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Human Genetics

, Volume 130, Issue 5, pp 635–643 | Cite as

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

  • Joseph F. Cubells
  • Xiangqing Sun
  • Wenbiao Li
  • Robert W. Bonsall
  • John A. McGrath
  • Dimitri Avramopoulos
  • Virginia K. Lasseter
  • Paula S. Wolyniec
  • Yi-Lang Tang
  • Kristina Mercer
  • Ann E. Pulver
  • Robert C. Elston
Original Investigation

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.

Keywords

Schizophrenia Linkage Signal Single Nucleotide Polymorphism Marker Octopamine Linkage Peak 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

439_2011_989_MOESM1_ESM.doc (67 kb)
Supplementary material 1 (DOC 67 kb)
439_2011_989_MOESM2_ESM.pptx (169 kb)
Supplementary material 2 (PPTX 169 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Joseph F. Cubells
    • 1
    • 2
  • Xiangqing Sun
    • 3
  • Wenbiao Li
    • 1
    • 5
  • Robert W. Bonsall
    • 2
  • John A. McGrath
    • 4
  • Dimitri Avramopoulos
    • 4
  • Virginia K. Lasseter
    • 4
  • Paula S. Wolyniec
    • 4
  • Yi-Lang Tang
    • 1
  • Kristina Mercer
    • 1
  • Ann E. Pulver
    • 4
  • Robert C. Elston
    • 3
  1. 1.Department of Human GeneticsEmory University School of MedicineAtlantaUSA
  2. 2.Department of Psychiatry and Behavioral SciencesEmory University School of MedicineAtlantaUSA
  3. 3.Department of Epidemiology and BiostatisticsCase Western Reserve University School of MedicineClevelandUSA
  4. 4.Department of PsychiatryJohns Hopkins School of MedicineBaltimoreUSA
  5. 5.Beijing Anding HospitalCapital Medical UniversityBeijingChina

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