scholarly journals Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank

2021 ◽  
pp. annrheumdis-2020-219796
Author(s):  
Gabriela Sandoval-Plata ◽  
Kevin Morgan ◽  
Abhishek Abhishek
Keyword(s):  
Genome Wide Association Study ◽  
Predictive Ability ◽  
Serum Urate ◽  
Polygenic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Using Data ◽  
The Uk

ObjectivesTo perform a genome-wide association study (GWAS) of gout cases versus asymptomatic hyperuricaemia (AH) controls, and gout cases versus normouricaemia controls, and to generate a polygenic risk score (PRS) to determine gout-case versus AH-control status.MethodsGout cases and AH controls (serum urate (SU) ≥6.0 mg/dL) from the UK Biobank were divided into discovery (4934 cases, 56 948 controls) and replication (2115 cases, 24 406 controls) cohorts. GWAS was conducted and PRS generated using summary statistics in discovery cohort as the base dataset and the replication cohort as the target dataset. The predictive ability of the model was evaluated. GWAS were performed to identify variants associated with gout compared with normouricaemic controls using SU <6.0 mg/dL and <7.0 mg/dL thresholds, respectively.ResultsThirteen independent single nucleotide polymorphisms (SNPs) in ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, PPM1K-DT, LOC105377323 and ADH1B reached genome-wide significance and replicated as predictors of AH to gout transition. Twelve of 13 associations were novel for this transition, and rs1229984 (ADH1B) was identified as GWAS locus for gout for the first time. The best PRS model was generated from association data of 17 SNPs; and had predictive ability of 58.5% that increased to 69.2% on including demographic factors. Two novel SNPs rs760077(MTX1) and rs3800307(PRSS16) achieved GWAS significance for association with gout compared with normouricaemic controls using both SU thresholds.ConclusionThe association of urate transporters with gout supports the central role of hyperuricaemia in its pathogenesis. Larger GWAS are required to identify if variants in inflammatory pathways contribute to progression from AH to gout.

scholarly journals Heritability And Genetic Correlations For Hormone-Sensitive Cancers In The UK Biobank: A Molecular Evidence of Shared Aetiology

2021 ◽  
Author(s):  
Muktar Ahmed ◽  
Ville-Petteri Mäkinen ◽  
Anwar Mulugeta ◽  
Jisu Shin ◽  
Terry Boyle ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Significant Proportion ◽  
Molecular Evidence ◽  
Nucleotide Polymorphisms ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Hormone Sensitive ◽  
The Uk

Abstract Hormone-related cancers, including cancers of the breast, prostate, ovaries, uterine, and thyroid, globally contribute to the majority of cancer incidence. We hypothesize that hormone-sensitive cancers share common genetic risk factors that have rarely been investigated by previous genomic studies of site-specific cancers. To test this hypothesis, we analysed five hormone-sensitive cancers in the UK Biobank as a single disease. We observed that a significant proportion of variance in disease liability was explained by the genome-wide single nucleotide polymorphisms (SNPs), i.e., SNP-based heritability on the liability scale was estimated as 10.06% (SE 0.70%) for the disease. Moreover, we found 55 genome-wide significant SNPs for the disease, using a genome-wide association study. Our finding suggests that heritable genetic factors may be a key driver in the mechanism of carcinogenesis shared by hormone-sensitive cancers.

Lifestyle factors and genetic variants on two biological age measures: evidence from 94,443 Taiwan Biobank participants

2021 ◽  
Author(s):  
Wan-Yu Lin
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Lifestyle Factors ◽  
Biological Age ◽  
Biological Aging ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

