Mutation and association analysis of the 5 ' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia

Although the association between the Ser9Gly polymorphism of the dopamine D 3 receptor gene (DRD3) and schizophrenia has been investigated by many rese arch groups, it is not known whether the Ser9Gly polymorphism alone or a va riation in linkage disequilibrium may effect susceptibility to schizophreni a. We searched the 5' region of the DRD3 gene and found three novel polymor phisms: -712G/C, -205A/G, and Ala38Thr, The Ala38Thr polymorphism is locate d in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients an d 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association bet ween the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0. 02), Furthermore, there was a highly significant association between haplot ypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia ( P = 0.0007, corrected P = 0.007), These positive findings were replicated i n an additional 99 Japanese schizophrenia patients and 132 controls (P = 0. 04 and 0.0004, respectively). The most allelic differences of the Ser9Gly p olymorphism between patient and control groups arose from the chromosome ca rrying specific alleles of the other three polymorphisms, This study indica tes unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes a ssociated with schizophrenia.