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Somatically acquired structural genetic differences: a longitudinal study of elderly Danish twins.

ABSTRACT: Structural genetic variants like copy number variants (CNVs) comprise a large part of human genetic variation and may be inherited as well as somatically acquired. Recent studies have reported the presence of somatically acquired structural variants in the human genome and it has been suggested that they may accumulate in elderly individuals. To further explore the presence and the age-related acquisition of somatic structural variants in the human genome, we investigated CNVs acquired over a period of 10 years in 86 elderly Danish twins as well as CNV discordances between co-twins of 18 monozygotic twin pairs. Furthermore, the presence of mosaic structural variants was explored. We identified four mosaic acquired uniparental disomy events on chromosome 4q and 14q in the follow-up samples from four individuals, and our study thereby supports the increasing prevalence of somatic mosaic variants with age.

SUBMITTER: Magaard Koldby K

PROVIDER: S-EPMC5027681 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Somatically acquired structural genetic differences: a longitudinal study of elderly Danish twins.

Magaard Koldby Kristina K Nygaard Marianne M Christensen Kaare K Christiansen Lene L

European journal of human genetics : EJHG 20160420 10

Structural genetic variants like copy number variants (CNVs) comprise a large part of human genetic variation and may be inherited as well as somatically acquired. Recent studies have reported the presence of somatically acquired structural variants in the human genome and it has been suggested that they may accumulate in elderly individuals. To further explore the presence and the age-related acquisition of somatic structural variants in the human genome, we investigated CNVs acquired over a pe ...[more]

PMID: 27094753

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Project description:BackgroundEpigenetic inactivation of O6-methylguanine DNA-methyltransferase (MGMT) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying MGMT gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to MGMT methylation in a Danish twin cohort.MethodsDNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the MGMT gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of MGMT for replication.ResultsUnivariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1, h2?>?0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2, h2?>?0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves (h2?>?0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years.ConclusionsWe have identified 6 CpG sites linked to the MGMT gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of MGMT gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.

Project description:BACKGROUND:Transient cognitive impairment is common in adult patients of all ages following anaesthesia and surgery. Apolipoprotein E (APOE) ?4 carriers may have a larger deterioration in short-term cognitive function after major surgery compared with APOE ?4 noncarriers. OBJECTIVES:The aim was to examine the effect of APOE ?4 on the association between exposure to surgery and anaesthesia, and subsequent cognitive functioning. A more pronounced deterioration in cognitive function in APOE ?4 carriers was hypothesised. DESIGN:An observational cross-sectional and a 6 to 10 years longitudinal twin cohort design. SETTING:Survey and register study of 2936 Danish twins aged 45 to 92 years. MAIN OUTCOME MEASURES:Cognitive function was assessed using five age-sensitive cognitive tests. In the cross-sectional study, we compared twins exposed to surgery with a reference group (unexposed). Linear regression models were used adjusting for sex and age and stratified by APOE ?4 carrier status. In the longitudinal cognitive follow-up study 1671 twins participated. Intrapair analyses were also performed using 70 same-sexed twin pairs concordant for APOE ?4 carrier status, but discordant for major surgery. RESULTS:APOE ?4 carriers had lower cognitive scores compared with noncarriers, and this was statistically significant in elderly twins 70+ years of age (mean difference, -0.67; 95% CI, -1.14 to -0.17). There was no significant impact on cognitive function after surgery according to APOE ?4 carrier status in the cross-sectional study. Similarly, there was no APOE ?4 modification in the longitudinal study. Also, in the intrapair analyses no evidence was found of lower cognitive score after major surgery compared with the nonexposed cotwins among APOE ?4 carriers. CONCLUSION:No evidence was found of more pronounced long-term deterioration in cognitive function after surgery among APOE ?4 carriers, but elderly APOE ?4 carriers in general performed worse on the cognitive tests than noncarriers.

Dataset Information

Somatically acquired structural genetic differences: a longitudinal study of elderly Danish twins.

Publications

Somatically acquired structural genetic differences: a longitudinal study of elderly Danish twins.

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