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.

Some Capabilities for Model-Based and Model-Free Linkage Analysis using the Program Package S.A.G.E. (Statistical Analysis for Genetic Epidemiology)

“…2 ). This is consistent with the earlier study showing that the best fitting model may not produce a better linkage result [9] . However, note that in the best fitting model, when 1 was estimated, its standard error was relatively large, i.e.…”

“…This type file can then be used for model-based linkage analysis by LODLINK or MLOD. For the quantitative trait pD ␤ H, a low-value dominant model under a square-root transformation was shown to produce the best genome-wide linkage signal, on chromosome 9 at the D ␤ H structural locus [9] . Here we illustrate the fitting of the low-value dominant model with SEGREG, incorporating residual familial correlations and various power transformations and covariates; we then investigate how these factors affect the linkage result.…”

“…An earlier study fitted the segregation model under a square-root transformation by fixing 1 = 0.5 and 2 = 0 [9] . In this study, we fixed 2 = 0.1.…”

“…Model-free linkage analysis of pD ␤ H activity in these pedigrees was reported in [9] . Here we concentrate on schizophrenia as our trait of interest.…”

Linkage Analysis in the Next-Generation Sequencing Era

“…Linkage methods have been successfully applied to quantitative traits as well. In a series of papers spanning almost 30 years, the specific activity of dopamine-beta hydroxylase activity, an enzyme that catalyzes the conversion of dopamine to norepinephrine, was localized to the chromosomal 9q34 region, and specific variants that were responsible, at least in part, for the variation of the trait activity have been identified [9][10][11][12][13][14] . It is important to note that in this case the phenotype, the specific activity of the enzyme, is functionally closely related to the underlying structural locus.…”