Catechol-O-methyltransferase (COMT) catalyzes the degradation of catecholamines and could therefore play a role in the etiology of schizophrenia. Moreover, microdeletions including the COMT locus have been found in schizophrenics presenting typical features of the velo-cardio-facial syndrome. In the present work, five single-strand conformation polymorphisms were detected in exons of the COMT gene. The linkage disequilibria between the polymorphisms were estimated, and the genotypic frequencies were calculated on a sample of 126 to 137 schizophrenics and 136 to 140 controls, depending on the marker. Patients and controls were matched for ethnicity and geographical origin. A trend toward association was found between schizophrenia and (i) genotype 11 of the Pml I polymorphism (p = 0.034; OR = 1.82); (ii) haplotype 1-2 for the Pml I and Bcl I polymorphisms (p = 0.022; OR = 1.75). The Pml I polymorphism is in complete linkage disequilibrium with the common Met-->Val(158) substitution, which affects the activity of the enzyme. This finding suggests a possible minor effect of COMT in a multifactorial threshold model of vulnerability to schizophrenia.

BACKGROUNDGenes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts.METHODSThe TPH intron 7 A218C polymorphism was determined using a polymerase chain reaction-based method in DNA samples from 152 patients with bipolar disorder and 94 healthy control subjects.RESULTSThere was a significant association between TPH genotypes and manic-depressive illness. Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior.CONCLUSIONSThis result suggests the involvement of the TPH gene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.

A decrease in age of onset of schizophrenia through consecutive family generations (anticipation) has been found in several studies. Anticipation is known to result from expansion of CAG repeats in genes that determine several neurodegenerative disorders. In a previous study we analysed 26 unilineal two-generation French pedigrees and found clinical evidence of anticipation. A 10-year mean reduction in age of onset of schizophrenia was found in the second generation compared with the parental generation. The repeat expansion detection method was used to screen for CAG expansion in 21 of the 26 families with evidence of anticipation for the disease and in 59 sporadic schizophrenics and 59 controls. Comparison of the frequency distributions of CAG/CTG repeat size observed in schizophrenics and controls showed no significant difference, even when we considered familial (P = 0.23) and sporadic (P = 0.25) affected individuals separately. These results do not support the association between long CAG repeats and schizophrenia. However, the possibility that expansions with fewer than 40 repeats are involved in schizophrenia cannot be excluded.

Anticipation has been described in bipolar affective disorder (BPAD). However, there are conflicting results from association studies screening for a link between BPAD and CAG/CTG repeat expansions, the molecular basis of anticipation in several hereditary neurodegenerative disorders. Here, the repeat expansion detection (RED) method was used to screen for CAG repeat expansion in 119 French BPAD patients. Western blotting was also used to search for polyglutamine stretches, encoded by CAG expansion, among proteins, extracted from lymphoblastoid cell lines, from six selected familial cases. Maximum CAG/CTG repeat length did not differ significantly (P = 0.38) between the 119 BPAD patients and the 88 controls included in the study. Several categories of subgroups were used, none of which showed significant association with a long repeat. Nor was a specific protein with an unusually long polyglutamine stretch (lower detection limit, approximately 33 polyglutamines) detected in cell lysates from the familial cases studied. In conclusion, an association between a long CAG/CTG repeat and BPAD in the French population sample studied was not found. Nonetheless, a short repeat (<40 repeats) might still be implicated, and this possibility warrants further study.

The pathogenesis of schizophrenia might involve abnormal development of the human brain. Interleukin-1β is a cytokine implicated in the development of the central nervous system and therefore its gene is a candidate gene in schizophrenia. Polymorphisms within the coding sequence and the 3'UTR of the IL1β gene were searched for using PCR-SSCP. Two polymorphisms, 1B-175/1B-173 and 1B-1765/1B-1763 were found in addition to the previously published TaqI site. Furthermore, a mutant was found in codon 106 (exon 5) of the IL1β gene located next to the published polymorphism at the TaqI site and abolishing this site. This novel mutation encodes an Asp in place of an Asn and was only observed in one patient in our French population. Association studies were conducted with the polymorphisms 1B-175/1B-173 and TaqI. There was no allelic or genotypic association between either of the two polymorphisms and schizophrenia. In our population, there is no evidence that the IL1β gene is involved in schizophrenia.

Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at θ = 0.00 (number of families: 36) assuming heterogeneity (α=15%,P=0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.

