scholarly journals Identification of novel genetic susceptibility loci for thoracic and abdominal aortic aneurysms via genome-wide association study using the UK Biobank Cohort

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0247287
Author(s):  
Tamara Ashvetiya ◽  
Sherry X. Fan ◽  
Yi-Ju Chen ◽  
Charles H. Williams ◽  
Jeffery R. O’Connell ◽  
...  
Keyword(s):  
Linkage Group ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
Abdominal Aortic ◽  
The Uk ◽  
Genome Wide Significance

Background Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component. Methods and results In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated. We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5x10-8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ~10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In FinnGen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA. Conclusions Our GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.

scholarly journals Analysis of UK Biobank Cohort Reveals Novel Insights for Thoracic and Abdominal Aortic Aneurysms

2021 ◽  
Author(s):  
Tamara Ashvetiya ◽  
Sherry X Fan ◽  
Yi-Ju Chen ◽  
Charles H Williams ◽  
Jeffery R. O’Connell ◽  
...  
Keyword(s):  
Linkage Group ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Marfan Syndrome ◽  
Genome Wide Association Study ◽  
Uk Biobank ◽  
Genome Wide ◽  
Abdominal Aortic ◽  
The Uk ◽  
Genome Wide Significance

AbstractBackgroundThoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) are known to have a strong genetic component.Methods and ResultsIn a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 1,363 individuals with AAA compared to 27,260 age, ancestry, and sex-matched controls (1:20 case:control study design). A similar analysis was repeated for 435 individuals with TAA compared to 8,700 controls. Polymorphism with minor allele frequency (MAF) >0.5% were evaluated.We identified novel loci near LINC01021, ATOH8 and JAK2 genes that achieved genome-wide significance for AAA (p-value <5×10−8), in addition to three known loci. For TAA, three novel loci in CTNNA3, FRMD6 and MBP achieved genome-wide significance. There was no overlap in the genes associated with AAAs and TAAs. Additionally, we identified a linkage group of high-frequency variants (MAFs ∼10%) encompassing FBN1, the causal gene for Marfan syndrome, which was associated with TAA. In Finngen PheWeb, this FBN1 haplotype was associated with aortic dissection. Finally, we found that baseline bradycardia was associated with TAA, but not AAA.ConclusionsOur GWAS found that AAA and TAA were associated with distinct sets of genes, suggesting distinct underlying genetic architecture. We also found association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. We also found a common FBN1 linkage group that is associated with TAA and aortic dissection in patients who do not have Marfan syndrome. These FBN1 variants suggest shared pathophysiology between Marfan disease and sporadic TAA.Condensed AbstractIn genome-wide association study (GWAS) of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using UK Biobank database, we found 3 novel loci associated with TAA, and 3 novel loci associated AAA. We also found significant association between baseline bradycardia and TAA. These findings, including JAK2 association, offer plausible mechanistic and therapeutic insights. Additionally, we identified a common FBN1 linkage group associated with TAA in patients who do not have Marfan syndrome. In the FinnGen cohort, this haplotype is associated with aortic dissection. These results suggest a shared pathophysiology between Marfan disease and sporadic TAA.Study LimitationsAs with any GWAS study, the discovery of novel loci associated with aortopathies does not prove functional causality, and the findings described herein needs to be validated by analysis of other databases, ideally in a patient population of more diverse genetic origins than the UK Biobank. The use of the ICD10 codes to classify disease carriers and noncarriers in a population cohort may not be the most accurate assessment of prevalence of aortopathies. The association between baseline bradycardia and TAA does not take into account the concurrent use of medications that may impact heart rate.HighlightsIdentification of 3 novel AAA-associated loci near LINC01021, ATOH8 and JAK2 genes.Identification of 3 novel TAA-associated loci near CTNNA3, FRMD6 and MBP genes.Identification of a linkage group of common FBN1 variants associated with non-syndromic TAA in the UK Biobank and with aortic dissection in the FinnGen cohort, strengthening the evidence for a shared pathophysiology between Marfan disease and nonsyndromic aortopathy.Association between baseline bradycardia and TAA but not AAA.

scholarly journals Genome-wide association study reveals genetic risk factors for trigeminal neuralgia

2021 ◽  
Author(s):  
Andrew T. Hale ◽  
Jing He ◽  
Oluwatoyin Akinnusotu ◽  
Rebecca L. Sale ◽  
Janey Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Trigeminal Neuralgia ◽  
Genetic Risk ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
The Uk ◽  
Genome Wide Significance

