EXCLUSION OF CLOSE LINKAGE OF BIPOLAR DISORDER TO THE G(S)-ALPHA-SUBUNIT GENE IN 9 AUSTRALIAN PEDIGREES

Growing evidence suggests that guanine nucleotide binding proteins (G proteins) may be involved in both the pathogenesis and treatment of bi polar affective disorder. Both overactive G proteins and increased lev els of the a subunit of the stimulatory form (G(s)-alpha) have been de monstrated in peripheral leucocytes of manic patients while an increas e of G(s)-alpha subunit levels has also been found in a postmortem stu dy of bipolar disorder. The function of G(s) and G(i) alpha subunits h as now been shown to be affected by lithium. The present study aimed t o determine whether bipolar affective disorder was linked to the G(s)- alpha subunit gene which has been mapped to chromosomal region 20q13.2 . Linkage analysis utilized the PCR amplification of a portion of the G(s)-alpha gene that contains a dinucleotide repeat (CA repeat) polymo rphism. Linkage of bipolar disorder and recurrent depression to the G( s)-alpha subunit gene was tested using a series of autosomal dominant and recessive models with varying penetrance levels. Additionally, lin kage was examined using a series of levels of definitions of affective illness Close linkage to the G(s)-alpha subunit gene was strongly exc luded using each model and definition. Thus, our study indicates that a genetic defect in the G(s)-alpha subunit gene is unlikely to be the cause of bipolar disorder.