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

Author(s):  
Muktar Ahmed ◽  
Ville-Petteri Mäkinen ◽  
Anwar Mulugeta ◽  
Jisu Shin ◽  
Terry Boyle ◽  
...  

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.

2017 ◽  
Author(s):  
Weihua Meng ◽  
Mark J Adams ◽  
Harry L Hebert ◽  
Ian J Deary ◽  
Andrew M McIntosh ◽  
...  

AbstractHeadache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. We identified 3,343 SNPs which reached the genome-wide significance level of P < 5 × 10−8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 × 10−47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 × 10−15 in the LINC02210-CRHR1 gene was the top SNP.Positive relationships (P < 0.001) between multiple brain tissues and genetic associations were identified through tissue expression analysis, whereas no vascular related tissues showed significant relationships. We identified several significant positive genetic correlations between headache and other psychological traits including neuroticism, depressive symptoms, insomnia, and major depressive disorder.Our results suggest that brain function is closely related to broadly-defined headache. In addition, we also found that many psychological traits have genetic correlations with headache.


2017 ◽  
Author(s):  
Rona J. Strawbridge ◽  
Joey Ward ◽  
Breda Cullen ◽  
Elizabeth M. Tunbridge ◽  
Sarah Hartz ◽  
...  

AbstractRisk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome wide association study in 116 255 UK Biobank participants who responded yes/no to the question “Would you consider yourself a risk-taker?” Risk-takers (compared to controls) were more likely to be men, smokers and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait which has a major impact on a range of common physical and mental health disorders.


2021 ◽  
pp. annrheumdis-2020-219796
Author(s):  
Gabriela Sandoval-Plata ◽  
Kevin Morgan ◽  
Abhishek Abhishek

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.


Author(s):  
Wan-Yu Lin

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.


2018 ◽  
Vol 77 (4) ◽  
pp. 620-623 ◽  
Author(s):  
Elisabetta Casalone ◽  
Ioanna Tachmazidou ◽  
Eleni Zengini ◽  
Konstantinos Hatzikotoulas ◽  
Sophie Hackinger ◽  
...  

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.


2020 ◽  
Vol 29 (8) ◽  
pp. 1396-1404 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  

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.


2019 ◽  
Author(s):  
J Bralten ◽  
CJHM Klemann ◽  
NR Mota ◽  
W De Witte ◽  
C Arango ◽  
...  

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.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madeleine E. Urbanek ◽  
Jian Zuo

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.


2019 ◽  
Author(s):  
Weihua Meng ◽  
Mark J Adams ◽  
Colin NA Palmer ◽  
Jingchunzi Shi ◽  
Adam Auton ◽  
...  

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.


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