P. McGuffin

Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder

Catechol-O-methyltransferase (COMT) plays a major role in the breakdown of catecholamines.1 An amino acid polymorphism (val-108-met) determines high and low activity of the enzyme.2,3 A recent study in a small sample of patients with velo-cardio-facial syndrome who had bipolar affective disorder suggested that the Met (low activity) COMT allele might be associated with rapid-cycling in this population.4 We therefore tested the hypothesis that the Met allele might be associated with rapid cycling bipolar disorder in the wider population. We studied a sample of British Caucasian DSM-IV bipolar patients, of whom 55 met criteria for rapid cycling at some time during the illness and 110 met stringent criteria for a definite non-rapid cycling course. The COMT genotype was determined using a PCR assay. The low activity allele was more frequent in the group of rapid cyclers: 0.55 vs 0.42 (one-tailed χ2 = 5.12, d.f. = 1, P = 0.012), and bearers of low activity alleles showed a dose-dependent increased risk of lifetime occurrence of rapid cycling: χ2 test of linear association = 4.84, d.f. = 1, P = 0.014. Our data support the hypothesis that variation in the COMT gene modifies the course of bipolar disorder.

Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT)

The human serotonin transporter gene (hSERT) is a strong candidate for involvement in the pathogenesis of mood disorder and, using a UK Caucasian case-control sample, Collier et al found a significant association between bipolar disorder and the 12 allele of the VNTR polymorphism in intron 2 of this gene. In a European collaborative sample, Collier et al found a significant association between affective disorder and a functional deletion polymorphism in the promoter of hSERT. We have undertaken association studies using these polymorphisms in a British Caucasian sample comprising 171 DSM-IV bipolar probands, 80 DSM-IV major depression probands and 121 unrelated controls matched to bipolar probands for age, sex and ethnicity. We found no association between the promoter deletion and affective disorder but our findings with the VNTR polymorphism are similar to those of Collier and colleagues: we found a significant excess of the 12 repeat allele in bipolar probands (Pu2009=u20090.031, one-tail) with a suggestion of a gene dosage effect (using genotypes bearing no 12 repeat allele as baseline, the increased risks conferred by genotypes bearing 12 repeat alleles were: heterozygote, ORu2009=u20091.24; homozygote, ORu2009=u20091.76). Our findings add to the evidence that variation at or near hSERT influences susceptibility to bipolar disorder in the British Caucasian population.

A multicentre inter-rater reliability study using the OPCRIT computerized diagnostic system

We examined the reliability of the OPCRIT system from ratings produced by 30 USA and European clinicians involved in molecular genetic research. The OPCRIT system facilitates a polydiagnostic approach to research on severe psychiatric disorders. OPCRIT comprises a 90-item checklist of signs and symptoms and a suite of computer programs, which together generate diagnoses according to the operational criteria of 12 major classificatory systems (e.g. DSM-III, DSM-III-R, RDC, ICD-10). Thirty summaries of actual cases ranging in signs and symptoms, taken from independent sources, were rated by participants from research centres across Europe and the USA using the OPCRIT system. Each rating was then compared to a standard rating using a kappa statistic. Good levels of reliability were observed within all classifications (e.g. DSM-III-R, kappa = 0.73, RDC, kappa = 0.71; ICD-10, kappa = 0.70) and a similar pattern of ratings was found in both the European and USA samples. We conclude that the OPCRIT system, is both flexible and practicable retaining the top-down advantage of operational definitions as well as the bottom-up potential offered by well defined signs, symptoms and other component items. Within the limitations of an international, multicentre design this study shows that the OPCRIT system affords good reliability with raters from a variety of geographical and theoretical backgrounds.

Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (pu200a=u200a1.4×10−8), and with rs7555523, located in TMCO1 at 1q24.1 (pu200a=u200a1.6×10−8). In a meta-analysis of 4 case-control studies (total Nu200a=u200a1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (pu200a=u200a2.4×10−2 for rs11656696 and pu200a=u200a9.1×10−4 for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families

Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamine, noradrenaline and adrenaline. It exists as common high and low activity alleles in the population (determined by a valine 158 methionine polymorphism), and high red blood cell activity of COMT has previously been associated with schizophrenia. To examine the relationship between COMT and schizophrenia genetically, the transmission disequilibrium test was performed on 22 multiply affected Caucasian and Japanese families genotyped for val158met and a second, silent, polymorphism (C256G), using PCR based assays. The high activity val158 allele was transmitted from parents to the affected individuals more frequently than the low activity met158 allele, although this was not statistically significant. Combining this data with a previous study using Chinese family trios with schizophrenia (Li et al., 1996) gave a highly significant result (p = 0.0015). The G256 allele was also transmitted preferentially to the affected offspring, and this was statistically significant when schizophrenia, schizoaffective disorder and unspecified functional psychosis were included in the definition of the affected phenotype (p = 0.03). Overall, these findings may indicate an effect of COMT alleles on susceptibility to schizophrenia, or reflect linkage disequilibrium with a different causative polymorphism in the vicinity. Other reported associations of COMT with obsessive compulsive and rapid cycling bipolar disorder indicate that the COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.

Suggestive evidence for linkage of schizophrenia to markers on chromosome 13q14.1-q32.

