scholarly journals Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci

2020 ◽  
pp. annrheumdis-2020-219065
Author(s):  
Eunji Ha ◽  
Sang-Cheol Bae ◽  
Kwangwoo Kim
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
T Cell Activation ◽  
Fixed Effects ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Chromatin Interaction ◽  
Susceptibility Loci ◽  
European Populations

ObjectivesNearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations.MethodsGenome-wide RA association summary statistics in three large case–control collections consisting of 311 292 individuals of Korean, Japanese and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritise causal variants and genes, RA variant-implicating features (tissues, pathways and transcription factors) and potentially repurposable drugs for RA treatment.ResultsWe identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the single-nucleotide polymorphism-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-human leukocyte antigens (HLA) susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription–activation histone marks that simultaneously highlighted the importance of CD4+ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications.ConclusionOur findings provide useful insights regarding RA genetic aetiology and variant-driven RA pathogenesis.

Abstract 56: Fine-Mapping of Metabochip Lipid Regions in Global Populations Identifies Signals Unique to Hispanic Descent Populations and Refines Previously Identified Lipid Loci

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Niha Zubair ◽  
Mariaelisa Graff ◽  
Danyu Lin ◽  
Ani Manichaikul ◽  
Ida Chen ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Fixed Effects ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Ethnically Diverse ◽  
Lipid Lowering ◽  
Targeted Prevention ◽  
Genome Wide Association Studies ◽  
Functional Variants

INTRODUCTION: Genome wide association studies (GWAS) have identified over 150 loci associated with lipids traits. The majority of these GWAS were performed in European Americans (EA); no large-scale studies exist for Hispanic descent populations. Additionally, in many cases, the genetic architecture of these trait-influencing loci remains largely unknown. To address these gaps in knowledge, we performed one of the most ethnically diverse fine-mapping genetic studies on HDL-C, LDL-C, and triglycerides (TG) to-date. HYPOTHESIS: Here we aimed to identify variants with the strongest association at each locus, detect population-specific signals, and refine previously identified EA GWAS loci. METHODS: We used Metabochip data from African American (AA, ~21,000), Hispanic American (HA, ~20,000), Asian (AS, ~2,000), and Native American (NA, ~550) participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study. We applied multiple linear regression models and assumed an additive mode of inheritance to test for association between genotypes and HDL-C, LDL-C, or log-transformed TG levels; lipid levels were corrected for lipid-lowering medication use. Model covariates included age, sex, and principal components of ancestry. We first conducted a meta-analysis within each ethnic group separately and then performed a combined trans-ethnic fixed effects meta-analysis. Significance was defined as p < 1 x 10 -6 ; equivalent to 0.05/ the mean number of variants at each Metabochip lipid locus. RESULTS: For HDL-C, 19 loci significantly associated in the trans-ethnic meta-analysis; the top signals at 5 of these loci, APOB, LIPC, STARD3, LIPG, and APOC1, have not been reported in EA. We identified a signal unique to HA at APOA5. In addition, we refined the set of candidate functional variants at PPP1R3B, LPL, and PLTP. For LDL-C, 16 loci significantly associated in the trans-ethnic meta-analysis; the top signals at 5 of these loci, PCSK9, APOB, APOA5, CLIP2, and APOC1, have not been reported in EA. We identified a signal unique to HA at SLC22A1. In addition, we refined the set of candidate functional variants at TIMD4 and LDLR. For TG, 15 loci significantly associated in the trans-ethnic meta-analysis; the top signals at 3 of these loci, APOB, APOA5, and LIPC, have not been reported in EA. In addition, we refined the set of candidate functional variants at ANGPTL3, MLXIPL, PPP1R3B, and LPL. CONCLUSIONS: By taking advantage of the genetic architecture of ethnically diverse populations, we identified novel lipid-influencing variants in HA and refined the set of candidate functional variants at GWAS lipid loci. Anticipated conditional analyses will provide further insight into secondary and ethnic-specific signals. Our results can guide the creation of more informed risk models, which can then be used for targeted prevention efforts, especially for underrepresented populations.

scholarly journals Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Muhammad Muaaz Aslam ◽  
Peter John ◽  
Kang-Hsien Fan ◽  
Attya Bhatti ◽  
Wajahat Aziz ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Autoimmune Disorder ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Pakistani Population ◽  
Genome Wide ◽  
Genetic And Environmental Factors ◽  
European Populations

Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.

scholarly journals A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shenping Zhou ◽  
Rongrong Ding ◽  
Fanming Meng ◽  
Xingwang Wang ◽  
Zhanwei Zhuang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Growth And Development ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Average Daily Gain ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Daily Gain

