Exclusion of close linkage of bipolar disorder to the G_s-α subunit gene in nine Australian pedigrees

Growing evidence suggests that guanine nucleotide binding proteins (G proteins) may be involved in both the pathogenesis and treatment of bipolar affective disorder. Both overactive G proteins and increased levels of the α subunit of the stimulatory form (G_s-α) have been demonstrated in peripheral leucocytes of manic patients while an increase of G_s-α subunit levels has also been found in a postmortem study of bipolar disorder. The function of G_s and G_i α subunits has now been shown to be affected by lithium. The present study aimed to determine whether bipolar affective disorder was linked to the G_s-α subunit gene which has been mapped to chromosomal region 20q13.2. Linkage analysis utilized the PCR amplification of a portion of the G_s-α gene that contains a dinucleotide repeat (CA repeat) polymorphism. Linkage of bipolar disorder and recurrent depression to the G_s-α subunit gene was tested using a series of autosomal dominant and recessive models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective illness. Close linkage to the G_s-α subunit gene was strongly excluded using each model and definition. Thus, our study indicates that a genetic defect in the G_s-α subunit gene is unlikely to be the cause of bipolar disorder.