scholarly journals Genetic basis of falling risk susceptibility in the UK Biobank Study

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Katerina Trajanoska ◽  
Lotta J. Seppala ◽  
Carolina Medina-Gomez ◽  
Yi-Hsiang Hsu ◽  
Sirui Zhou ◽  
...  
Keyword(s):  
Genetic Correlations ◽  
Well Being ◽  
Risk Scores ◽  
Subjective Well Being ◽  
Uk Biobank ◽  
Mineral Density ◽  
Polygenic Inheritance ◽  
Intrinsic Factors ◽  
A Genome ◽  
The Uk

Abstract Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual’s fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (Pcombined ≤ 5 × 10−8). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics.

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 Biological and clinical insights from genetics of insomnia symptoms

2018 ◽  
Author(s):  
Jacqueline M Lane ◽  
Samuel Jones ◽  
Hassan S Dashti ◽  
Andrew R Wood ◽  
Krishna Aragam ◽  
...  
Keyword(s):  
Muscle Development ◽  
Reproductive Traits ◽  
Well Being ◽  
Brain Regions ◽  
Causal Link ◽  
Subjective Well Being ◽  
Uk Biobank ◽  
The Uk ◽  
Genomic Regions ◽  
Insomnia Symptoms

ABSTRACTInsomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes, but underlying pathophysiological processes and causal relationships with disease are poorly understood. Here we identify 57 loci for self-reported insomnia symptoms in the UK Biobank (n=453,379) and confirm their impact on self-reported insomnia symptoms in the HUNT study (n=14,923 cases, 47,610 controls), physician diagnosed insomnia in Partners Biobank (n=2,217 cases, 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n=83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis, phototransduction and muscle development pathways and of genes expressed in multiple brain regions, skeletal muscle and adrenal gland. Evidence of shared genetic factors is found between frequent insomnia symptoms and restless legs syndrome, aging, cardio-metabolic, behavioral, psychiatric and reproductive traits. Evidence is found for a possible causal link between insomnia symptoms and coronary heart disease, depressive symptoms and subjective well-being.One Sentence SummaryWe identify 57 genomic regions associated with insomnia pointing to the involvement of phototransduction and ubiquitination and potential causal links to CAD and depression.

scholarly journals Using major depression polygenic risk scores to explore the depressive symptom continuum

2021 ◽  
pp. 1-10
Author(s):  
Bradley S. Jermy ◽  
Saskia P. Hagenaars ◽  
Kylie P. Glanville ◽  
Jonathan R. I. Coleman ◽  
David M. Howard ◽  
...  
Keyword(s):  
Factor Analysis ◽  
Major Depression ◽  
Well Being ◽  
Risk Scores ◽  
Subjective Well Being ◽  
Polygenic Risk ◽  
Symptom Level ◽  
Continuous Phenotype ◽  
The Uk ◽  
And Control

Abstract Background Major depression (MD) is often characterised as a categorical disorder; however, observational studies comparing sub-threshold and clinical depression suggest MD is continuous. Many of these studies do not explore the full continuum and are yet to consider genetics as a risk factor. This study sought to understand if polygenic risk for MD could provide insight into the continuous nature of depression. Methods Factor analysis on symptom-level data from the UK Biobank (N = 148 957) was used to derive continuous depression phenotypes which were tested for association with polygenic risk scores (PRS) for a categorical definition of MD (N = 119 692). Results Confirmatory factor analysis showed a five-factor hierarchical model, incorporating 15 of the original 18 items taken from the PHQ-9, GAD-7 and subjective well-being questionnaires, produced good fit to the observed covariance matrix (CFI = 0.992, TLI = 0.99, RMSEA = 0.038, SRMR = 0.031). MD PRS associated with each factor score (standardised β range: 0.057–0.064) and the association remained when the sample was stratified into case- and control-only subsets. The case-only subset had an increased association compared to controls for all factors, shown via a significant interaction between lifetime MD diagnosis and MD PRS (p value range: 2.23 × 10−3–3.94 × 10−7). Conclusions An association between MD PRS and a continuous phenotype of depressive symptoms in case- and control-only subsets provides support against a purely categorical phenotype; indicating further insights into MD can be obtained when this within-group variation is considered. The stronger association within cases suggests this variation may be of particular importance.

