scholarly journals Alcohol consumption and telomere length: observational and Mendelian randomization approaches

2021 ◽  
Author(s):  
Anya Topiwala ◽  
Bernd Taschler ◽  
Klaus P Ebmeier ◽  
Steve Smith ◽  
Hang Zhou ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Telomere Length ◽  
Alcohol Use Disorder ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Prevention Strategies ◽  
Genome Wide ◽  
Non Linear ◽  
Alcoholic Drinks ◽  
Potential Threshold

Alcohols impact on telomere length, a proposed marker of biological age, is unclear. We performed the largest observational study to date and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption and alcohol use disorder (AUD). Non-linear MR employed UK Biobank individual data. MR analyses suggest a causal relationship between alcohol and telomere length: both genetically predicted alcohol traits were inversely associated with telomere length. 1 S.D. higher genetically-predicted log-transformed alcoholic drinks weekly had a -0.07 S.D. effect on telomere length (95% confidence interval [CI]:-0.14 to -0.01); genetically-predicted AUD -0.06 S.D. effect (CI:-0.10 to -0.02). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings have implications for potential aging-related disease prevention strategies.

scholarly journals Association between genetically predicted telomere length and facial skin aging in the UK Biobank: a Mendelian randomization study

GeroScience ◽  
2020 ◽  
Author(s):  
Yiqiang Zhan ◽  
Sara Hägg
Keyword(s):  
Telomere Length ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Large Population ◽  
Uk Biobank ◽  
Facial Aging ◽  
Genome Wide ◽  
A Genome ◽  
Weighted Median ◽  
The Uk

Abstract Are shorter telomeres causal risk factors for facial aging on a large population level? To examine if longer, genetically predicted telomeres were causally associated with less facial aging using Mendelian randomization analysis. Two-sample Mendelian randomization methods were applied to the summary statistics of a genome-wide association study (GWAS) for self-reported facial aging from 417, 772 participants of the UK Biobank data. Twenty single-nucleotide polymorphisms (SNPs) that were of genome-wide significance were selected as instrumental variables for leukocyte telomere length. The main analyses were performed primarily using the random-effects inverse-variance weighted method and were complemented with the MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was used to assess horizontal pleiotropy. Longer genetically predicted telomeres were associated with a lower likelihood of facial aging (β = − 0.02, 95% confidence interval: − 0.04, − 0.002). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. The intercept of MR-Egger regression was close to zero (0.002) that was not suggestive of horizontal pleiotropy. Our findings provided evidence to support a potential causal relationship between longer genetically predicted telomeres and less facial aging.

scholarly journals Genetic Determinants of Telomere Length in African American Youth

2018 ◽  
Author(s):  
Andrew M. Zeiger ◽  
Marquitta J. White ◽  
Sam S. Oh ◽  
Jonathan Witonsky ◽  
Maria G. Contreras ◽  
...  
Keyword(s):  
African American ◽  
Telomere Length ◽  
Genome Wide Association Study ◽  
African Ancestry ◽  
African American Youth ◽  
Genetic Associations ◽  
Disease States ◽  
Genome Wide ◽  
Pediatric Populations ◽  
Genetic And Environmental Factors

ABSTRACTTelomere length (TL) is associated with numerous disease states and is affected by genetic and environmental factors. However, TL has been mostly studied in adult populations of European or Asian ancestry. These studies have identified 34 TL-associated genetic variants recently used as genetic proxies for TL. The generalizability of these associations to pediatric populations and racially diverse populations, specifically of African ancestry, remains unclear. Furthermore, six novel variants associated with TL in a population of European children have been identified but not validated. We measured TL from whole blood samples of 492 healthy African American youth (children and adolescents between 8 and 20 years old) and performed the first genome-wide association study of TL in this population. We were unable to replicate neither the 34 reported genetic associations found in adults nor the six genetic associations found in European children. However, we discovered a novel genome-wide significant association between TL and rs1483898 on chromosome 14. Our results underscore the importance of examining these genetic associations with TL in diverse pediatric populations such as African Americans.

scholarly journals Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases

Epigenomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 789-800
Author(s):  
Honghuang Lin ◽  
Fan Wang ◽  
Andrew J Rosato ◽  
Lindsay A Farrer ◽  
David C Henderson ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Genome Wide ◽  
Morphine Addiction ◽  
Methylation Patterns ◽  
Methylation Quantitative Trait Loci

