B. Mahieu

Expanded trinucleotide CAG repeats in families with bipolar affective disorder

Clinical anticipation has been reported in bipolar affective disorder (BPAD). The hypothesis that expanded trinucleotide repeats are related to anticipation and transmission pattern in families with bipolar affective disorder is tested in this study. Eighty-seven two-generation pairs of patients recruited from 29 bipolar families were analyzed. The repeat expansion detection method was used to detect CAG repeat expansions between successive generations. Significant changes in age at onset and episode frequency in successive generations were observed. Mean trinucleotide CAG repeat length between parental and offspring generation significantly increased when the phenotype increased in severity, i.e., changed from major depression, single episode or unipolar recurrent depression to BPAD. A parent-of-origin effect was also observed with a significant increase in median length CAG between G1 and G2 with maternal inheritance. This increase was observed notably in female offspring. Our findings indicate for the first time that expansion of CAG repeat length could explain the clinical observation of anticipation in families with BPAD. These results provide further support for expanded trinucleotide repeat sequences as risk factors in major affective disorders.

No association between bipolar affective disorder and a serotonin receptor (5-HT2A) polymorphism

The serotonergic system is implicated in the pathogenesis of affective disorders. In particular, the role of the postsynaptic 5-hydroxytryptamine (serotonin) type 2 receptor (5-HT2) has been documented by several studies. The 5-HT2A receptor gene located on chromosome 13 (13q14-21) can be considered a candidate gene for bipolar affective disorder (BPAD). We tested association between a 5-HT2A receptor DNA variant and BPAD using a case-control design. Eighty-three BPAD patients and 129 unrelated normal controls, carefully matched for sex and geographical origin, were studied. Allele and genotype frequencies as well as homo-heterozygote distribution at the 5-HT2A receptor polymorphism were compared between the two groups. No significant allelic or genotypic associations were observed. There was no significant difference for homo-heterozygote distribution between the two groups. These preliminary results may indicate that in our sample the 5-HT2 receptor polymorphism studied is unlikely to play a role in the genetic susceptibility to BPAD.

Excess tyrosine hydroxylase restriction fragment length polymorphism homozygosity in unipolar but not bipolar patients: A preliminary report

Searching for genetic risk factors of major affective disorders, segregation and association methodologies are being applied to these complex diseases which will hopefully lead to a better understanding of their genetic etiology. Tyrosine hydroxylase (TH), the rate-limiting enzyme in the metabolism of catecholamines, has been considered a candidate gene in bipolar affective disorder (BPAD) and unipolar affective disorder (UPAD). Indeed, a dysfunction of the catecholaminergic system is likely to be implicated in the pathogenesis of affective disorders (Schatzberg and Schildkraut 1995 for review). The TH gene is located on the short arm of chromosome 11 (1 lp15) and has been the subject of numerous linkage and association studies in BPAD. Linkage with TH was tested in different set of BPAD families. Most reports significantly excluded linkage between the TH gene and BPAD (Pauls et al 1991; Mendlewicz et al 1991; Mitchell et al 1991; Coon et al 1993; De bruyn et al 1994; Detera-Wadleigh et al 1994; Ewald et al 1994), however, in some families linkage

Molecular genetics of mental disorders with particular reference to affective disorders

The present article reviews the recent molecular genetic findings in affective disorders. Results of linkage and association studies are discussed in regard to the main limitations of these approaches in psychiatric disorders. On the whole, linkage and association studies contributed to the localisation of some potential vulnerability genes for Bipolar affective disorder on chromosomes 18, 5, 11, 4, 21 and X. The hypothesis of anticipation in affective disorders is also considered in light of interesting results with trinucleotide repeat mutations.