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

Abstract

Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH 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 pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, 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 pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH 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 pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.

Fig. 1

Model-based linkage analysis of pDβH activity on chromosome 9. Model-based linkage analysis of pDβH activity was performed using MLOD within S.A.G.E., as described in the text. The red solid-line profile shows the multi-point linkage for pDβH activity under a square root transformation, low-value dominant model. The green dash-dot line shows the linkage for the new trait formed after adjusting for three SNPs in the DBH gene, under the new untransformed, dominant model. The blue dotted-line profile is the multi-point linkage for the new trait formed after adjusting for the 25 SNPs in the linkage region on chromosome 9, under the new additive, logarithmic transformation model

Fig. 2

Model-free linkage analysis of pDβH activity on chromosome 9. Model-free linkage analysis was performed in SIBPAL, as described in the text. The red solid line shows linkage of square root pDβH activity. The green dash-dot line shows the linkage of the new trait formed by adjusting for three SNPs in the DBH gene. The dotted-line profile is for the new trait created by additionally adjusting for the 25 SNPs in this linkage region

Fig. 3

Model-based linkage analysis of pDβH activity on chromosome 20. The red solid line shows the multi-point linkage of pDβH activity under the square root transformation, low-value dominant model. The blue dotted-line shows the multi-point linkage analysis of the new trait created by adjusting for the 25 SNPs in the chromosome 9 linkage region, under the new additive model, with square root transformation