Large-scale genome-wide association studies in east Asians identify new genetic loci influencing metabolic traits

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

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Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference

Scientific Reports ◽

10.1038/srep17958 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 38

Author(s):

Wanqing Wen ◽

Norihiro Kato ◽

Joo-Yeon Hwang ◽

Xingyi Guo ◽

Yasuharu Tabara ◽

...

Keyword(s):

Waist Circumference ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

East Asians ◽

Waist Hip Ratio ◽

Genome Wide

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GWASpro: a high-performance genome-wide association analysis server

Bioinformatics ◽

10.1093/bioinformatics/bty989 ◽

2018 ◽

Vol 35 (14) ◽

pp. 2512-2514 ◽

Cited By ~ 4

Author(s):

Bongsong Kim ◽

Xinbin Dai ◽

Wenchao Zhang ◽

Zhaohong Zhuang ◽

Darlene L Sanchez ◽

...

Keyword(s):

High Performance ◽

Large Scale ◽

Linear Mixed Model ◽

Association Studies ◽

Learning Curves ◽

Experimental Designs ◽

Genome Wide Association ◽

Supplementary Information ◽

Genome Wide Association Studies ◽

Genome Wide

Abstract Summary We present GWASpro, a high-performance web server for the analyses of large-scale genome-wide association studies (GWAS). GWASpro was developed to provide data analyses for large-scale molecular genetic data, coupled with complex replicated experimental designs such as found in plant science investigations and to overcome the steep learning curves of existing GWAS software tools. GWASpro supports building complex design matrices, by which complex experimental designs that may include replications, treatments, locations and times, can be accounted for in the linear mixed model. GWASpro is optimized to handle GWAS data that may consist of up to 10 million markers and 10 000 samples from replicable lines or hybrids. GWASpro provides an interface that significantly reduces the learning curve for new GWAS investigators. Availability and implementation GWASpro is freely available at https://bioinfo.noble.org/GWASPRO. Supplementary information Supplementary data are available at Bioinformatics online.

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Abstract 18836: Integrative Pathway Analysis of Genome-wide Association Studies of Carotid Plaque Phenotypes

Circulation ◽

10.1161/circ.132.suppl_3.18836 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Yuqi Zhao ◽

Sander M van der Laan ◽

Hester M den Ruijter ◽

Saskia Haitjema ◽

Gerard Pasterkamp ◽

...

Keyword(s):

Smooth Muscle ◽

Cardiovascular Events ◽

Association Studies ◽

Genome Wide Association ◽

Sphingolipid Metabolism ◽

Genome Wide Association Studies ◽

Plaque Composition ◽

Genetic Loci ◽

Genetic Components ◽

Genome Wide

Introduction: The composition of atherosclerotic plaques differs between individuals and contributes to the incidence of cardiovascular events. A better understanding of the biology underlying variability in plaque composition will provide insights into the progression of cardiovascular diseases. We carried out genome-wide association studies (GWAS) to investigate the genetic underpinnings of the plaque. Methods: We included carotid endarterectomy patients from the Athero-Express Biobank Study (n = 1,439). We quantified the percentage of macrophages and smooth muscle cells, the number of intraplaque vessels, the amount of collagen and calcification, the atheroma size, and the presence of plaque hemorrhage. GWAS was performed for all 9 plaque traits, and combined with summary level from GWAS consortia data on coronary artery disease (CAD), and ischemic stroke. Next, these data were integrated with data from human expression quantitative trait loci analyses, and pathway analyses of the plaque traits. Results: No individual locus reached genome-wide significance, likely due to the moderate sample size involved. However, it is plausible that perturbations of diverse pathways by a large number of genetic loci with small effects together contribute to the regulation of plaque composition. We identified 42-97 pathways significantly associated with each plaque phenotype, with many specific to each trait, supporting the presence of unique genetic components of individual plaque phenotypes. We also detected 39 pathways associated with at least four plaque phenotypes, among which were CAD-associated processes such as “extracellular matrix”, “complement and coagulation cascades” and stroke-associated pathways such as “Toll-like receptor signaling”. Interestingly, we found that smooth muscle cell percentage and atheroma size shared more genetic loci and pathways with intraplaque hemorrhage (such as “Sphingolipid metabolism”); the latter trait is associated with secondary cardiovascular events. Conclusion: There are genetic correlations among plaque phenotypes as well as between plaque phenotypes that provide mechanistic insight into the composition of the plaque and progression to secondary events.

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Genome-Wide Association Study of Renal Function Traits: Results from the Japan Multi-Institutional Collaborative Cohort Study

American Journal of Nephrology ◽

10.1159/000488946 ◽

2018 ◽

Vol 47 (5) ◽

pp. 304-316 ◽

Cited By ~ 5

Author(s):

Asahi Hishida ◽

Masahiro Nakatochi ◽

Masato Akiyama ◽

Yoichiro Kamatani ◽

Takeshi Nishiyama ◽

...

