scholarly journals 1625 Genome-Wide Association Analysis and Replication In 810,625 Individuals Identifies Novel Therapeutic Targets for Varicose Veins

2021 ◽  
Vol 108 (Supplement_6) ◽  
Author(s):  
W U l R Ahmed ◽  
A Wiberg ◽  
M Ng ◽  
W Wang ◽  
A Auton ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Varicose Veins ◽  
Genetic Risk Score ◽  
Personalised Medicine ◽  
Therapeutic Targets ◽  
Biological Pathways ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
Weighted Genetic Risk Score

Abstract Aim To elucidate the genetic architecture of varicose veins (VVs) and identify genes and biological pathways central to their pathobiology. Method We performed hitherto the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe, Inc (total 135,514 VVs cases and 675,111 controls). Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for VVs was constructed to compare genetic susceptibility in surgical vs non-surgical VVs patients. Results 109 genome-wide significant (P ≤ 5 × 10-8) loci were identified in UK Biobank, 46 of which successfully replicated in the 23andMe cohort. Twenty-eight loci have not been previously reported. We mapped 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis. The wGRS analysis demonstrated that VVs patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 2.46 × 10−13). Conclusions This study has advanced our understanding of VVs pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to VVs.

scholarly journals 1540 Genome-Wide Association Analysis In 401,583 Individuals Identifies Novel Therapeutic Targets for Haemorrhoids

2021 ◽  
Vol 108 (Supplement_6) ◽  
Author(s):  
W U l R Ahmed ◽  
A Wiberg ◽  
M Ng ◽  
N J Smart ◽  
K T Zondervan ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Genome Wide Association Study ◽  
Therapeutic Potential ◽  
Genetic Risk Score ◽  
Personalised Medicine ◽  
Therapeutic Targets ◽  
Biological Pathways ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Weighted Genetic Risk Score

Abstract Aim To elucidate the genetic architecture of haemorrhoids and identify genes and biological pathways central to their pathobiology. Method We report the first ever genome-wide association study of haemorrhoids in 31,652 cases and 369,931 controls from UK Biobank. Genes and biological pathways were prioritised using several bioinformatic approaches, and potential therapeutic targets were identified in the Open Targets Platform. A weighted genetic risk score (wGRS) for haemorrhoids was constructed to compare genetic susceptibility in surgical vs non-surgical haemorrhoids patients. Results Twelve novel genome-wide significant susceptibility loci were discovered to be associated with haemorrhoids. Seventeen genes were mapped to these loci, and gene sets in biological pathways relating to extracellular matrix regulation and TGF-β signalling were strongly implicated. Seven gene-products (41.2%) were predicted tractable to antibody and/or small molecule targeting, and three products (17.6%) have known pharmaceutical interactions (ACHE, ADRA2B, ELN). The wGRS analysis demonstrated that haemorrhoid patients requiring surgery have a higher inherent genetic susceptibility than those managed non-surgically (P = 4.58 × 10-27). Conclusions This study has advanced our understanding of haemorrhoids pathobiology with the identification of several biologically plausible genes and pathways, many of which demonstrate strong therapeutic potential. The wGRS correlated with disease severity, representing a first step in personalised medicine approaches to haemorrhoids.

scholarly journals Genome-wide association analysis and replication in 810,625 individuals identifies novel therapeutic targets for varicose veins

2020 ◽  
Author(s):  
Waheed-Ul-Rahman Ahmed ◽  
Akira Wiberg ◽  
Michael Ng ◽  
Wei Wang ◽  
Adam Auton ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Risk ◽  
Varicose Veins ◽  
Genetic Risk Score ◽  
Therapeutic Targets ◽  
Genome Wide Association ◽  
Western Society ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
Novel Therapeutic

