POSSIBLE LOCUS OF BIPOLAR DISORDER NEAR THE DOPAMINE TRANSPORTER ON CHROMOSOME-5

The dopamine transporter (DAT) plays a key role in the regulation of d opaminergic neurotransmission by mediating the active reuptake of syna ptic dopamine. It is an important candidate gene for bipolar disorder because of data implicating dopamine abnormalities in mania, and becau se it is the site of action of amphetamine, which has activating and p sychotogenic properties. DAT has recently been cloned by its homology to a family of transporters, and mapped to chromosome 5p15.3. We teste d DAT for linkage to bipolar disorder in a collection of 21 families f rom the general North American population (University of California, S an Diego/University of British Columbia [UCSD/UBC] families), three Ic elandic pedigrees, and Old Order Amish pedigree 110. We examined three markers at DAT, including a 5' TaqI RFLP (HDAT-TaqI), a highly polymo rphic variable number of tandem repeats marker (VNTR) (HDAT-VNTR1), an d a 3' 40-bp repeat marker (HDAT-PCR1), as well as two nearby microsat ellite markers, D5S392 and D5S406. A maximum lod score of 2.38 was obt ained at D5S392 in one of the UCSD/UBC families under an autosomal-dom inant model. A lod score of 1.09 was also obtained under the same domi nant model in the Amish at HDAT-PCR1. In the combined set of families, a maximum lod score of 1.76 was obtained under an autosomal-recessive model at HDAT-TaqI. Positive results were also obtained at several ma rkers, using three nonparametric methods in the UCSD/UBC family set: t he affected pedigree member method (P = 0.001), an affected sib pair m ethod (ESPA, P = 0.0008), and the transmission disequilibrium test (P = 0.024). These results suggest the presence of a susceptibility locus for bipolar disorder near the DAT locus on chromosome 5. (C) 1996 Wil ey-Liss, Inc.