In response to reported schizophrenia linkage findings on chromosomes 3, 6 and 8, fourteen research groups genotyped 14 microsatellite markers in an unbiased, collaborative (New) sample of 403–567 informative pedigrees per marker, and in the Original sample which produced each finding (the Johns Hopkins University sample of 46–52 informative pedigrees for chromosomes 3 and 8, and the Medical College of Virginia sample of 156–191 informative pedigrees for chromosome 6). Primary planned analyses (New sample) were two-point heterogeneity lod score (lod2) tests (dominant and recessive affected-only models), and multipoint affected sibling pair (ASP) analysis, with a narrow diagnostic model (DSM-IIIR schizophrenia and schizoaffective disorders). Regions with positive results were also analyzed in the Original and Combined samples. There was no evidence for linkage on chromosome 3. For chromosome 6, ASP maximum lod scores (MLS) were 2.19 (New sample, nominal p = .001) and 2.68 (Combined sample, p=.0004). For chromosome 8, maximum lod2 scores (tests of linkage with heterogeneity) were 2.22 (New sample, p=.0014) and 3.06 (Combined sample, p = .00018). Results are interpreted as inconclusive but suggestive of linkage in the latter two regions. We discuss possible reasons for failing to achieve a conclusive result in this large sample. Design issues and limitations of this type of collaborative study are discussed, and it is concluded that multicenter follow-up linkage studies of complex disorders can help to direct research efforts toward promising regions.

S: 1996 World Congress on Psychiatric Genetics: IV. (A) THE RELEVANCE OF UNSTABLE TRINUCLEOTIDE REPEATS: PDF Only

We investigated the frequency of a rare variant of a common microsatellite tetrarepeat allele in the tyrosine hydroxylase gene in 2 independent ethnic groups of schizophrenic patients and their matched controls. In a French population we found the rare variant allele in 5 of 94 (5%) unrelated chronic schizophrenic patients and in none of 145 unaffected controls, thus yielding a significant association (p < 0.01) between schizophrenia and the tyrosine hydroxylase gene. Similarly, in a replication study, we found the rare allele in 4 of 44 (9%) unrelated chronic schizophrenic patients and in none of 44 unaffected controls in a Tunisian population. Albeit the reason of this association is at the moment unknown, it is possible that this polymorphism in the tyrosine hydroxylase gene may be involved in the regulation of its activity.

Catechol-O-methyltransferase is a candidate in the predisposition to schizophrenia both because of its function and the position of its gene. A multipoint non-parametric linkage analysis and a transmission disequilibrium test were performed on 42 multiplex families genotyped for Pml I and Bcl I polymorphisms using two definitions of the affected phenotype. Neither linkage nor preferential transmission of any allele or haplotype was detected, failing to replicate previous positive findings.

A new structural polymorphism (Ser311/Cys311) in the dopamine D2 receptor (DRD2) gene has recently been reported to be associated with schizophrenia, particularly in patients with a positive family history of schizophrenia (Arinimi et al., 1994). However these findings remain controversial (Asherson et al., 1994; Nanko et al., 1994; Nöthen et al., 1994; Shaikh et al., 1994). Thus we investigated the role of the Cys311 mutation in schizophrenia using both association and family studies. First, we screened for the Cys311 mutation in 113 unrelated Caucasian schizophrenics (mean age 42 +/- 0.6; 34 females and 79 males) including 25 familial cases, and 184 unrelated controls (mean age 49 +/- 0.5, 74 females and 110 males) free of any psychiatric disorders. Diagnoses were ascertained according to DSM-III criteria (Campion et al., 1994). All patients and controls were native to the area of Rouen.

Family, twin, and adoption studies suggest the involvement of genetic factors in manic-depressive illness (MDI) but the mode of inheritance remains elusive. The remarkable success with which the classical logarithm of odds (lod) score method has contributed to the localization of loci for numerous diseases has led many authors to apply this strategy to complex illnesses such as affective disorders. Most pertinent was the study conducted by Egeland et al. in 1987, which was based on an extended pedigree in order to minimize a possible genetic heterogeneity. These investigators reported a linkage between MDI and insulin (INS) and c-Harvey-ras-1 oncogene (HRAS) markers located within 11p15. But a recent reinvestigation of the Amish pedigree and the study of a set of non-Amish pedigrees call into question this initial finding (Kelsoe et al. 1989).