Linkage disequilibrium analysis of G-olf sub( alpha ) (GNAL) in bipolar affective disorder

This study examines G-olf sub( alpha ) as a possible candidate gene for susceptibility to bipolar affective disorder (BPAD) using the Transmission Disequilibrium Test (TDT). G-olf sub( alpha ), which encodes a subunit of a G-protein involved in intracellular signaling, maps within a region of chromosome 18 that has been implicated by two different linkage studies as a potential site of BPAD susceptibility loci. The expression pattern of G-olf sub( alpha ) in the brain, its coupling to dopamine receptors, and the effects of lithium salts on G-proteins all support G-olf sub( alpha ) as a candidate gene for BPAD. Our study population consisted of 106 probands and sibs with bipolar I disorder, with a median age-at-onset of 21.5 years ascertained from the United States. There was no evidence of linkage disequilibrium between BPAD and any of the observed G-olf sub( alpha ) alleles in our sample. Division of families based on sex of the transmitting parent did not significantly change the results. This sample had good power (78%) to detect linkage disequilibrium with alleles conferring a relative risk equal to that estimated for the putative 18p locus (2.58). Our results do not support a major role for G-olf sub( alpha ) as a susceptibility locus for BPAD in a substantial portion of our sample. Other genes lying near G-olf sub( alpha ) within the linked region on chromosome 18 cannot be excluded by our data. This study illustrates the use of the TDT in evaluating candidate genes within linked chromosome regions.