AbstractBackgroundWhile many clinical risk factors of trigeminal neuralgia (TN) have been identified, the genetic basis of TN is largely unknown. Here, we perform the first genome-wide association study (GWAS) for TN using three independent DNA biobanks – BioVU, the UK Biobank, and Finngen.ObjectiveTo elucidate the genetic basis of TN.MethodsUsing GWAS summary statistics generated from BioVU, the UK Biobank, and Finngen, we performed fixed-effect meta-analysis across 490,912 individuals (1,188 TN cases and 489,724 controls) to identify genetic risk factors for TN. Genome-wide significance was defined as p < 5.0×10−8.ResultsWe identify an intergenic locus on chromosome 1p22.2 flanked by ZNF326 and SNORD3G containing 5 SNPs (rs77449572, rs543311093, rs35117749, rs71666259, and rs116010656) reaching genome-wide significance (p < 5.0 x 10−8), where rs77449572 is the sentinel variant (p = 1.72 x 10−9). The SNP rs77449572 overlaps an enhancer element in cortex-derived neurospheres. In addition, rs71666259 and rs116010656 are located in enhancer elements in embryonic stem cells (HUES48), suggesting potential functional consequences of this locus. We also identify a second locus on chromosome 5q35.1 containing sentinel variant rs62376947 reaching genome-wide significance (p = 2.49 x 10−8).ConclusionsTo our knowledge, we perform the first GWAS of TN. Future studies should be aimed at understanding the extent to which genetic variation stratifies response to neuropathic pain medication and whether genetic information may be used to identify patients who are likely to benefit (or not) from surgical intervention.

scholarly journals Genome-wide association study of knee pain identifies associations with GDF5 and COL27A1 in UK Biobank

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Weihua Meng ◽  
◽  
Mark J. Adams ◽  
Colin N. A. Palmer ◽  
Jingchunzi Shi ◽  
...  
Keyword(s):  
Knee Pain ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Medical Attention ◽  
Supporting Evidence ◽  
Uk Biobank ◽  
Genome Wide ◽  
Osteoarthritis Initiative ◽  
The Uk ◽  
Genome Wide Significance

AbstractKnee pain is one of the most common musculoskeletal complaints that brings people to medical attention. Approximately 50% of individuals over the age of 50 report an experience of knee pain within the past 12 months. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and seek supporting evidence in cohorts from 23andMe, the Osteoarthritis Initiative, and the Johnston County Osteoarthritis Project. We identified two loci that reached genome-wide significance in the UK Biobank: rs143384, located in GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis; and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were supported in cohorts with self-reported osteoarthritis/radiographic knee osteoarthritis without pain information. In this report on genome-wide association of knee pain, we identified two loci in or near GDF5 and COL27A1 that are associated with knee pain.

scholarly journals Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

2021 ◽  
Author(s):  
Mengyao Yu ◽  
Sergiy Kyryachenko ◽  
Stephanie Debette ◽  
Philippe Amouyel ◽  
Jean-Jacques Schott ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Additional Risk ◽  
Genome Wide ◽  
The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

scholarly journals A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

2020 ◽  
Vol 29 (8) ◽  
pp. 1396-1404 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  
Keyword(s):  
Association Study ◽  
Shoulder Pain ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Significant Locus ◽  
The Uk

Abstract Background Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Methods A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. Results We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). Conclusions We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

scholarly journals Genome-wide association study of medication-use and associated disease in the UK Biobank

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yeda Wu ◽  
Enda M. Byrne ◽  
Zhili Zheng ◽  
Kathryn E. Kemper ◽  
Loic Yengo ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Medication Use ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
The Uk

scholarly journals A genome-wide association study identifies that the GDF5 and COL27A1 genes are associated with knee pain in UK Biobank (N = 171, 516)

2019 ◽  
Author(s):  
Weihua Meng ◽  
Mark J Adams ◽  
Colin NA Palmer ◽  
Jingchunzi Shi ◽  
Adam Auton ◽  
...  
Keyword(s):  
Knee Pain ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Narrow Sense ◽  
Narrow Sense Heritability ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

SUMMARYObjectiveKnee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo).MethodsWe performed a genome-wide association study of knee pain in the UK Biobank, where knee pain was ascertained through self-report and defined as “knee pain in the last month interfering with usual activities”. A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 × 10−8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of knee pain using Genome-wide Complex Trait Analysis (GCTA).ResultsWe identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 × 10−12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 × 10−8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 × 10−18; rs2808772: P −11 = 2.56 × 10−1’). The narrow sense heritability of knee pain was 0.08.ConclusionIn this first reported genome-wide association meta-analysis of knee pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with knee pain.

scholarly journals Genome-wide Association Study of Pulmonary Function in Europeans and Africans from the UK Biobank Identifies Distinct Variants

2022 ◽  
Author(s):  
Musalula Sinkala ◽  
Samar S. M. Elsheikh ◽  
Mamana Mbiyavanga ◽  
Joshua Cullinan ◽  
Nicola Mulder
Keyword(s):  
Pulmonary Function ◽  
Genome Wide Association Study ◽  
Well Being ◽  
Genome Wide Association ◽  
Significant Finding ◽  
Uk Biobank ◽  
Chromosome 11 ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. FEV1, FVC, and PEF are quantitively used to assess pulmonary function. We conducted a genome-wide association analysis of pulmonary function in 383,471 individuals of European and 5,978 African descent represented in the UK Biobank. Here, we report 817 variants in Europeans and 3 in Africans associated (p-values < 5 x 10-8) with three pulmonary function parameters; FEV1, FVC and PEF. In addition to 377 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identified 330 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans and a KDM2A intron variant rs12790261 on chromosome 11 in Europeans. Remarkably, we find no shared variants among Africans and Europeans. Enrichment analyses of variants separately for each ancestry background revealed significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes revealed individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings offer a better understanding of the different variants that modify pulmonary function in Africans and Europeans, a significant finding for future GWAS studies and medicine.

Sign in / Sign up

Export Citation Format

Share Document