THE DOPAMINE TRANSPORTER PROTEIN GENE (SLC6A3) - PRIMARY LINKAGE MAPPING AND LINKAGE STUDIES IN TOURETTE SYNDROME

The dopamine transporter, the molecule responsible for presynaptic reu ptake of dopamine and a major site of action of psychostimulant drugs, including cocaine, is encoded by locus SLC6A3 (alias DAT1), The prote in's actions and DAT's specific localization to dopaminergic neurons m ake it a candidate gene for several psychiatric illnesses. Alleles at this locus have been reported to be associated with cocaine-induced pa ranoia and attention deficit disorder, SLC6A3 has been mapped to dista l chromosome 5p, using physical methods. Our goal was to place SLC6A3 in the genetic linkage map and to test for linkage to Tourette syndrom e. Genetic linkage methods were used to place SLC6A3 in the genetic li nkage map. Four extended pedigrees (one of which overlaps with CEPH) w ere typed. Linkage with Tourette syndrome (TS) was also examined. SLC6 A3 showed close linkage with several markers previously mapped to dist al chromosome 5p, including D5S11 (Z(max) = 16.0, theta(M) = theta(F) = 0.03, results from four families) and D5S678 (Z(max) = 7.84, theta(M ) = theta(F) = 0, results from two families). Observed crossovers esta blished that SLC6A3 is a distal marker close to D5S10 and D5S678, but these three distal markers could not be ordered, Linkage between TS an d SLC6A3 could be excluded independently in two branches of a large ki ndred segregating TS; the lod score in a third family was also negativ e, but not significant: Cumulative results show a lod score of -6.2 at theta = 0 and of -3.9 at theta = 0.05 (dominant model, narrow disease definition). SLC6A3 thus maps to distal chromosome 5p by linkage anal ysis, in agreement with previous physical mapping data. A mutation at SLC6A3 is not causative for TS in the two large families that generate d significant negative lod scores (if the parameters of our analyses w ere correct) and is unlikely to be causative in the family that genera ted a negative lod score that did not reach significance. These result s do not exclude a role for the dopamine transporter in influencing ri sk for TS in combination with other loci. (C) 1995 Academic Press, Inc .