scholarly journals Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain

2020 ◽  
Author(s):  
Md Shafiqur Rahman ◽  
Bendik S Winsvold ◽  
S.O. Chavez Chavez ◽  
Sigrid Børte ◽  
Yakov A. Tsepilov ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Correlation ◽  
Musculoskeletal Pain ◽  
Tissue Specificity ◽  
Genome Wide Association Study ◽  
The Body ◽  
Genome Wide Association ◽  
List Type ◽  
Genome Wide

AbstractBackground and ObjectivesChronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP.MethodsNorthern Europeans from UK Biobank comprising 6,914 cases reporting pain all over the body lasting more than 3 months and 242,929 controls were studied. Replication of three lead genome-wide significant single nucleotide polymorphisms (SNPs) was attempted in 6 independent European cohorts (N=43,080; cases=14,177). Genetic correlations with risk factors, tissue specificity, and colocalization were examined.ResultsThree genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes RNF123, ATP2C1, and COMT. The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227), and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth, and years of schooling were identified. Tissue specificity and colocalization analysis highlight the relevance of skeletal muscle in CWP.ConclusionsWe report a novel association of RNF123 locus with CWP and suggest a role of ATP2C1, consistent with a role of calcium regulation in CWP. The association to COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.Key messagesWhat is already known about this subject?Chronic widespread musculoskeletal pain (CWP) is a primary diagnostic feature of fibromyalgia.CWP is moderately heritable, but precise genes involved in the pathogenesis of CWP are yet to be identified.What does this study add?This is the largest genetic study conducted on CWP to date and identified novel genetic risk loci (RNF123 and ATP2C1).The genetic signal points to peripheral pain mechanisms in CWP, and shows genetic correlation with other traits, including BMI and depression.How might this impact on clinical practice or future developments?The findings add to etiological basis of CWP.

scholarly journals Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain

2021 ◽  
pp. annrheumdis-2020-219624
Author(s):  
Md Shafiqur Rahman ◽  
Bendik S Winsvold ◽  
Sergio O Chavez Chavez ◽  
Sigrid Børte ◽  
Yakov A Tsepilov ◽  
...  
Keyword(s):  
Association Study ◽  
Musculoskeletal Pain ◽  
Tissue Specificity ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
The Body ◽  
Genome Wide Association ◽  
Suggestive Association ◽  
Genome Wide ◽  
A Genome

Background and objectivesChronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%–54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP.MethodsNorthern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined.ResultsThree genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca2+transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP.ConclusionsWe report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

scholarly journals Genome-wide association study of social relationship satisfaction: significant loci and correlations with psychiatric conditions

2017 ◽  
Author(s):  
Varun Warrier ◽  
Thomas Bourgeron ◽  
Simon Baron-Cohen ◽  
Keyword(s):  
Relationship Satisfaction ◽  
Association Study ◽  
Genetic Correlation ◽  
Social Relationship ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Psychiatric Conditions

AbstractDissatisfaction in social relationships is reported widely across many psychiatric conditions. We investigated the genetic architecture of family relationship satisfaction and friendship satisfaction in the UK Biobank. We leveraged the high genetic correlation between the two phenotypes (rg = 0.87±0.03; P < 2.2x10-16) to conduct multi-trait analysis of Genome Wide Association Study (GWAS) (Neffective family = 164,112; Neffective friendship = 158,116). We identified two genome-wide significant associations for both the phenotypes: rs1483617 on chromosome 3 and rs2189373 on chromosome 6, a region previously implicated in schizophrenia. eQTL and chromosome conformation capture in neural tissues prioritizes several genes including NLGN1. Gene-based association studies identified several significant genes, with highest expression in brain tissues. Genetic correlation analysis identified significant negative correlations for multiple psychiatric conditions including highly significant negative correlation with cross-psychiatric disorder GWAS, underscoring the central role of social relationship dissatisfaction in psychiatric diagnosis. The two phenotypes were enriched for genes that are loss of function intolerant. Both phenotypes had modest, significant additive SNP heritability of approximately 6%. Our results underscore the central role of social relationship satisfaction in mental health and identify genes and tissues associated with it.

scholarly journals Common Susceptibility Loci for Male Breast Cancer

2020 ◽  
Author(s):  
Sarah Maguire ◽  
Eleni Perraki ◽  
Katarzyna Tomczyk ◽  
Michael E Jones ◽  
Olivia Fletcher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Association Study ◽  
Genetic Correlation ◽  
Male Breast Cancer ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Single Nucleotide ◽  
Genome Wide

Abstract Background The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. Methods We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10–06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. Results The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P &lt; 5 × 10–08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor–positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10–30). Conclusions These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

scholarly journals Genome-Wide Association Study in an Amerindian Ancestry Population Reveals Novel Systemic Lupus Erythematosus Risk Loci and the Role of European Admixture

2016 ◽  
Vol 68 (4) ◽  
pp. 932-943 ◽  
Author(s):  
Marta E. Alarcón-Riquelme ◽  
Julie T. Ziegler ◽  
Julio Molineros ◽  
Timothy D. Howard ◽  
Andrés Moreno-Estrada ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Association Study ◽  
Lupus Erythematosus ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Systemic Lupus ◽  
Genome Wide

scholarly journals Large-scale genome-wide association study of food liking reveals genetic determinants and genetic correlations with distinct neurophysiological traits.

