scholarly journals Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis

2021 ◽  
Author(s):  
Kazuyoshi Ishigaki ◽  
Saori Sakaue ◽  
Chikashi Terao ◽  
Yang Luo ◽  
Kyuto Sonehara ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Fine Mapping ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genetic Research ◽  
Genome Wide Association ◽  
Polygenic Risk Score ◽  
Genome Wide

AbstractTrans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.

scholarly journals Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

2010 ◽  
Vol 42 (6) ◽  
pp. 508-514 ◽  
Author(s):  
Eli A Stahl ◽  
◽  
Soumya Raychaudhuri ◽  
Elaine F Remmers ◽  
Gang Xie ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Rheumatoid Arthritis Risk ◽  
Genome Wide

scholarly journals A large-scale genome-wide association study meta-analysis of cannabis use disorder

2020 ◽  
Vol 7 (12) ◽  
pp. 1032-1045 ◽  
Author(s):  
Emma C Johnson ◽  
Ditte Demontis ◽  
Thorgeir E Thorgeirsson ◽  
Raymond K Walters ◽  
Renato Polimanti ◽  
...  
Keyword(s):  
Association Study ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Cannabis Use ◽  
Genome Wide Association ◽  
Cannabis Use Disorder ◽  
Genome Wide

Myasthenia gravis genome-wide association study implicates AGRN as a risk locus

2021 ◽  
pp. jmedgenet-2021-107953
Author(s):  
Apostolia Topaloudi ◽  
Zoi Zagoriti ◽  
Alyssa Camille Flint ◽  
Melanie Belle Martinez ◽  
Zhiyu Yang ◽  
...  
Keyword(s):  
Myasthenia Gravis ◽  
Association Study ◽  
Fine Mapping ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Late Onset ◽  
Meta Analysis ◽  
Susceptibility Gene ◽  
Genome Wide Association ◽  
Genome Wide

BackgroundMyasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date.MethodsWe performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders.ResultsWe confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10−13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders.DiscussionOur gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

scholarly journals Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels

2020 ◽  
Author(s):  
Mary Hoekstra ◽  
Hao Yu Chen ◽  
Jian Rong ◽  
Line Dufresne ◽  
Jie Yao ◽  
...  
Keyword(s):  
Association Study ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Linear Regression Models ◽  
Lipoprotein A ◽  
Genome Wide ◽  
A Genome

Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P ≤5×10 -8 ). In addition to validating previous associations at LPA , APOE , and CETP , we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047–0.081]; P =2.8×10 -13 ) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076–0.10]; P =3.8×10 -42 ). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044–0.28]; P =0.0071). Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

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