Abstract Background Biological age (BA) can be estimated by phenotypes and is useful for predicting lifespan and healthspan. Levine et al. proposed a PhenoAge and a BioAge to measure BA. Although there have been studies investigating the genetic predisposition to BA acceleration in Europeans, little has been known regarding this topic in Asians. Methods I here estimated PhenoAgeAccel (age-adjusted PhenoAge) and BioAgeAccel (age-adjusted BioAge) of 94,443 Taiwan Biobank (TWB) participants, wherein 25,460 TWB1 subjects formed a discovery cohort and 68,983 TWB2 individuals constructed a replication cohort. Lifestyle factors and genetic variants associated with PhenoAgeAccel and BioAgeAccel were investigated through regression analysis and a genome-wide association study (GWAS). Results A unit (kg/m 2) increase of BMI was associated with a 0.177-year PhenoAgeAccel (95% C.I. = 0.163~0.191, p = 6.0×) and 0.171-year BioAgeAccel (95% C.I. = 0.165~0.177, p = 0). Smokers on average had a 1.134-year PhenoAgeAccel (95% C.I. = 0.966~1.303, p = 1.3×) compared with non-smokers. Drinkers on average had a 0.640-year PhenoAgeAccel (95% C.I. = 0.433~0.847, p = 1.3×) and 0.193-year BioAgeAccel (95% C.I. = 0.107~0.279, p = 1.1×) relative to non-drinkers. A total of 11 and 4 single-nucleotide polymorphisms (SNPs) were associated with PhenoAgeAccel and BioAgeAccel (p&lt;5× in both TWB1 and TWB2), respectively. Conclusions A PhenoAgeAccel-associated SNP (rs1260326 in GCKR) and two BioAgeAccel-associated SNPs (rs7412 in APOE; rs16998073 near FGF5) were consistent with the finding from the UK Biobank. The lifestyle analysis shows that prevention from obesity, cigarette smoking, and alcohol consumption is associated with a slower rate of biological aging.

scholarly journals A novel variant in GLIS3 is associated with osteoarthritis

2018 ◽  
Vol 77 (4) ◽  
pp. 620-623 ◽  
Author(s):  
Elisabetta Casalone ◽  
Ioanna Tachmazidou ◽  
Eleni Zengini ◽  
Konstantinos Hatzikotoulas ◽  
Sophie Hackinger ◽  
...  
Keyword(s):  
Complex Disease ◽  
Genome Wide Association Study ◽  
Total Joint Replacement ◽  
Population Based ◽  
Uk Biobank ◽  
Proteomics Data ◽  
Glucose Levels ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

ObjectivesOsteoarthritis (OA) is a complex disease, but its genetic aetiology remains poorly characterised. To identify novel susceptibility loci for OA, we carried out a genome-wide association study (GWAS) in individuals from the largest UK-based OA collections to date.MethodsWe carried out a discovery GWAS in 5414 OA individuals with knee and/or hip total joint replacement (TJR) and 9939 population-based controls. We followed-up prioritised variants in OA subjects from the interim release of the UK Biobank resource (up to 12 658 cases and 50 898 controls) and our lead finding in operated OA subjects from the full release of UK Biobank (17 894 cases and 89 470 controls). We investigated its functional implications in methylation, gene expression and proteomics data in primary chondrocytes from 12 pairs of intact and degraded cartilage samples from patients undergoing TJR.ResultsWe detect a genome-wide significant association at rs10116772 with TJR (P=3.7×10−8; for allele A: OR (95% CI) 0.97 (0.96 to 0.98)), an intronic variant in GLIS3, which is expressed in cartilage. Variants in strong correlation with rs10116772 have been associated with elevated plasma glucose levels and diabetes.ConclusionsWe identify a novel susceptibility locus for OA that has been previously implicated in diabetes and glycaemic traits.

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 Genetic underpinnings of sociability in the UK Biobank

2019 ◽  
Author(s):  
J Bralten ◽  
CJHM Klemann ◽  
NR Mota ◽  
W De Witte ◽  
C Arango ◽  
...  
Keyword(s):  
Social Anxiety ◽  
Psychiatric Disorders ◽  
Genetic Correlation ◽  
Genome Wide Association Study ◽  
Autism Spectrum ◽  
Self Report ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

ABSTRACTDifficulties with sociability include a tendency to avoid social contacts and activities, and to prefer being alone rather than being with others. While sociability is a continuously distributed trait in the population, decreased sociability represent a common early manifestation of multiple neuropsychiatric disorders such as Schizophrenia (SCZ), Bipolar Disorder (BP), Major Depressive Disorder (MDD), Autism Spectrum Disorders (ASDs), and Alzheimer’s disease (AD). We aimed to investigate the genetic underpinnings of sociability as a continuous trait in the general population. In this respect, we performed a genome-wide association study (GWAS) using a sociability score based on 4 social functioning-related self-report questions in the UK Biobank sample (n=342,461) to test the effect of individual genetic variants. This was followed by LD score analyses to investigate the genetic correlation with psychiatric disorders (SCZ, BP, MDD, ASDs) and a neurological disorder (AD) as well as related phenotypes (Loneliness and Social Anxiety). The phenotypic data indeed showed that the sociability score was decreased in individuals with ASD, (probable) MDD, BP and SCZ, but not in individuals with AD. Our GWAS showed 604 genome-wide significant SNPs, coming from 18 independent loci (SNP-based h2=0.06). Genetic correlation analyses showed significant correlations with SCZ (rg=0.15, p=9.8e-23), MDD (rg=0.68, p=6.6e-248) and ASDs (rg=0.27, p=4.5e-28), but no correlation with BP (rg=0.01, p=0.45) or AD (rg=0.04, p=0.55). Our sociability trait was also genetically correlated with Loneliness (rg=0.45, p=2.4e-8) and Social Anxiety (rg=0.48, p=0.002). Our study shows that there is a significant genetic component to variation in population levels of sociability, which is relevant to some psychiatric disorders (SCZ, MDD, ASDs), but not to BP and AD.

