scholarly journals Genome-wide association study of multisite chronic pain in UK Biobank

PLoS Genetics ◽  
2019 ◽  
Vol 15 (6) ◽  
pp. e1008164 ◽  
Author(s):  
Keira J. A. Johnston ◽  
Mark J. Adams ◽  
Barbara I. Nicholl ◽  
Joey Ward ◽  
Rona J. Strawbridge ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide

scholarly journals Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009428
Author(s):  
Keira J. A. Johnston ◽  
Joey Ward ◽  
Pradipta R. Ray ◽  
Mark J. Adams ◽  
Andrew M. McIntosh ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sex Differences ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Chronic Widespread Pain ◽  
Genome Wide Association ◽  
System Component ◽  
Widespread Pain ◽  
Uk Biobank ◽  
Genome Wide

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.

scholarly journals Genome-wide Association Study of Multisite Chronic Pain in UK Biobank

2018 ◽  
Author(s):  
Keira J.A. Johnston ◽  
Mark J. Adams ◽  
Barbara I. Nicholl ◽  
Joey Ward ◽  
Rona J Strawbridge ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Association Study ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
System Component ◽  
Uk Biobank ◽  
Genome Wide ◽  
Polygenic Component

AbstractChronic pain is highly prevalent worldwide, contributing a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype, chronic pain grade, have been shown to be complex, heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual’s overall sensitivity to experiencing and reporting chronic pain have also been suggested. We have here made use of a measure of the number of sites of chronic pain in individuals within the general UK population. This measure, termed Multisite Chronic Pain (MCP), is also a complex trait, but its genetic architecture has not previously been investigated. To address this, a large-scale genome-wide association study (GWAS) of MCP was carried out in ~380,000 UK Biobank participants to identify associated genetic variants. Findings were consistent with MCP having a significant polygenic component with a SNP heritability of 10.2%, and 76 independent lead single nucleotide polymorphisms (SNPs) at 39 risk loci were identified. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as being enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits including major depressive disorder (MDD), asthma and BMI. Furthermore, in Mendelian randomisation (MR) analyses a bi-directional causal relationship was observed between MCP and MDD. A polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. These findings support the proposition that chronic pain involves a strong nervous system component and have implications for our understanding of the physiology of chronic pain and for the development of novel treatment strategies.

scholarly journals Sex-Stratified Genome-Wide Association Study of Multisite Chronic Pain in UK Biobank

2020 ◽  
Author(s):  
Keira JA Johnston ◽  
Joey Ward ◽  
Pradipta R Ray ◽  
Mark J Adams ◽  
Andrew M McIntosh ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sex Differences ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Chronic Widespread Pain ◽  
Genome Wide Association ◽  
Mouse Tissue ◽  
Widespread Pain ◽  
Uk Biobank ◽  
Genome Wide

AbstractChronic pain is highly prevalent worldwide and imparts significant socioeconomic and public health burden and is more prevalent in women than in men. Factors that influence susceptibility and mechanisms of chronic pain development, are not fully understood.To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype in UK Biobank. Genetic correlations between MCP in each sex and a range of psychiatric, autoimmune, and anthropometric phenotypes were examined. The relationship between female and male MCP, and chronic widespread pain was investigated using polygenic risk scoring. Expression of sex-specific MCP-associated loci in a range of tissues was examined using GTEx, and separately in neural and non-neural human tissues with assessment for dorsal-root ganglion (DRG) enrichment. For genes enriched for neural-tissue expression the full GTEx database was queried for sex-differential gene expression in CNS regions, and for high expression in sex-specific tissues. Expression in neural mouse tissue was also examined for orthologs of these genes.A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS output found 87 independent SNPs to be significantly associated with MCP. We found sex-specific MCP-associated genes, with 31 genes and 37 genes associated with female and male MCP respectively and one gene associated with MCP in both sexes (DCC).We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at rg significantly less than 1. All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the DRG, and many showed elevated expression in sex-specific tissues.Overall, findings indicate sex differences in chronic pain at the SNP, gene and transcriptomic level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong nervous-system component to chronic pain in both sexes, emphasise the importance of the DRG, and indicate specific loci which may play a specialised role in nociception.

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.

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 Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kenneth Fung ◽  
Julia Ramírez ◽  
Helen R. Warren ◽  
Nay Aung ◽  
Aaron M. Lee ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Stiffness Index ◽  
Uk Biobank ◽  
Genome Wide ◽  
Arterial Stiffness Index

scholarly journals A genome-wide association study of deviated nasal septum using UK Biobank cohort

2020 ◽  
Author(s):  
Li Liu ◽  
CuiYan Wu ◽  
Xiaoxia Dai ◽  
Yan Wen ◽  
Shiqiang Cheng ◽  
...  
Keyword(s):  
Association Study ◽  
Nasal Septum ◽  
Genome Wide Association Study ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Genetic Mechanism ◽  
Uk Biobank ◽  
Deviated Nasal Septum ◽  
Gene Sets ◽  
Genome Wide

Abstract Background Deviated nasal septum (DNS) is a common otolaryngology disease. The genetic mechanism underlying DNS remains largely unknown. Methods Totally, 2, 978 DNS patients and 2,978 randomly selected controls from the UK biobank were used in this study. Genotyping was done using the Affymetrix UK BiLEVE Axiom or UK Biobank Axiom array. Genome-wide association study (GWAS) was performed by PLINK 2.0, using age, sex, population structure PC1, PC2 and PC3 as covariates. eQTLs analysis and gene set enrichment analysis (GSEA) were also performed to explore the functional relevance of identified loci with DNS. Results GWAS identified multiple candidate genetic loci for DNS, such as rs75651247 located in DLGAP1 (β=-5.3398, P=9.31×10-8), rs141366706 located in CCND3 (β=-4.7036, P=2.56×10-6), rs76606504 located in FAF1 (β=-4.5013, P=6.76×10-6), and rs142537880 located in SVIL (β= 4.4336, P=9.27×10-6). GSEA detected multiple DNS associated gene sets or pathways, such as KEGG_CALCIUM_SIGNALING_PATHWAY (FDR=3.35×10-3, P=5×10-5) and DAVICIONI_TARGETS_OF_PAX_FOXO1_FUSIONS_UP (FDR=1.60×10-3, P=5×10-5). Conclusions Our study reported multiple candidate genes and gene sets for DNS, providing novel clues for understanding the genetic mechanism of DNS.

scholarly journals Genome-wide association study of susceptibility to hospitalised respiratory infections

2021 ◽  
Vol 6 ◽  
pp. 290
Author(s):  
Alexander T. Williams ◽  
Nick Shrine ◽  
Hardeep Naghra-van Gijzel ◽  
Joanna C. Betts ◽  
Edith M. Hessel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Association Study ◽  
Respiratory Infection ◽  
Genome Wide Association Study ◽  
Respiratory Infections ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Biological Mechanisms ◽  
Genome Wide ◽  
Infection Susceptibility

Background: Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods: We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank. We followed-up well-imputed top signals from the UK Biobank discovery analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts. We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results: In the discovery analysis, we report 56 signals at P<5×10-6, one of which was genome-wide significant (P<5×10-8). The genome-wide significant signal was in an intron of PBX3, a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in the 11 follow-up cohorts. None of the 40 signals replicated, with effect estimates attenuated. Conclusions: Our discovery analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate when aggregating effect estimates across 11 independent cohorts. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility.

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