Claudia Émond

Significant Linkage for Tourette Syndrome in a Large French Canadian Family

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS.

A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to medication, and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with haloperidol or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region.

Cluster analysis of cognitive deficits may mark heterogeneity in schizophrenia in terms of outcome and response to treatment

Abstract Cognitive impairments are central to schizophrenia, but their clinical utility for tagging heterogeneity in lifetime outcome and response to treatment is not conclusive. By exploiting four cognitive domains consistently showing large deficits in studies, we tested whether cluster analysis would define separate subsets of patients and then whether the disease heterogeneity marked by these clusters would be related to lifetime outcome and response to treatment. A total of 112 schizophrenia patients completed a neuropsychological evaluation. The PANSS, GAF-S and GAF-F were rated at the onset and endpoint of the illness trajectory. A blind judgment of the lifetime response to treatment was made. The first cluster presented near-normal cognitive performance. Two other clusters of severely impaired patients were identified: one generally impaired in the four cognitive domains and another selectively impaired in visual episodic memory and processing speed, each relating to a different lifetime evolution of disease and treatment response. Although the two impaired clusters were clinically indistinguishable in symptom severity and functioning at disease onset, patients with selective cognitive impairments demonstrated better improvement at outcome, whereas the generally impaired patients were more likely to be treatment refractory. The findings have implications for the management of patients and for clinical trials since particular combinations of cognitive deficits in patients would influence their treatment response.

Decomposing the autism phenotype into familial dimensions.

The objective of this article is to decompose the level of functioning phenotype in autism to see if it can be conceptualized as two simpler, but still familial, dimensional phenotypes of language and non‐verbal IQ. We assembled 80 sibpairs with either autism, Asperger syndrome or atypical autism. To see whether the familial correlation on language scores was accounted for by the familial correlation on non‐verbal IQ, residual language scores were calculated for each member of the sibpair based on a multiple regression equation using their IQ score as an explanatory or independent variable and controlling for the age and gender of the affected individual. These residual scores were then used to calculate intraclass correlations between affected sibs. This process was repeated using IQ as the dependent variable and language as a covariate. Within affected individuals there was a strong relation between non‐verbal IQ (as measured by the Leiter performance scale) and language (as measured by the Vineland Communication Scale). In addition, there was familial correlation between sibs on both measures. Evidence of familial aggregation on both non‐verbal IQ and language remained even after partialling out the effect of the covariates by regression analysis and by generalized estimating equation. These findings suggest that non‐verbal IQ and language in PDD may arise from independent genetic mechanisms. The implications of this finding for linkage analysis and for identifying genetically informative phenotypes are discussed.

Replication of linkage with bipolar disorder on chromosome 16p in the eastern Quebec population

In a previous study [Maziade et al. (2005); Mol Psychiatry 10:486–499], we provided evidence for linkage (parametric lod score of 4.05) on chromosome 16p for bipolar affective disorder (BP) in 21 kindreds from Eastern Quebec, a population characterized by a founder effect. Using a stringent design, we performed a replication study in a second sample of 27 kindreds (sample 2) collected from the same population and assessed with the same methodologies as in our original sample (sample 1), that is with the same diagnostic procedure and using a common set of 23 markers studied with model‐based (parametric) and model‐free (nonparametric) linkage analyses. We replicated our initial finding with P values <0.001. Indeed, maximum NPLall scores of 3.7 and 3.52 were found at marker D16S3060 in sample 2 for the narrow and broad BP phenotype definition, respectively. For the latter definition, the nonparametric score reached 3.87 in the combined sample, a value that exceeded the maximum NPL score obtained in each individual sample (NPLall = 2.32 in sample 1; NPLall = 3.52 in sample 2). Moreover, a refined phenotype restricted to BP associated with psychosis yielded significant evidence for linkage in each individual sample (NPLall = 2.38 in sample 1; NPLall = 2.72) while yielding the best result (NPLall score = 3.90) in the combined sample (samples 1 and 2), despite an important reduction in the number of affected individuals. It is also noteworthy that the use of the refined phenotype provided a location of the maximum linkage peak shared by both samples, that is, at marker D16S668 in 16p13.12, suggesting consistency across samples. Our study provided one of the strongest pieces of evidence for linkage with BP in 16p and illustrated the heuristic potential of a replication study in a second sample ascertained from the same population and using homogeneous methodologies.

La thérapie cognitivo-comportementale des psychoses en début d'évolution: étude ouverte en milieu clinique.

OBJECTIVE Meta-analysis results confirm that cognitive-behavioural therapy in psychosis (CBTp) is efficient for persistent symptoms. However, external validity remains unexplored. CBTp in early psychosis (in the first 5 years after diagnosis) seems especially relevant, given a possible impact on long-term course. However, the few studies that experimented with CBTp with this population had poor results. They all introduced therapy during an acute psychotic phase and most of them performed a limited number of sessions. Therefore, our introductory open study aimed to evaluate the efficiency of a 25-session Australian CBTp program, introduced during a stable phase in Quebec patients with early psychosis. METHOD The Active Cognitive Psychotherapy for Early Psychosis program was offered to 20 patients aged 14 years or older, at a rate of 1 weekly session during 6 months. RESULTS The acceptance rate was 75%, the mean session compliance rate was 84%, and participants were satisfied with the program. Pre- and post-CBTp analyses indicated statistically significant improvements of psychotic symptomatology, which were maintained at 6-month follow-up. Self-criticism improvement was also statistically significant, post-CBTp. CONCLUSION CBTp seems to be appropriate in our clinical settings, including with adolescents. Moreover, the treatment dosage used seems to foster session compliance.