scholarly journals A genome-wide association study finds novel genetic associations with broadly-defined headache in UK Biobank (N = 223,773)

2017 ◽  
Author(s):  
Weihua Meng ◽  
Mark J Adams ◽  
Harry L Hebert ◽  
Ian J Deary ◽  
Andrew M McIntosh ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Psychological Traits ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

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.

scholarly journals Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)

2019 ◽  
Author(s):  
Adrián I. Campos ◽  
Luis M. García-Marín ◽  
Enda M. Byrne ◽  
Nicholas G. Martin ◽  
Gabriel Cuéllar-Partida ◽  
...  
Keyword(s):  
Genetic Correlations ◽  
Whole Body ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Obstructive Sleep ◽  
Polygenic Scores ◽  
The Uk ◽  
Cardinal Symptom

ABSTRACTWe conducted the largest study of snoring using data from the UK Biobank (n ∼ 408,000; snorers ∼152,000). A genome-wide association study (GWAS) identified 42 genome-wide significant loci, with a SNP-based heritability estimate of ∼10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism were observed. Gene-based associations identified 173 genes, including DLEU7, MSRB3 and POC5 highlighting genes expressed in brain, cerebellum, lungs, blood, and oesophagus tissues. We used polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n∼8,000). Mendelian randomisation analyses provided evidence that larger whole body fat mass causes snoring. Altogether, our results uncover new insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond being a cardinal symptom of OSA.

scholarly journals Exploring polygenic-environment and residual-environment interactions for depressive symptoms within the UK Biobank

2021 ◽  
Author(s):  
Alexandra Claire Gillett ◽  
Bradley Jermy ◽  
S. Hong Lee ◽  
Oliver Pain ◽  
David M Howard ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
A Priori ◽  
Reaction Norm ◽  
Risk Scores ◽  
Environment Interaction ◽  
Uk Biobank ◽  
Negative Results ◽  
Residual Variation ◽  
A Genome ◽  
The Uk

Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N=61294-91644), we investigate whether the polygenic and residual variation of depressive symptoms are modulated by 25 a-priori selected covariate traits: 12 environmental variables, 5 biomarkers and polygenic risk scores for 8 mental health disorders. MRNMs provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. Of the 25 selected covariates, 11 significantly modulate depressive symptoms, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic score, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably non-zero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% CI [0.54,1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.

scholarly journals Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort

2017 ◽  
Author(s):  
Rona J. Strawbridge ◽  
Joey Ward ◽  
Breda Cullen ◽  
Elizabeth M. Tunbridge ◽  
Sarah Hartz ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Risk Taking ◽  
Genome Wide Association Study ◽  
Genetic Correlations ◽  
Uk Biobank ◽  
Physical And Mental Health ◽  
Post Traumatic Stress ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

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.

scholarly journals Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank

2017 ◽  
Author(s):  
Lynsey S. Hall ◽  
Mark J. Adams ◽  
Aleix Arnau-Soler ◽  
Toni-Kim Clarke ◽  
David M. Howard ◽  
...  
Keyword(s):  
Multiple Testing ◽  
Well Being ◽  
Subjective Well Being ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Sample Sizes ◽  
Genome Wide ◽  
Generation Scotland ◽  
A Genome ◽  
Significant Locus

AbstractFew replicable genetic associations for Major Depressive Disorder (MDD) have been identified. However recent studies of depression have identified common risk variants by using either a broader phenotype definition in very large samples, or by reducing the phenotypic and ancestral heterogeneity of MDD cases. Here, a range of genetic analyses were applied to data from two large British cohorts, Generation Scotland and UK Biobank, to ascertain whether it is more informative to maximize the sample size by using data from all available cases and controls, or to use a refined subset of the data - stratifying by MDD recurrence or sex. Meta-analysis of GWAS data in males from these two studies yielded one genome-wide significant locus on 3p22.3. Three associated genes within this region (CRTAP, GLB1, and TMPPE) were significantly associated in subsequent gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD were each genetically correlated with 6 of 200 health-correlated traits, namely neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder. Meta-analyzed male MDD showed no statistically significant correlations with these traits after correction for multiple testing. Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, the equivalent SNP-based heritability estimates and the consistent pattern of genetic correlation with other health-related traits suggests that phenotypic stratification in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.

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.

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