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

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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.

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Acknowledgments

The authors thank Kim Wardlaw for technical assistance. We are grateful to the patients and family members who participated in this study. This work was supported by NIH grants R01 MH 077233 (JFC) and RR 03655 (RCE).

Conflict of interest

To the best knowledge of the authors, there are no or any potential conflicts of interest relevant to the content of the current manuscript.

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Author notes

  1. Wenbiao Li

    Present address: Beijing Anding Hospital, Capital Medical University, Beijing, 10088, China

Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, Atlanta, 30322, GA, USA

    Joseph F. Cubells, Wenbiao Li, Yi-Lang Tang & Kristina Mercer

  2. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Joseph F. Cubells & Robert W. Bonsall

  3. Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Xiangqing Sun & Robert C. Elston

  4. Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA

    John A. McGrath, Dimitri Avramopoulos, Virginia K. Lasseter, Paula S. Wolyniec & Ann E. Pulver

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  1. Joseph F. Cubells
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Correspondence to Joseph F. Cubells.

Additional information

The authors wish to dedicate this manuscript to V. K. Lasseter’s memory.

J. F. Cubells and X. Sun contributed equally to this manuscript.

V. K. Lasseter: deceased.

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Cubells, J.F., Sun, X., Li, W. et al. Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia. Hum Genet 130, 635–643 (2011). https://doi.org/10.1007/s00439-011-0989-6

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