected relatives implicate that these impairments may be associated with genetic predisposition to bipolar disorder and thus fulfill the criteria of a valid endophenotype for the disorder. However, the most fundamental criterion, their heritability, has not been directly studied in any bipolar population. This population-based study estimated the heritability of cognitive functions in bipolar disorder. A comprehensive neuropsychological test battery and the Structured Clinical Interview for DSM-IV were administered to a population-based sample of 110 individuals from 52 families with bipolar disorder. Heritability of cognitive functions as assessed with neuropsychological test scores were estimated using the Solar package. Significant additive heritabilities were found in verbal ability, executive functioning, and psychomotor processing speed. Genetic contribution was low to verbal learning functions. High heritability, in executive functioning and psychomotor processing speed suggest that these may be valid endophenotypic traits for genetic studies of bipolar disorder.     

A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.     

Viruses, schizophrenia, and bipolar disorder.

The hypothesis that viruses or other infectious agents may cause schizophrenia or bipolar disorder dates to the 19th century but has recently been revived. It could explain many clinical, genetic, and epidemiologic aspects of these diseases, including the winter-spring birth seasonality, regional differences, urban birth, household crowding, having an older sibling, and prenatal exposure to influenza as risk factors. It could also explain observed immunological changes such as abnormalities of lymphocytes, proteins, autoantibodies, and cytokines. However, direct studies of viral infections in individuals with these psychiatric diseases have been predominantly negative. Most studies have examined antibodies in blood or cerebrospinal fluid, and relatively few studies have been done on viral antigens, genomes, cytopathic effect on cell culture, and animal transmission experiments. Viral research on schizophrenia and bipolar disorder is thus comparable to viral research on multiple sclerosis and Parkinson's disease: an attractive hypothesis with scattered interesting findings but no clear proof. The application of molecular biological techniques may allow the identification of novel infectious agents and the associations of these novel agents with serious mental diseases.     

Serotonin and bipolar disorder

With the emergence of specific pharmacological probes for various serotonin (5-HT) receptors and radio-ligands for central 5-HT, it has now become possible to investigate its role in the pathogenesis of bipolar disorder more closely.This paper critically reviews the scientific literature regarding the relationship between bipolar disorder and serotonergic systems. The evidence suggests that central serotonergic activity is reduced in the depressive phase of bipolar disorder. Similar findings have been reported in bipolar patients when euthymic, indicating that that lower 5-HT activity could be a trait marker for bipolar disorder. Findings reported in the manic phase of this illness are inconsistent.     

The genetics of bipolar disorder

Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.     

Molecular genetics of bipolar disorder

Alteration of monoaminergic neurotransmission is implicated in the pathophysiology of bipolar disorder (manic-depressive illness). Candidate genes participating in monoaminergic neurotransmission, especially serotonin transporter and monoamine oxidase A, may be associated with bipolar disorder. And the regulating regions of these genes and the molecules participating in intracellular signal transduction are now under investigation. To date, 13 whole genome positional cloning studies have been performed and many candidate loci identified. Using patients from a pedigree in which schizophrenia, depression or bipolar disorder have been linked with a balanced translocation at 1 and 11, candidate pathogenetic genes were cloned as DISC1 (disrupted in schizophrenia-1) and DISC2. Recently, pathogenetic mutations have been identified in two genetic diseases frequently co-morbid with mood disorder; WFS1 for Wolfram syndrome and ATP2A2 (SERCA2) for Darier's disease. Transmission of bipolar disorder may be characterized by anticipation and parent-of-origin effect, and extended CTG repeat at SEF2-1B gene was identified from a bipolar patient. However, its pathogenetic role was not supported by subsequent studies. Association of bipolar disorder with mitochondrial DNA has also been suggested. The role of genomic imprinting is also possible because linkage to 18p11 is limited to paternally transmitted pedigrees. These results warrant further study of molecular genetics of bipolar disorder.     

The neurobiology of bipolar disorder

The neurobiology of bipolar disorder is reviewed. Bipolar disorder is associated with alterations in central nervous system (CNS) function from the level of large-scale brain circuits to intracellular signal transduction mechanisms. Because of the broad spectrum over which these abnormalities appear, the causative effects are most likely present in the lowest common denominator of all of these systems. Current evidence points to subtle alterations in signal transduction that reverberate downstream both intra- and extracellularly to produce the symptoms of bipolar disorder.