Family, twin and adoption studies highlight the influence of genes in the aetiology of schizophrenia, though the mode of inheritance is unclear. We have been conducting a systematic search for major genes in schizophrenia using a series of multiply affected families and report preliminary results of linkage under heterogeneity with markers on chromosome 13. A lod2 score of 1.61 for marker D13S144 was obtained at 0 = 0 and α of 0.5 and nearby markers also produced positive values.

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder

There are several lines of evidence which suggest that chromosome 4p may contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophrenia and schizoaffective disorder which gave maximum lod scores of 1.96 and 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which gives a maximum lod score of 4.1 with the marker D4S394, which lies 10u2009cM from D4S403. They obtained a combined maximum lod of 3.3 in their total sample of 12 bipolar families and found significant evidence of heterogeneity (χ2u2009=u200918.8, dfu2009=u20092, Pu2009=u20090.00008). Here we report the results of a linkage study of chromosome 4p markers in a sample of 24 multiply affected families with schizophrenia and related disorders. We obtained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. However, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al examined families included in a genetic linkage study of bipolar disorder. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affective symptoms. It is therefore possible that a broad phenotype including unipolar depression, bipolar disorder, schizoaffective disorder and schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 receptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In family 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSCP) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schizophrenia. Finally association studies of the (TC)n repeat in the promoter and schizophrenia, and DRD5-M and bipolar disorder were performed. These studies provided no further evidence supporting the possibility that mutations in DRD5 give rise to the linkage findings or are acting as susceptibility loci in schizophrenia or bipolar disorder.

The reliability of the SADS-LA in a family study setting.

SummaryThe joint-rater and test-retest reliability study of two translated versions of the SADS-LA (Schedule for Affective Disorders and Schizophrenia-Lifetime version — modified for the study of anxiety disorders), one in French and the other in German, have been tested in family study settings, in a sample of patients and firstdegree relatives. The test-retest reliability study demonstrated that identification of major affective disorders and schizophrenia was performed with sufficient reliability; however, diagnoses of subtypes of major disorders (e.g. bipolar II disorder) and identification of minor disorders was cless reliable. The implications of these findings in phenotype identification during family studies in psychiatry are discussed.

A linkage study of schizophrenia with DNA markers from the long arm of chromosome 11

We report the results of a collaborative linkage study using 12 polymorphic markers (9 loci) from the long arm of chromosome 11, and 24 families multiply affected with schizophrenia and other closely related disorders. This region is of interest because several families have been reported in which balanced translocations involving 11q apparently co-segregate with psychotic illness. In addition, the dopamine D2 receptor, porphobilinogen deaminase, and tyrosinase genes map within the region studied and may be aetiologically involved in schizophrenia. We have primarily analysed genotypic data by the LOD score method using a range of single gene models. In order to minimize error due to mis-specification of genetic parameters we have analysed data from markers at candidate gene loci by the non-parametric extended sib-pair method in addition to the LOD score method. Our results suggest that most of the region can be excluded from containing a gene of major effect in the aetiology of this disease.

A transmission disequilibrium and linkage analysis of D22S278 marker alleles in 574 families: further support for a susceptibility locus for schizophrenia at 22q12

Patients with schizophrenia rarely develop rheumatoid arthritis, an autoimmune disease that exhibits genetic association with the HLA DRB1*04 gene. We previously investigated the hypothesis that schizophrenia is negatively associated with DRB1*04, and found that only half the expected number of schizophrenic patients had this gene when compared with controls. We now report the results of DRB1*04 genotyping in pedigrees multiply affected with schizophrenia. Polymerase chain reaction amplification and sequence-specific oligonucleotide probes were used to determine the DRB1 genotypes of the 187 members of 23 pedigrees multiply affected with RDC schizophrenia. DQA1, DQB1 and DPB1 genotypes were similarly determined. We analysed data using the extended transmission/disequilibrium test and found a trend for the preferential non-transmission of DRB1*04 alleles from heterozygous parents to their schizophrenic offspring (16 of 23 alleles not transmitted, chi 2 = 3.5, p = 0.06). We found no evidence for a gene of major effect using GENEHUNTER for parametric and non-parametric linkage analysis. The results from this small sample need to be interpreted with caution, but they are in keeping with previous reports and suggest that HLA DRB1*04 alleles may be associated with a reduced risk of schizophrenia.Previously, a combined analysis by the Chromosome 22 Collaborative Linkage Group (1996; Am. J. Med Genet. 67, 40-45) used an affected sib-pair analysis of a single marker (D22S278) in 574 families multiply affected by schizophrenia and found some evidence for linkage (chi 2 = 9.35, 1 df, p = 0.001), suggesting the presence of a disease locus nearby on chromosome 22q12. In order to further investigate the importance of this result, we have performed the transmission disequilibrium test (TDT) and additional parametric and non-parametric linkage analysis of the same data. The most positive result obtained was an admixture lod score of 0.9 under the assumption of locus heterogeneity and dominant transmission. The result of the TDT analysis was significant at p = 0.015 (allele-wise; chi 2 = 22, 10 df) and p = 0.00016 (genotype-wise; chi 2 = 66.2, 30 df, empirical p value = 0.0009). Overall, these results further strengthen the notion that there is a susceptibility locus for schizophrenia close to D22S278.