Abstract Background Average daily gain (ADG) and lean meat percentage (LMP) are the main production performance indicators of pigs. Nevertheless, the genetic architecture of ADG and LMP is still elusive. Here, we conducted genome-wide association studies (GWAS) and meta-analysis for ADG and LMP in 3770 American and 2090 Canadian Duroc pigs. Results In the American Duroc pigs, one novel pleiotropic quantitative trait locus (QTL) on Sus scrofa chromosome 1 (SSC1) was identified to be associated with ADG and LMP, which spans 2.53 Mb (from 159.66 to 162.19 Mb). In the Canadian Duroc pigs, two novel QTLs on SSC1 were detected for LMP, which were situated in 3.86 Mb (from 157.99 to 161.85 Mb) and 555 kb (from 37.63 to 38.19 Mb) regions. The meta-analysis identified ten and 20 additional SNPs for ADG and LMP, respectively. Finally, four genes (PHLPP1, STC1, DYRK1B, and PIK3C2A) were detected to be associated with ADG and/or LMP. Further bioinformatics analysis showed that the candidate genes for ADG are mainly involved in bone growth and development, whereas the candidate genes for LMP mainly participated in adipose tissue and muscle tissue growth and development. Conclusions We performed GWAS and meta-analysis for ADG and LMP based on a large sample size consisting of two Duroc pig populations. One pleiotropic QTL that shared a 2.19 Mb haplotype block from 159.66 to 161.85 Mb on SSC1 was found to affect ADG and LMP in the two Duroc pig populations. Furthermore, the combination of single-population and meta-analysis of GWAS improved the efficiency of detecting additional SNPs for the analyzed traits. Our results provide new insights into the genetic architecture of ADG and LMP traits in pigs. Moreover, some significant SNPs associated with ADG and/or LMP in this study may be useful for marker-assisted selection in pig breeding.

scholarly journals Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

2020 ◽  
Vol 79 (11) ◽  
pp. 1438-1445
Author(s):  
Young-Chang Kwon ◽  
Jiwoo Lim ◽  
So-Young Bang ◽  
Eunji Ha ◽  
Mi Yeong Hwang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Large Fraction ◽  
Genome Wide Association ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Bioinformatics Analyses ◽  
Specific Expression ◽  
Genome Wide

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

scholarly journals Transcriptionally Less Active Prodynorphin Promoter Alleles are Associated with Temporal Lobe Epilepsy: A Case-Control Study and Meta-Analysis

2008 ◽  
Vol 24 (3) ◽  
pp. 135-140 ◽  
Author(s):  
Marcelo A. Kauffman ◽  
Damián Consalvo ◽  
Moron Dolores Gonzalez ◽  
Silvia Kochen
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Fixed Effects ◽  
Association Studies ◽  
Hippocampal Sclerosis ◽  
Meta Analysis ◽  
Case Control ◽  
Healthy Controls ◽  
Fixed Effects Model ◽  
Familial Predisposition

We performed an association study in a population of patients with Mesial Temporal Lobe Epilepsy (TLE) with Hippocampal Sclerosis (MTEHS) together with a systematic revision of the literature to investigate the role of transcriptionally less active polymorphic alleles of Prodynorphin (PDYN) gene in this pathology. We included 102 patients with a diagnosis of MTEHS and 86 healthy controls. The positive antecedent of family history for epileptic events defined a TLE subgroup with familial predisposition for epileptic disorders. The PDYN promoter polymorphism was genotyped by means of a PCR assay. For meta-analysis, we identified case-control association studies between TLE and PDYN by searching PUBMED. The pooled OR was estimated using a fixed effects model under dominant and co-dominant heredity models. No differences in genotypic and allelic frequencies were found between cases and controls (p= 0.61) in our population, neither in the whole cohort nor in the analysis limited to TLE with familial predisposition (p= 0.71). The Meta-Analysis included 591 TLE patients and 1117 healthy controls. We found an association between L allele (p= 0.003; OR = 1.40; IC 95 = 1.12–1.74) and a modestly higher risk to develop TLE in the group of patients with familial predisposition. Therefore, functional allelic variants in the PDYN promoter might modify the risk to develop TLE in subjects with familial predisposition.

scholarly journals Identification of type 2 diabetes loci in 433,540 East Asian individuals

2019 ◽  
Author(s):  
Cassandra N Spracklen ◽  
Momoko Horikoshi ◽  
Young Jin Kim ◽  
Kuang Lin ◽  
Fiona Bragg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

scholarly journals Associations between genetic polymorphisms of TLRs and susceptibility to tuberculosis: A meta-analysis

2019 ◽  
Vol 26 (2) ◽  
pp. 75-83 ◽  
Author(s):  
Yong Zhou ◽  
Mengtao Zhang
Keyword(s):  
Genetic Association ◽  
Fixed Effects ◽  
Web Of Science ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Association Studies ◽  
Random Effects Models ◽  
Literature Research ◽  
Fixed Effects Models ◽  
Subgroup Analyses

Some genetic association studies have tried to investigate potential associations between TLR polymorphisms and tuberculosis. However, the results of these studies have not been consistent. Thus, we performed the present meta-analysis to explore associations between TLR polymorphisms and tuberculosis in a larger combined population. A systematic literature research of PubMed, Web of Science and Embase was performed to identify eligible studies for combined analyses. I2 statistics were employed to assess between-study heterogeneities. If I2 was >50%, random-effects models were used to combine the data. Otherwise, fixed-effects models were applied for synthetic analyses. A total of 39 genetic association studies were included in the analyses. The combined analyses showed that TLR1 rs4833095, TLR1 rs5743557, TLR1 rs5743596, TLR2 rs3804099, TLR2 rs5743704, TLR2 rs5743708, TLR6 rs5743810 and TLR8 rs3764879 polymorphisms were significantly associated with susceptibility to TB in the overall population. Further subgroup analyses revealed similar significant findings for TLR1 rs4833095, TLR1 rs5743557, TLR1 rs5743596, TLR1 rs5743618, TLR2 rs3804099, TLR2 rs5743704, TLR2 rs5743708, TLR4 rs4986790 and TLR4 rs4986791 polymorphisms in certain ethnicities. In conclusion, our findings support that these TLR polymorphisms may be used to identify individuals at high risk of developing tuberculosis.

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