2021 ◽  
Author(s):  
Sebastian May-Wilson ◽  
Nana Matoba ◽  
Kaitlin H Wade ◽  
Jouke-Jan Hottenga ◽  
Maria Pina Concas ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Correlation ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Taste Receptor ◽  
Genome Wide Association ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Food Liking

Variable preferences for different foods are among the main determinants of their intake and are influenced by many factors, including genetics. Despite considerable twins' heritability, studies aimed at uncovering food-liking genetics have focused mostly on taste receptors. Here, we present the first results of a large-scale genome-wide association study of food liking conducted on 161,625 participants from UK Biobank. Liking was assessed over 139 specific foods using a 9-point hedonic scale. After performing GWAS, we used genetic correlations coupled with structural equation modelling to create a multi-level hierarchical map of food liking. We identified three main dimensions: high caloric foods defined as "Highly palatable", strong-tasting foods ranging from alcohol to pungent vegetables, defined as "Learned" and finally "Low caloric" foods such as fruit and vegetables. The "Highly palatable" dimension was genetically uncorrelated from the other two, suggesting that two independent processes underlie liking high reward foods and the Learned/Low caloric ones. Genetic correlation analysis with the corresponding food consumption traits revealed a high correlation, while liking showed twice the heritability compared to consumption. For example, fresh fruit liking and consumption showed a genetic correlation of 0.7 with heritabilities of 0.1 and 0.05, respectively. GWAS analysis identified 1401 significant food-liking associations located in 173 genomic loci, with only 11 near taste or olfactory receptors. Genetic correlation with morphological and functional brain data (33,224 UKB participants) uncovers associations of the three food-liking dimensions with non-overlapping, distinct brain areas and networks, suggestive of separate neural mechanisms underlying the liking dimensions. In conclusion, we created a comprehensive and data-driven map of the genetic determinants and associated neurophysiological factors of food liking beyond taste receptor genes.

17 Genome-wide Association Study for Heat Stress Tolerance in Swine Using Weighted Single-step GBLUP

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 8-8
Author(s):  
Gabriella R Dodd ◽  
Breno O Fragomeni ◽  
Kent A Gray ◽  
Yijian Huang
Keyword(s):  
Heat Stress ◽  
Association Study ◽  
Stress Tolerance ◽  
Genetic Correlation ◽  
Genome Wide Association Study ◽  
Single Step ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Heat Stress Tolerance ◽  
Genomic Regions

Abstract The purpose of this study was to perform a genome-wide association study to determine the genomic regions associated with heat stress tolerance in swine as well as analyze the accuracy of prediction. Phenotypic information on carcass weight was available for 227,043 individuals from commercial farms in North Carolina and Missouri. Individuals were a commercial cross of a Duroc sire and a dam resulting from a Landrace and Large White cross. Genotypic information was available for 8,232 animals with 33,581 SNP. The pedigree file contained 553,448 animals. A 78 on the Temperature Humidity Index (THI) was used as a threshold for heat stress. A two-trait analysis was used with the phenotypes heat stress (trait one) and non-heat stress (trait two). Variance components were calculated via AIREML and breeding values were calculated using single step GBLUP (ssGBLUP). The heritability for trait one and two were calculated at 0.25 and 0.20, respectively, and the genetic correlation was calculated as 0.63. Validation was calculated for 163 genotyped sires with progeny in the last generation. The GEBV of complete data was used as the benchmark, and the accuracy was determined as the correlation between the GEBV of the reduced and complete data for the validation sires. Weighted ssGBLUP did not increase the accuracies, both methods showed a maximum accuracy of 0.32 for trait one and 0.54 for trait two. Manhattan Plots for trait one, trait two, and the difference between the two were created from the results of the two-trait analysis. Windows explaining around 1% of the genetic variance were identified. The only difference between the two traits was a peak at chromosome 14. The genetic correlation suggests different mechanisms for growth under heat stress. The GWAS results show that both traits are highly polygenic, with few genomic regions explaining more than 1% of variance.

scholarly journals Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jeremy Manry ◽  
Quentin B. Vincent ◽  
Christian Johnson ◽  
Maya Chrabieh ◽  
Lazaro Lorenzo ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Buruli Ulcer ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Autophagy Pathway

scholarly journals Major role of iron uptake systems in the intrinsic extra-intestinal virulence of the genus Escherichia revealed by a genome-wide association study

PLoS Genetics ◽  
2020 ◽  
Vol 16 (10) ◽  
pp. e1009065
Author(s):  
Marco Galardini ◽  
Olivier Clermont ◽  
Alexandra Baron ◽  
Bede Busby ◽  
Sara Dion ◽  
...  
Keyword(s):  
Association Study ◽  
Iron Uptake ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals Defining the genetic control of human blood plasma N-glycome using genome-wide association study

2018 ◽  
Author(s):  
Sodbo Zh. Sharapov ◽  
Yakov A. Tsepilov ◽  
Lucija Klaric ◽  
Massimo Mangino ◽  
Gaurav Thareja ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Association Study ◽  
Genetic Control ◽  
Human Blood ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Human Blood Plasma ◽  
Genome Wide ◽  
A Genome

AbstractGlycosylation is a common post-translational modification of proteins. It is known, that glycans are directly involved in the pathophysiology of every major disease. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here, we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people. We discovered and replicated twelve loci. This allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG glycosylation. Majority of loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which potentially highlights the role of glycoprotein degradation pathway, and such transcription factor as IKZF1.

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.

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