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

• Type of Material: Article
• Authors: Joseph F Cubells, Emory University; Xiangqing Sun, Case Western Reserve University; Wenbiao Li, Emory University; Robert W. Bonsall, Emory University; John A. McGrath, Johns Hopkins University; Dimitri Avramopoulos, Johns Hopkins University; Virginia K. Lasseter, Johns Hopkins University; Paula S. Wolyniec, Johns Hopkins University; Yilang Tang, Emory University; Kristina Mercer, Emory University; Ann E. Pulver, Johns Hopkins; Robert C. Elston, Case Western Reserve University
• Language: English
• Date: 2011-11
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Springer-Verlag 2011
• Final Published Version (URL): http://link.springer.com/article/10.1007%2Fs00439-011-0989-6
• Title of Journal or Parent Work: Human Genetics
• ISSN: 0340-6717
• Volume: 130
• Issue: 5
• Start Page: 635
• End Page: 643
• Grant/Funding Information: This work was supported by NIH grants R01 MH 077233 (JFC) and RR 03655 (RCE).
• Research Categories: Biology, Genetics

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.