scholarly journals Genome-wide association study of nociceptive musculoskeletal pain treatment response in UK Biobank

2022 ◽  
Author(s):  
Song Li ◽  
Geert Poelmans ◽  
Rianne van Boekel ◽  
Marieke Coenen
Keyword(s):  
Association Study ◽  
Treatment Response ◽  
Musculoskeletal Pain ◽  
Genome Wide Association Study ◽  
Pain Treatment ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Primary Analysis ◽  
Analgesic Ladder ◽  
Genome Wide

Drug treatment for nociceptive musculoskeletal pain (NMP) follows a three-step analgesic ladder proposed by the World Health Organization (WHO), starting from non-steroidal anti-inflammatory drugs (NSAIDs), followed by weak or strong opioids until the pain is under control. However, effective pain treatment is challenged by inter-individual differences, and unsatisfied pain treatment response (PTR) rates ranging from 34 to 79% in those suffering from NMP. To investigate the underlying genetic component of PTR, we performed a genome-wide association study (GWAS) in ~ 23,000 participants with NMP from the UK Biobank. In our primary analysis, we compared NSAID vs. opioid users as a reflection of (non)response to NSAIDs, adjusting for age, sex, BMI, population substructure, and study-specific covariates. One genome-wide significant hit was identified in an intergenic region on chromosome 4, rs549224715 (P = 3.88x10-8), and seven signals pass the suggestively significant threshold (P < 1x10-6). All identified loci were in non-coding regions, but most variants showed potential regulatory functions. SNPs in LD (r2 > 0.6) with the lead SNPs passing the nominal significant threshold (P < 0.05) were mapped to 28 target genes in FUMA. Eight of these 28 genes are involved in processes linked to neuropathic pain and musculoskeletal development. Pathway and network analyses with Ingenuity resulted in the identification of immunity-related processes and a (putative) central role of EGFR. Genetic correlation analysis including 596 traits resulted in the identification of 67 nominally significant (P < 0.05) genetic correlations, and these traits were significantly enriched for chronic pain and socioeconomic status traits (P = 3.35 x 10-12). Additionally, we conducted a subtype GWAS for inflammatory NMP and a secondary GWAS for participants with NMP disease history, but no significant hits or overlap with the primary analysis were observed. Overall, we identified one genome-wide significant association in this first GWAS focusing on pain treatment using the analgesic ladder as phenotype. However, we realize that this study lacked power and should be viewed as a first step to elucidate the genetic background of NMP treatment.

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 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 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 of response to cognitive–behavioural therapy in children with anxiety disorders

2016 ◽  
Vol 209 (3) ◽  
pp. 236-243 ◽  
Author(s):  
Jonathan R. I. Coleman ◽  
Kathryn J. Lester ◽  
Robert Keers ◽  
Susanna Roberts ◽  
Charles Curtis ◽  
...  
Keyword(s):  
Anxiety Disorders ◽  
Association Study ◽  
Treatment Response ◽  
Genome Wide Association Study ◽  
Behavioural Therapy ◽  
Post Treatment ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Cognitive Behavioural

BackgroundAnxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.AimsTo perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).MethodPresence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.ResultsNo variants passed a genome-wide significance threshold (P=5×10–8) in either analysis. Four variants met criteria for suggestive significance (P<5×10–6) in association with response post-treatment, and three variants in the 6-month follow-up analysis.ConclusionsThis is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.

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 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.

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