Keyword(s):

Renal Function ◽

Japanese Population ◽

Gene Locus ◽

Association Studies ◽

East Asian ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Asian Populations ◽

Genome Wide

Background: Chronic kidney disease (CKD) is a rapidly growing, worldwide public health problem. Recent advances in genome-wide-association studies (GWAS) revealed several genetic loci associated with renal function traits worldwide. Methods: We investigated the association of genetic factors with the levels of serum creatinine (SCr) and the estimated glomerular filtration rate (eGFR) in Japanese population-based cohorts analyzing the GWAS imputed data with 11,221 subjects and 12,617,569 variants, and replicated the findings with the 148,829 hospital-based Japanese subjects. Results: In the discovery phase, 28 variants within 4 loci (chromosome [chr] 2 with 8 variants including rs3770636 in the LDL receptor related protein 2 gene locus, on chr 5 with 2 variants including rs270184, chr 17 with 15 variants including rs3785837 in the BCAS3 gene locus, and chr 18 with 3 variants including rs74183647 in the nuclear factor of activated T-cells 1 gene locus) reached the suggestive level of p < 1 × 10–6 in association with eGFR and SCr, and 2 variants on chr 4 (including rs78351985 in the microsomal triglyceride transfer protein gene locus) fulfilled the suggestive level in association with the risk of CKD. In the replication phase, 25 variants within 3 loci (chr 2 with 7 variants, chr 17 with 15 variants and chr 18 with 3 variants) in association with eGFR and SCr, and 2 variants on chr 4 associated with the risk of CKD became nominally statistically significant after Bonferroni correction, among which 15 variants on chr 17 and 3 variants on chr 18 reached genome-wide significance of p < 5 × 10–8 in the combined study meta-analysis. The associations of the loci on chr 2 and 18 with eGFR and SCr as well as that on chr 4 with CKD risk have not been previously reported in the Japanese and East Asian populations. Conclusion: Although the present GWAS of renal function traits included the largest sample of Japanese participants to date, we did not identify novel loci for renal traits. However, we identified the novel associations of the genetic loci on chr 2, 4, and 18 with renal function traits in the Japanese population, suggesting these are transethnic loci. Further investigations of these associations are expected to further validate our findings for the potential establishment of personalized prevention of renal disease in the Japanese and East Asian populations.

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Secure large-scale genome-wide association studies using homomorphic encryption

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1918257117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11608-11613 ◽

Cited By ~ 1

Author(s):

Marcelo Blatt ◽

Alexander Gusev ◽

Yuriy Polyakov ◽

Shafi Goldwasser

Keyword(s):

Large Scale ◽

Homomorphic Encryption ◽

Association Studies ◽

Genome Wide Association ◽

Single Server ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

User Interactions ◽

Individual Level ◽

Genome Wide

Genome-wide association studies (GWASs) seek to identify genetic variants associated with a trait, and have been a powerful approach for understanding complex diseases. A critical challenge for GWASs has been the dependence on individual-level data that typically have strict privacy requirements, creating an urgent need for methods that preserve the individual-level privacy of participants. Here, we present a privacy-preserving framework based on several advances in homomorphic encryption and demonstrate that it can perform an accurate GWAS analysis for a real dataset of more than 25,000 individuals, keeping all individual data encrypted and requiring no user interactions. Our extrapolations show that it can evaluate GWASs of 100,000 individuals and 500,000 single-nucleotide polymorphisms (SNPs) in 5.6 h on a single server node (or in 11 min on 31 server nodes running in parallel). Our performance results are more than one order of magnitude faster than prior state-of-the-art results using secure multiparty computation, which requires continuous user interactions, with the accuracy of both solutions being similar. Our homomorphic encryption advances can also be applied to other domains where large-scale statistical analyses over encrypted data are needed.

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A critical evaluation of results from genome-wide association studies of micronutrient status and their utility in the practice of precision nutrition

British Journal Of Nutrition ◽

10.1017/s0007114519001119 ◽

2019 ◽

Vol 122 (2) ◽

pp. 121-130 ◽

Cited By ~ 2

Author(s):

Marie-Joe Dib ◽

Ruan Elliott ◽

Kourosh R. Ahmadi

Keyword(s):

Large Scale ◽

Association Studies ◽

Critical Evaluation ◽

Water Soluble ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Micronutrient Deficiencies ◽

Micronutrient Status ◽

Genome Wide ◽

Fat Soluble Vitamins

AbstractRapid advances in ‘omics’ technologies have paved the way forward to an era where more ‘precise’ approaches – ‘precision’ nutrition – which leverage data on genetic variability alongside the traditional indices, have been put forth as the state-of-the-art solution to redress the effects of malnutrition across the life course. We purport that this inference is premature and that it is imperative to first review and critique the existing evidence from large-scale epidemiological findings. We set out to provide a critical evaluation of findings from genome-wide association studies (GWAS) in the roadmap to precision nutrition, focusing on GWAS of micronutrient disposition. We found that a large number of loci associated with biomarkers of micronutrient status have been identified. Mean estimates of heritability of micronutrient status ranged between 20 and 35 % for minerals, 56–59 % for water-soluble and 30–70 % for fat-soluble vitamins. With some exceptions, the majority of the identified genetic variants explained little of the overall variance in status for each micronutrient, ranging between 1·3 and 8 % (minerals), <0·1–12 % (water-soluble) and 1·7–2·3 % for (fat-soluble) vitamins. However, GWAS have provided some novel insight into mechanisms that underpin variability in micronutrient status. Our findings highlight obvious gaps that need to be addressed if the full scope of precision nutrition is ever to be realised, including research aimed at (i) dissecting the genetic basis of micronutrient deficiencies or ‘response’ to intake/supplementation (ii) identifying trans-ethnic and ethnic-specific effects (iii) identifying gene–nutrient interactions for the purpose of unravelling molecular ‘behaviour’ in a range of environmental contexts.

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