scholarly journals Genetic predisposition to tinnitus in the UK Biobank population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madeleine E. Urbanek ◽  
Jian Zuo
Keyword(s):  
Cochlear Nucleus ◽  
Genome Wide Association Study ◽  
Dorsal Cochlear Nucleus ◽  
Diagnostic Tools ◽  
Nucleotide Polymorphisms ◽  
Structural Reinforcement ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome ◽  
The Uk

AbstractTinnitus, the phantom perception of noise originating from the inner ear, has been reported by 15% of the world’s population, with many patients reporting major deficits to cognition and mood. However, both objective diagnostic tools and targeted therapeutic strategies have yet to be established. To better understand the underlying genes that may preclude tinnitus, we performed a genome-wide association study of the UK Biobank’s 49,960 whole exome sequencing participants to identify any loci strongly associated with tinnitus. We identified 17 suggestive single nucleotide polymorphisms (p < 1e−5) spanning 13 genes in two sex-separated cohorts reporting chronic, bothersome tinnitus (control males n = 7,315, tinnitus males n = 226, control females n = 11,732, tinnitus females n = 300). We also found a significant missense mutation in WDPCP (p = 3.959e−10) in the female cohort, a mutation which has been previously implicated in typical neuronal functioning through axonal migration and structural reinforcement, as well as in Bardet-Biedl syndrome-15, a ciliopathy. Additionally, in situ hybridization in the embryonic and P56 mouse brain demonstrated that the majority of these genes are expressed within the dorsal cochlear nucleus, the region of the brain theorized to initially induce tinnitus. Further RT-qPCR and RNAScope data also reveals this expression pattern. The results of this study indicate that predisposition to tinnitus may span across multiple genomic loci and be established by weakened neuronal circuitry and maladaptive cytoskeletal modifications within the dorsal cochlear nucleus.

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.

scholarly journals Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema

2019 ◽  
Vol 28 (23) ◽  
pp. 4022-4041 ◽  
Author(s):  
Åsa Johansson ◽  
Mathias Rask-Andersen ◽  
Torgny Karlsson ◽  
Weronica E Ek
Keyword(s):  
Genome Wide Association Study ◽  
Hay Fever ◽  
Genome Wide Association ◽  
The Novel ◽  
Nucleotide Polymorphisms ◽  
Genetic Contribution ◽  
Uk Biobank ◽  
Specific Effects ◽  
Genome Wide ◽  
The Uk

Abstract Even though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this genome-wide association study, we include 346 545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema and replicate novel loci in three independent cohorts. We further investigate if associated lead single nucleotide polymorphisms (SNPs) have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease-specific effects. We identified 141 loci, of which 41 are novel, to be associated (P ≤ 3 × 10−8) with asthma, hay fever or eczema, analyzed separately or as disease phenotypes that includes the presence of different combinations of these diseases. The largest number of loci was associated with the combined phenotype (asthma/hay fever/eczema). However, as many as 20 loci had a significantly larger effect on hay fever/eczema only compared to their effects on asthma, while 26 loci exhibited larger effects on asthma compared with their effects on hay fever/eczema. At four of the novel loci, TNFRSF8, MYRF, TSPAN8, and BHMG1, the lead SNPs were in Linkage Disequilibrium (LD) (&gt;0.8) with potentially casual missense variants. Our study shows that a large amount of the genetic contribution is shared between the diseases. Nonetheless, a number of SNPs have a significantly larger effect on one of the phenotypes, suggesting that part of the genetic contribution is more phenotype specific.

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