AbstractBackgroundVaricose veins (VVs) affect one-third of Western society, with a significant subset of patients developing venous ulceration, and ongoing management of venous leg ulcers costing around $14.9 billion annually in the USA. There is no current medical management for VVs, with approaches limited to compression stockings, ablation techniques, or open surgery for more advanced disease. A significant proportion of patients report a positive family history, and heritability is ~17%, suggesting a strong genetic component. We aimed to identify novel therapeutic targets by improving our understanding of the aetiopathology and genetic architecture of VVs.MethodsWe performed the largest two-stage genome-wide association study of VVs in 401,656 subjects from UK Biobank, and replication in 408,969 subjects from 23andMe (total 135,514 varicose veins cases and 675,111 controls). We constructed a genetic risk score for VVs to investigate its use as a prognostic tool. Genes and pathways were prioritised using a suite of bioinformatic tools, and therapeutic targets identified using the Open Targets Platform.ResultsWe discovered 49 signals at 46 susceptibility loci associated with VVs, including 29 previously unreported genetic associations (28 susceptibility loci). We demonstrated that patients with VVs requiring surgery have a higher genetic risk score than those managed non-surgically. We map 237 genes to these loci, many of which are biologically relevant and tractable to therapeutic targeting or repurposing (notably VEGFA, COL27A1, EFEMP1, PPP3R1 and NFATC2). Tissue enrichment analyses implicated vascular tissue, and several genes were enriched in biological pathways relating to extracellular matrix biology, inflammation, angiogenesis, lymphangiogenesis, vascular smooth muscle cell migration, and apoptosis.ConclusionsGenes and pathways identified represent biologically plausible contributors to the pathobiology of VVs, identifying promising candidates for further investigation of venous biology and potential therapeutic targets. We have provided the proof-of-principle that genetic risk score correlates with disease severity, which represents a first step in personalised medicine approaches to varicose veins.

scholarly journals An Integrative Genomics Approach for Associating Genome-Wide Association Studies Information With Localized and Metastatic Prostate Cancer Phenotypes

2017 ◽  
Vol 12 ◽  
pp. 117727191769581 ◽  
Author(s):  
Chindo Hicks ◽  
Ritika Ramani ◽  
Oliver Sartor ◽  
Ritu Bhalla ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Susceptibility ◽  
Metastatic Prostate Cancer ◽  
Association Studies ◽  
Biological Pathways ◽  
Genome Wide Association ◽  
Molecular Networks ◽  
Genome Wide Association Studies ◽  
Disease States ◽  
Genome Wide

High-throughput genotyping has enabled discovery of genetic variants associated with an increased risk of developing prostate cancer using genome-wide association studies (GWAS). The goal of this study was to associate GWAS information of patients with primary organ–confined and metastatic prostate cancer using gene expression data and to identify molecular networks and biological pathways enriched for genetic susceptibility variants involved in the 2 disease states. The analysis revealed gene signatures for the 2 disease states and a gene signature distinguishing the 2 patient groups. In addition, the analysis revealed molecular networks and biological pathways enriched for genetic susceptibility variants. The discovered pathways include the androgen, apoptosis, and insulinlike growth factor signaling pathways. This analysis established putative functional bridges between GWAS discoveries and the biological pathways involved in primary organ–confined and metastatic prostate cancer.

scholarly journals Identification of two novel breast cancer loci through large-scale genome-wide association study in the Japanese population

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Siew-Kee Low ◽  
Yoon Ming Chin ◽  
Hidemi Ito ◽  
Keitaro Matsuo ◽  
Chizu Tanikawa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Risk ◽  
Japanese Population ◽  
Risk Group ◽  
Association Studies ◽  
Genetic Risk Score ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Weighted Genetic Risk Score

AbstractGenome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10−8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.

scholarly journals A Genome-Wide Association Study of the Frailty Index Highlights Synaptic Pathways in Aging

2019 ◽  
Author(s):  
Janice L Atkins ◽  
Juulia Jylhävä ◽  
Nancy L Pedersen ◽  
Patrik K Magnusson ◽  
Yi Lu ◽  
...  
Keyword(s):  
Association Study ◽  
Risk Score ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Genetic Risk Score ◽  
Frailty Index ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome

ABSTRACTFrailty is a common geriatric syndrome, strongly associated with disability, mortality and hospitalisation. The mechanisms underlying frailty are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 19 and 45%. Understanding the genetic determinants and biological mechanisms underpinning frailty may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) of a frailty index (FI) in European descent participants from UK Biobank (n=164,610, aged 60-70 years). FI calculation was based on 49 self-reported items on symptoms, disabilities and diagnosed diseases. We identified 26 independent genetic signals at 24 loci associated with the FI (p<5*10−8). Many of these loci have previously been associated with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, three appear to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 14% (0.14, SE 0.006). A genetic risk score for the FI, derived solely from the UK Biobank data, was significantly associated with FI in the Swedish TwinGene study (n=10,616, beta: 0.11, 95% CI: 0.02-0.20, p=0.015). In pathway analysis, genes associated with synapse function were significantly enriched (p<3*10−6). We also used Mendelian randomization to identify modifiable traits and exposures that may affect the risk of frailty, with a higher educational attainment genetic risk score being associated with a lower risk of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on synapse maintenance pathways.

scholarly journals O21: GENOME-WIDE ASSOCIATION STUDY OF VARICOSE VEINS IN 810,625 INDIVIDUALS IDENTIFIES 45 GENETIC RISK LOCI

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
WUR Ahmed ◽  
A Wiberg ◽  
M Ng ◽  
D Furniss
Keyword(s):  
Association Study ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Varicose Veins ◽  
Phenotypic Expression ◽  
Cell Activity ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genetic Components ◽  
Genome Wide

Abstract Introduction Varicose veins (VV) impact a third of the UK adult population; 10% of patients develop lipodermatosclerosis and ulceration. VV often requires surgical management, however, there is a high-risk of recurrence. VV is a complex disease, where genetic and non-genetic components contribute to overall phenotypic expression. The genetic architecture of VV is poorly understood; we aimed to uncover its genetic basis. Method We conducted hitherto the largest genome-wide association study of VV. In stage one, using UK Biobank, we compared 22,473 VV patients and 379,183 controls. In stage two, replication and meta-analysis were performed in an independent cohort of 113,041 VV cases and 295,928 controls from 23&Me (California, USA). In-silico analysis was conducted in FUMA, MAGMA, and XGR. Result 109 genome-wide significant (P≤ 5×10-8) loci were identified in UK Biobank, 45 of which successfully replicated in the 23&Me cohort. Twenty-seven loci have not been previously reported. FUMA positionally-mapped 128 genes at the replicated loci, with 84 having a combined annotation-dependent depletion score (CADD) &gt;12.37, suggesting functional, deleterious variants. MAGMA analysis implicated pathways involved in cardiovascular system development (P=1.57×10-08) and tube morphogenesis (P=9.35×10-08). Furthermore, XGR revealed enriched pathways in downstream signalling in naive CD8+ T cells (P=0.0017), and encoding structural and core extracellular glycoproteins (both P=0.007). Conclusion We identified 45 variants conferring risk of VV, which provide insights into disease biology. Implicated genes are enriched in pathways involved in vascular development, immune cell activity and extracellular matrix function, and provide new targets for therapeutic development. Take-home message Unravelling the genetic architecture of varicose veins may facilitate our understanding of the disease and guide therapeutic approaches.

scholarly journals Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena R. R. Wells ◽  
Fatin N. Zainul Abidin ◽  
Maxim B. Freidin ◽  
Frances M. K. Williams ◽  
Sally J. Dawson
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Significance Threshold ◽  
Genome Wide ◽  
Final Sample ◽  
Close Proximity ◽  
Repressor Complex

AbstractTinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E−08), rs4900545 (p = 1.8E−08) and 14:103042287_CT_C (p = 3.50E−08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p < 1E−06.

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