Dataset Information

Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a: implications for secretion and blood pressure.

ABSTRACT: 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.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.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.

SUBMITTER: O'Connor DT

PROVIDER: S-EPMC2654229 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a: implications for secretion and blood pressure.

O'Connor Daniel T DT Zhu Gu G Rao Fangwen F Taupenot Laurent L Fung Maple M MM Das Madhusudan M Mahata Sushil K SK Mahata Manjula M Wang Lei L Zhang Kuixing K Greenwood Tiffany A TA Shih Pei-an Betty PA Cockburn Myles G MG Ziegler Michael G MG Stridsberg Mats M Martin Nicholas G NG Whitfield John B JB

Circulation 20080630 3

<h4>Background</h4>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.<h4>Methods and results</h4>Hypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in tw ...[more]

PMID: 18591442

Similar Datasets

Project description:IntroductionPerinatal outcomes for singleton pregnancies are poorer, on average, for Aboriginal people than non-Aboriginal people, but little is known about Aboriginal multifetal pregnancies. Yet multifetal pregnancies and births are often more complicated and have poorer outcomes than singleton pregnancies. We describe the pregnancies, births and perinatal outcomes for Aboriginal twins born in Western Australia (WA) and New South Wales (NSW) with comparisons to Aboriginal singletons in both states and to non-Aboriginal births in NSW.Materials and methodsWhole-population birth records and birth and death registrations were linked for all births during 2000-2013 (WA) and 2002-2008 (NSW). Hospital records and the WA Register of Developmental Anomalies - Cerebral Palsy were linked for all WA births and hospital records for a subset of NSW births. Descriptive statistics are reported for maternal and child demographics, maternal health, pregnancy complications, births and perinatal outcomes.ResultsThirty-four thousand one hundred twenty-seven WA Aboriginal, 32,352 NSW Aboriginal and 601,233 NSW non-Aboriginal births were included. Pregnancy complications were more common among mothers of Aboriginal twins than Aboriginal singletons (e.g. 17% of mothers of WA twins had hypertension/pre-eclampsia/eclampsia vs 8% of mothers of singletons) but similar to mothers of NSW non-Aboriginal twins. Most Aboriginal twins were born in a principal referral, women's or large public hospital. The hospitals were often far from the mother's home (e.g. 31% of mothers of WA Aboriginal twins gave birth at hospitals located more than 3 h by road from their home). Outcomes were worse for Aboriginal liveborn twins than Aboriginal singletons and non-Aboriginal twins (e.g. 58% of NSW Aboriginal twins were preterm compared to 9% of Aboriginal singletons and 49% non-Aboriginal twins).ConclusionsMothers of Aboriginal twins faced significant challenges during the pregnancy, birth and the postnatal period in hospital and, in addition to accessible specialist medical care, these mothers may need extra practical and psychosocial support throughout their journey.

Project description:Studies of copy-number variation and linkage disequilibrium (LD) have typically excluded complex regions of the genome that are rich in duplications and prone to rearrangement. In an attempt to assess the heritability and LD of copy-number polymorphisms (CNPs) in duplication-rich regions of the genome, we profiled copy-number variation in 130 putative "rearrangement hotspot regions" among 269 individuals of European, Yoruba, Chinese, and Japanese ancestry analyzed by the International HapMap Consortium. Eighty-four hotspot regions, corresponding to 257 bacterial artificial chromosome (BAC) probes, showed evidence of copy-number differences. Despite a predisposing genetic architecture, no polymorphism was ever observed in the remaining 46 "rearrangement hotspots," and we suggest these represent excellent candidate sites for pathogenic rearrangements. We used a combination of BAC-based and high-density customized oligonucleotide arrays to resolve the molecular basis of structural rearrangements. For common variants (frequency >10%), we observed a distinct bias against copy-number losses, suggesting that deletions are subject to purifying selection. Heritability estimates did not differ significantly from 1.0 among the majority (30 of 34) of loci analyzed, consistent with normal Mendelian inheritance. Some of the CNPs in duplication-rich regions showed strong LD with nearby single-nucleotide polymorphisms (SNPs) and were observed to segregate on ancestral SNP haplotypes. However, LD with the best available SNP markers was weaker than has been reported for deletion polymorphisms in less complex regions of the genome. These observations may be accounted for by a low density of SNP data in duplicated regions, challenges in mapping and typing the CNPs, and the possibility that CNPs in these regions have rearranged on multiple haplotype backgrounds. Our results underscore the need for complete maps of genetic variation in duplication-rich regions of the genome.

Project description:IMPORTANCE:Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction. OBJECTIVE:To estimate familial risk and heritability of cancer types in a large twin cohort. DESIGN, SETTING, AND PARTICIPANTS:Prospective study of 80,309 monozygotic and 123,382 same-sex dizygotic twin individuals (N?=?203,691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50,990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up. EXPOSURES:Shared environmental and heritable risk factors among pairs of twins. MAIN OUTCOMES AND MEASURES:The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin's development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death. RESULTS:A total of 27,156 incident cancers were diagnosed in 23,980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%). CONCLUSIONS AND RELEVANCE:In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

Dataset Information

Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a: implications for secretion and blood pressure.

Publications

Heritability and genome-wide linkage in US and australian twins identify novel genomic regions controlling chromogranin a: implications for secretion and blood pressure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets