The D4 dopamine receptor (DRD4) maps to distal 11p close to HRAS

Dopaminergic pathophysiology is important in several psychiatric illnesses. The recently cloned D4 dopamine receptor gene (DRD4) shows considerable homology to the D2 and D3 dopamine receptors (DRD2 and DRD3); pharmacologically, its affinity for the atypical antipsychotic clozapine is much higher than that of these other dopamine receptors. Probe pB28 for this locus recognizes an informative HincII polymorphism. We typed this polymorphism on several large reference families (a total of about 271 individuals) to place DRD4 in the genetic linkage map. Pairwise linkage analysis (using ILINK) provided evidence for close linkage to the distal 11p loci tyrosine hydroxylase (TH) and the Harvey ras oncogene (HRAS). We used our version of LINKMAP adapted to run under distributed parallel processing (Linda-LINKMAP) for an analysis moving DRD4 across a fixed map with HRAS set 3.8 cM distal to TH. This localized DRD4 close to HRAS, with no crossovers observed between those loci and a maximum lod score of 19.9 (2 cM distal to HRAS). The one LOD unit support interval extends from about 1 cM proximal to HRAS to 8 cM distal to HRAS. Crossovers identified in one kindred place DRD4 distal to TH, providing further evidence for its location close to HRAS, making DRD4 one of the most telomeric of 11p markers. (This also places DRD4 in band 11p15.5.)