A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

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.

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Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

Human Molecular Genetics ◽

10.1093/hmg/ddy327 ◽

2018 ◽

Vol 28 (1) ◽

pp. 166-174 ◽

Cited By ~ 109

Author(s):

Sara L Pulit ◽

Charli Stoneman ◽

Andrew P Morris ◽

Andrew R Wood ◽

Craig A Glastonbury ◽

...

Keyword(s):

Body Fat ◽

Association Studies ◽

Meta Analysis ◽

Fat Distribution ◽

Body Fat Distribution ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

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Genetic variations and risk of placental abruption: A genome-wide association study and meta-analysis of genome-wide association studies

Placenta ◽

10.1016/j.placenta.2018.04.008 ◽

2018 ◽

Vol 66 ◽

pp. 8-16 ◽

Cited By ~ 2

Author(s):

Tsegaselassie Workalemahu ◽

Daniel A. Enquobahrie ◽

Bizu Gelaye ◽

Sixto E. Sanchez ◽

Pedro J. Garcia ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Placental Abruption ◽

Association Studies ◽

Meta Analysis ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa658 ◽

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 < 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.

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A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Journal of the American Academy of Child & Adolescent Psychiatry ◽

10.1016/j.jaac.2016.05.025 ◽

2016 ◽

Vol 55 (10) ◽

pp. 896-905.e6 ◽

Cited By ~ 68

Author(s):

Christel M. Middeldorp ◽

Anke R. Hammerschlag ◽

Klaasjan G. Ouwens ◽

Maria M. Groen-Blokhuis ◽

Beate St. Pourcain ◽

...

Keyword(s):

Attention Deficit Hyperactivity Disorder ◽

Attention Deficit ◽

Meta Analysis ◽

Population Based ◽

Genome Wide Association ◽

Hyperactivity Disorder ◽

Genome Wide ◽

A Genome

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Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke

Stroke ◽

10.1161/strokeaha.120.029123 ◽

2020 ◽

Vol 51 (8) ◽

pp. 2454-2463

Author(s):

Keith L. Keene ◽

Hyacinth I. Hyacinth ◽

Joshua C. Bis ◽

Steven J. Kittner ◽

Braxton D. Mitchell ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Meta Analysis ◽

African Descent ◽

Genome Wide Association ◽

Minority Population ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P <1×10 −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.

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