Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia

Dopamine beta-hydroxylase (D beta H) catalyzes the conversion of dopamine to norepinephrine. D beta H enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma D beta H activity (pD beta H) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pD beta H to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pD beta H. Prior studies have suggested that variation in pD beta H, or genetic variants at D beta H, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pD beta H in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pD beta H under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pD beta H, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pD beta H, and suggest that a locus near 20p12 also influences pD beta H.