Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization

Rheumatology ◽  
2019 ◽  
Vol 59 (5) ◽  
pp. 940-947 ◽  
Author(s):  
Zhen Zeng ◽  
Wanting Zhang ◽  
Yu Qian ◽  
Huijun Huang ◽  
David J H Wu ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Genome Wide ◽  
Inverse Variance ◽  
A Genome ◽  
Mean Differences

Abstract Objective To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA. Methods Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association. Results In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association. Conclusion Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.

scholarly journals Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Songzan Chen ◽  
Fangkun Yang ◽  
Tian Xu ◽  
Yao Wang ◽  
Kaijie Zhang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Plasma Homocysteine ◽  
Fixed Effect ◽  
Sensitivity Analyses ◽  
Causal Association ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

BackgroundAlthough several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.MethodsA two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10–8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.ResultsIn total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.ConclusionsThis two-sample MR analysis found no evidence to support causal association of Hcy with AF.

Abstract 16003: Genetic Variation Associated With Favorable Exercise Response in Patients With Systolic Heart Failure: A Hf-action Trial Substudy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sara Coles ◽  
Stephanie Giamberardino ◽  
Carol Haynes ◽  
Ruicong She ◽  
Hongsheng Gui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trial ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Systolic Heart Failure ◽  
Genome Wide Association ◽  
Supervised Exercise ◽  
Genome Wide ◽  
A Genome ◽  
Response To Exercise

Background: Exercise has shown benefit in patients with systolic heart failure, including in the clinical trial Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). There is heterogeneity in who derives benefit from exercise, and the biologic mechanisms of favorable response to exercise in systolic heart failure are not well understood. Hypothesis: Genetic variation is an underlying factor influencing heterogeneity in response to exercise in patients with systolic heart failure. Methods: The HF-ACTION trial randomized individuals with systolic heart failure (left ventricular ejection fraction <35%) to supervised exercise versus usual care. In this study, we performed a genome wide association study (GWAS) in the HF-ACTION biorepository using the Axiom Biobank1 genotyping array (13,403,591 single nucleotide polymorphisms [SNPs] after quality control on directly genotyped and 1000 genomes imputed data), in N=377 study subjects who completed the supervised exercise arm. Using change in peak VO2 as our outcome, we ran within-ancestry GWASes, modeling SNP effects as both additive and dominant, and conducted across-ancestry meta-analysis within each genetic model. Results: Five loci met genome-wide significance in the European ancestry analyses, 5 loci in the African ancestry, and 8 in the meta-analyses. The two most significantly associated loci across both additive and dominant meta-analysis models were rs111577308 located in the histone acetylation for transcription elongator complex 3 gene ( ELP3, p=1.212x10 -9 ) and rs75444785 located in the phosphodiesterase 4D gene ( PDE4D , p=1.565x10 -9 ). ELP3 is responsible for histone modifications related to DNA transcription factor complexes, and PDE4D is involved in cyclic AMP cell signaling. In silico analysis of these loci showed that they are in linkage with regions associated with skeletal muscle and peripheral vascular disease phenotypes. Conclusions: Using a genome-wide association study in a well-phenotyped clinical trial of exercise in systolic heart failure, we found common genetic variants in genes involved in DNA transcription histone modification and cyclic AMP cell signaling that are associated with a more favorable response to exercise.

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

2020 ◽  
Vol 105 (12) ◽  
pp. 3854-3864
Author(s):  
Jin-Fang Chai ◽  
Shih-Ling Kao ◽  
Chaolong Wang ◽  
Victor Jun-Yu Lim ◽  
Ing Wei Khor ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hba1c Level ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Specific Reference ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P &lt; 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

scholarly journals A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

Bone Reports ◽  
2016 ◽  
Vol 5 ◽  
pp. 233-242 ◽  
Author(s):  
Kira C. Taylor ◽  
Daniel S. Evans ◽  
Digna R. Velez Edwards ◽  
Todd L. Edwards ◽  
Tamar Sofer ◽  
...  
Keyword(s):  
African American ◽  
Association Study ◽  
African American Women ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
American Women ◽  
Clinical Fracture ◽  
Genome Wide ◽  
A Genome

A GENOME-WIDE ASSOCIATION STUDY IN PROGRESSIVE SUPRANUCLEAR PALSY

2015 ◽  
Vol 86 (11) ◽  
pp. e4.68-e4
Author(s):  
Zhongbo Chen ◽  
Aleksey Shatunov ◽  
Gilbert Bensimon ◽  
Christine Payan ◽  
Albert Ludolph ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Chromosome 17 ◽  
Gene Variants ◽  
Genome Wide ◽  
Mapt Gene ◽  
Common Genetic Variants ◽  
A Genome

BackgroundProgressive supranuclear palsy (PSP) is a debilitating Parkinsonian movement disorder characterised by tau protein burden. We aimed to identify common genetic variants influencing PSP susceptibility through a genome-wide association analysis (GWAS) of a multi-centre European study, Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS), recruiting clinically well-characterised patients. We combined this with a meta-analysis of previously-identified gene variants.MethodsWe genotyped 275,684 single nucleotide polymorphisms using Illumina microarrays in 212 PSP cases from the UK, Germany and France, and compared these with 4,707 matched controls. GWAS was performed using PLINK. Meta-analysis was performed with METAL. Genome-wide significance was defined as p<5×10^–8.ResultsWe observed multiple associations on chromosome 17 within or close to the MAPT gene, a well-established risk locus for PSP, confirming the sample and method validity. Of nine other previously reported associations, meta-analysis only confirmed that the MOBP variation (rs1768208) modified PSP risk (p=3.29×10^–13).ConclusionIn the GWAS and meta-analysis, we found the chromosome 17 inversion region to be associated with PSP susceptibility. Furthermore, we have shown that MOBP can modify the risk of PSP, possibly through influencing oligodendrocyte tau inclusions. These identified gene variants provide novel insights into the underlying genetics of sporadic PSP.

scholarly journals Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort

2018 ◽  
Author(s):  
Sandra M. Meier ◽  
Kalevi Trontti ◽  
Thomas Damm Als ◽  
Mikaela Laine ◽  
Marianne Giørtz Pedersen ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Common Mental Disorders ◽  
Twin Studies ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Association Analyses ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range

AbstractAnxiety and stress-related disorders (ASRD) are among the most common mental disorders with the majority of patients suffering from additional disorders. Family and twin studies indicate that genetic and environmental factors are underlying their etiology. As ASRD are likely to configure various expressions of abnormalities in the basic stress-response system, we conducted a genome-wide association study including 12,655 cases with various anxiety and stress-related diagnoses and 19,225 controls. Standard association analyses were performed supplemented by a framework of sensitivity analyses. Variants in PDE4B showed consistent association with ASRD across a wide range of our analyses. In mice models, alternations in PDE4B expression were observed in those mice displaying anxious behavior after exposure to chronic stress. We also showed that 28% of the variance in ASRD was accounted for by common variants and that the genetic signature of ASRD overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success.

scholarly journals Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

2018 ◽  
Author(s):  
Jessica van Setten ◽  
Jennifer A. Brody ◽  
Yalda Jamshidi ◽  
Brenton R. Swenson ◽  
Anne M. Butler ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Electrical Activity ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Regulatory Regions ◽  
European Descent ◽  
Genome Wide ◽  
A Genome ◽  
Pr Interval

ABSTRACTElectrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

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