Aim: This study aimed to investigate the function of genome-wide association study (GWAS)-identified variants associated with alcohol use disorder (AUD)/comorbid psychiatric disorders. Materials & methods: Genome-wide genotype, transcriptome and DNA methylome data were obtained from postmortem prefrontal cortex (PFC) of 48 Caucasians (24 AUD cases/24 controls). Expression/methylation quantitative trait loci (eQTL/mQTL) were identified and their enrichment in GWAS signals for the above disorders were analyzed. Results: PFC cis-eQTLs (923 from cases+controls, 27 from cases and 98 from controls) and cis-mQTLs (9,932 from cases+controls, 264 from cases and 695 from controls) were enriched in GWAS-identified genetic variants for the above disorders. Cis-eQTLs from AUD cases were mapped to morphine addiction-related genes. Conclusion: PFC cis-eQTLs/ cis-mQTLs influence gene expression/DNA methylation patterns, thus increasing the disease risk.

scholarly journals Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample Mendelian randomization study

2016 ◽  
Vol 47 (5) ◽  
pp. 971-980 ◽  
Author(s):  
S. H. Gage ◽  
H. J. Jones ◽  
S. Burgess ◽  
J. Bowden ◽  
G. Davey Smith ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Control ◽  
Negative Control ◽  
Study Data ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Genome Wide Data

BackgroundObservational associations between cannabis and schizophrenia are well documented, but ascertaining causation is more challenging. We used Mendelian randomization (MR), utilizing publicly available data as a method for ascertaining causation from observational data.MethodWe performed bi-directional two-sample MR using summary-level genome-wide data from the International Cannabis Consortium (ICC) and the Psychiatric Genomics Consortium (PGC2). Single nucleotide polymorphisms (SNPs) associated with cannabis initiation (p < 10−5) and schizophrenia (p < 5 × 10−8) were combined using an inverse-variance-weighted fixed-effects approach. We also used height and education genome-wide association study data, representing negative and positive control analyses.ResultsThere was some evidence consistent with a causal effect of cannabis initiation on risk of schizophrenia [odds ratio (OR) 1.04 per doubling odds of cannabis initiation, 95% confidence interval (CI) 1.01–1.07, p = 0.019]. There was strong evidence consistent with a causal effect of schizophrenia risk on likelihood of cannabis initiation (OR 1.10 per doubling of the odds of schizophrenia, 95% CI 1.05–1.14, p = 2.64 × 10−5). Findings were as predicted for the negative control (height: OR 1.00, 95% CI 0.99–1.01, p = 0.90) but weaker than predicted for the positive control (years in education: OR 0.99, 95% CI 0.97–1.00, p = 0.066) analyses.ConclusionsOur results provide some that cannabis initiation increases the risk of schizophrenia, although the size of the causal estimate is small. We find stronger evidence that schizophrenia risk predicts cannabis initiation, possibly as genetic instruments for schizophrenia are stronger than for cannabis initiation.

scholarly journals Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data

2018 ◽  
Vol 19 (1) ◽  
pp. 303-327 ◽  
Author(s):  
Stephen Burgess ◽  
Christopher N. Foley ◽  
Verena Zuber
Keyword(s):  
Risk Factor ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Single Gene ◽  
Study Data ◽  
Causal Inferences ◽  
Genome Wide ◽  
Multiple Regions ◽  
Polygenic Analysis

An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences?

scholarly journals Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program

Circulation ◽  
2020 ◽  
Vol 142 (17) ◽  
pp. 1633-1646 ◽  
Author(s):  
Derek Klarin ◽  
Shefali Setia Verma ◽  
Renae Judy ◽  
Ozan Dikilitas ◽  
Brooke N. Wolford ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Family History ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Risk Variants ◽  
Genome Wide ◽  
Abdominal Aortic ◽  
A Genome ◽  
Current Screening

Background: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. Methods: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. Results: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24–1.66]; P =1.6×10 −6 ), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97–1.15]; P =0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratio PRS , 1.26 [95% CI, 1.18–1.36]; P PRS =2.7×10 −11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratio PRS+family history+smoking , 1.24 [95% CI, 1.14–1.35]; P PRS =1.27×10 −6 ). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. Conclusions: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

scholarly journals A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark Gormley ◽  
Tom Dudding ◽  
Eleanor Sanderson ◽  
Richard M. Martin ◽  
Steven Thomas ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Alcohol Consumption ◽  
Oropharyngeal Cancer ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Strong Association ◽  
Smoking Behaviour ◽  
Standard Deviation Increase ◽  
Independent Effects

AbstractThe independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.

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