Heritability and genome-wide linkage in US and Australian twins identify novel genomic regions controlling chromogranin A

O'Connor, Daniel T., Zhu, Gu, Rao, Fangwen, Taupenot, Laurent, Fung, Maple M., Das, Madhusudan, Mahata, Sushil K., Mahata, Manjula, Wang, Lei, Zhang, Kuixing, Greenwood, Tiffany A., Shih, Pei-an Betty, Cockburn, Myles G, Ziegler, Michael G., Stridsberg, Mats, Martin, Nicholas G. and Whitfield, John B. (2008) Heritability and genome-wide linkage in US and Australian twins identify novel genomic regions controlling chromogranin A. Circulation, 118 3: 247-257. doi:10.1161/CIRCULATIONAHA.107.709105


Author O'Connor, Daniel T.
Zhu, Gu
Rao, Fangwen
Taupenot, Laurent
Fung, Maple M.
Das, Madhusudan
Mahata, Sushil K.
Mahata, Manjula
Wang, Lei
Zhang, Kuixing
Greenwood, Tiffany A.
Shih, Pei-an Betty
Cockburn, Myles G
Ziegler, Michael G.
Stridsberg, Mats
Martin, Nicholas G.
Whitfield, John B.
Title Heritability and genome-wide linkage in US and Australian twins identify novel genomic regions controlling chromogranin A
Journal name Circulation   Check publisher's open access policy
ISSN 0009-7322
1524-4539
Publication date 2008-07-15
Sub-type Article (original research)
DOI 10.1161/CIRCULATIONAHA.107.709105
Volume 118
Issue 3
Start page 247
End page 257
Total pages 11
Place of publication Baltimore, MD, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
Background— Chromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits catecholamine release. We approached catestatin heritability using twin pairs, coupled with genome-wide linkage, in a series of twin and sibling pairs from 2 continents.
Methods and Results— Hypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in twins was 44% to 60%. Six hundred fifteen nuclear families yielded 870 sib pairs for linkage, with significant logarithm of odds peaks on chromosomes 4p, 4q, and 17q. Because acidification of catecholamine secretory vesicles determines CHGA trafficking and processing to catestatin, we genotyped at positional candidate ATP6N1, bracketed by peak linkage markers on chromosome 17q, encoding a subunit of vesicular H+-translocating ATPase. The minor allele diminished CHGA secretion and processing to catestatin. The ATP6N1 variant also influenced blood pressure in 1178 individuals with the most extreme blood pressure values in the population. In chromaffin cells, inhibition of H+-ATPase diverted CHGA from regulated to constitutive secretory pathways.
Conclusions— We established heritability of catestatin in twins from 2 continents. Linkage identified 3 regions contributing to catestatin, likely novel determinants of sympathochromaffin exocytosis. At 1 such positional candidate (ATP6N1), variation influenced CHGA secretion and processing to catestatin, confirming the mechanism of a novel trans-QTL for sympathochromaffin activity and blood pressure.
Keyword Catecholamines
Genes
Genetics
Hypertension
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Wed, 09 Nov 2011, 15:09:14 EST by Miss Kristy Reid on behalf of School of Medicine