scholarly journals Effects of pathogenic CNVs on physical traits in participants of the UK Biobank

2018 ◽  
Author(s):  
David Owen ◽  
Mathew Bracher-Smith ◽  
Kimberley Kendall ◽  
Elliott Rees ◽  
Mark Einon ◽  
...  
Keyword(s):  
Linear Regression Analysis ◽  
Copy Number Variants ◽  
Mirror Image ◽  
Therapeutic Interventions ◽  
Uk Biobank ◽  
Adverse Health Outcomes ◽  
Medical Disorders ◽  
Physical Measurements ◽  
Physical Traits ◽  
The Uk

ABSTRACTBackgroundCopy number variants (CNVs) have been shown to increase risk for physical anomalies, developmental, psychiatric and medical disorders. Some of them have been associated with changes in weight, height, and other physical traits. As most studies have been performed on children and young people, these effects of CNVs in adulthood are not well established.MethodsThe UK Biobank recruited half a million adults who provided a variety of physical measurements. We called all CNVs from the Affymetrix microarrays and selected a set of 54 CNVs implicated as pathogenic (including their reciprocal deletions/duplications) and that were present in five or more persons. Linear regression analysis was used to establish their association with 16 physical traits, relevant to human health.Results396,725 participants of white British or Irish descent (excluding first-degree relatives) passed our quality control filters. There were 214 CNV/trait associations significant at a false discovery rate of 0.1, most of them novel. These traits are associated with adverse health outcomes: e.g. increased weight, waist-to-hip ratio, pulse rate and body fat composition. Deletions at 16p11.2, 16p12.1, NRXN1 and duplications at 16p13.11 and 22q11.2 produced the highest numbers of significant associations. CNVs at 1q21.1, 2q13, 16p11.2, 16p11.2 distal, 16p12.1, 17p12 and 17q12 demonstrated one or more mirror image effects of deletions versus duplications.ConclusionsCarriers of many CNVs should be monitored for physical traits that increase morbidity and mortality. Genes within these CNVs can give insights into biological processes and therapeutic interventions.

scholarly journals Effects of pathogenic CNVs on biochemical markers: a study on the UK Biobank

2019 ◽  
Author(s):  
Matthew Bracher-Smith ◽  
Kimberley M Kendall ◽  
Elliott Rees ◽  
Mark Einon ◽  
Michael C O’Donovan ◽  
...  
Keyword(s):  
Statistical Power ◽  
Linear Regression Analysis ◽  
Copy Number Variants ◽  
Uk Biobank ◽  
Rare Cnvs ◽  
Medical Disorders ◽  
Affymetrix Microarrays ◽  
Increase Risk ◽  
Pathogenic Cnvs ◽  
The Uk

ABSTRACTBackgroundPathogenic copy number variants (CNVs) increase risk for medical disorders, even among carriers free from neurodevelopmental disorders. The UK Biobank recruited half a million adults who provided samples for biochemical and haematology tests which have recently been released. We wanted to assess how the presence of pathogenic CNVs affects these biochemical test results.MethodsWe called all CNVs from the Affymetrix microarrays and selected a set of 54 CNVs implicated as pathogenic (including their reciprocal deletions/duplications) and present in five or more persons. We used linear regression analysis to establish their association with 28 biochemical and 23 haematology tests.ResultsWe analysed 421k participants who passed our CNV quality control filters and self-reported as white British or Irish descent. There were 268 associations between CNVs and biomarkers that were significant at a false discovery rate of 0.05. Deletions at 16p11.2 had the highest number of significant associations, but several rare CNVs had higher effect sizes indicating that the lack of significance was likely due to the reduced statistical power for rarer events. The distribution of values can be visualised on our interactive website: http://kirov.psycm.cf.ac.uk/.ConclusionsCarriers of many pathogenic CNVs have changes in biochemical and haematology tests, and many of those are associated with adverse health consequences. These changes did not always correlate with increases in diagnosed medical disorders in this population. Carriers should have regular blood tests in order to identify and treat adverse medical consequences early. Levels of cholesterol and related lipids were unexpectedly lower in carriers of CNVs associated with increased weight gain, most likely due to the use of statins by such people.

scholarly journals Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

2018 ◽  
Vol 49 (15) ◽  
pp. 2499-2504 ◽  
Author(s):  
Valentina Escott-Price ◽  
Daniel J. Smith ◽  
Kimberley Kendall ◽  
Joey Ward ◽  
George Kirov ◽  
...  
Keyword(s):  
Environmental Exposure ◽  
Copy Number Variants ◽  
Season Of Birth ◽  
Uk Biobank ◽  
Month Of Birth ◽  
Risk Alleles ◽  
Gene Environment ◽  
Increased Risk ◽  
The Uk ◽  
Pathogenic Process

AbstractBackgroundThere is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon.MethodsHere we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth.ResultsNeither genetic measure was associated with season or month of birth within the UKBB sample.ConclusionsAs our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure.

scholarly journals Neuroticism and suicide in a general population cohort: results from the UK Biobank Project

BJPsych Open ◽  
2018 ◽  
Vol 4 (2) ◽  
pp. 62-68 ◽  
Author(s):  
Evyn M. Peters ◽  
Ann John ◽  
Rudy Bowen ◽  
Marilyn Baetz ◽  
Lloyd Balbuena
Keyword(s):  
General Population ◽  
Suicide Prevention ◽  
Suicide Risk ◽  
Cox Regression ◽  
Therapeutic Interventions ◽  
Uk Biobank ◽  
General Population Cohort ◽  
Health Related ◽  
The Uk ◽  
Social Demographic

BackgroundNeuroticism has often been linked to suicidal thoughts and behaviour.AimsTo examine whether neuroticism is associated with suicide deaths after adjusting for known risks.MethodUK Biobank participants (n = 389 365) were assessed for neuroticism as well as social, demographic and health-related variables at study entry and followed for up to 10 years. Suicide risk was modelled using Cox regression stratified by gender.ResultsNeuroticism increased the risk of suicide in both men (hazard ratio (HR) = 1.15, 95% CI 1.09–1.22) and women (HR = 1.16, 95% CI 1.06–1.27). In a subsample who were assessed for mood disorders, neuroticism remained a significant predictor for women (HR 1.25, 95% CI 1.03–1.51) but not for men.ConclusionsScreening and therapeutic interventions for neuroticism may be important for early suicide prevention.Declaration of interestNone.

scholarly journals Multiple linear regression allows weighted burden analysis of rare coding variants in an ethnically heterogeneous population

2020 ◽  
Author(s):  
David Curtis
Keyword(s):  
Linear Regression ◽  
Principal Components ◽  
Rare Variants ◽  
Linear Regression Analysis ◽  
Uk Biobank ◽  
Case Control Studies ◽  
Test Statistic ◽  
Functional Variants ◽  
The Uk ◽  
Coding Variants

AbstractWeighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using BMI as the phenotype the method produces a very inflated test statistic. However this is almost completely corrected by including 20 population principal components as covariates. When this is done the top 30 genes include a few which are quite plausibly associated with the phenotype, including LYPLAL1 and NSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.

scholarly journals Schizophrenia-associated genomic copy number variants and subcortical brain volumes in the UK Biobank

2019 ◽  
Vol 25 (4) ◽  
pp. 854-862 ◽  
Author(s):  
Anthony Warland ◽  
Kimberley M. Kendall ◽  
Elliott Rees ◽  
George Kirov ◽  
Xavier Caseras
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Uk Biobank ◽  
Brain Volumes ◽  
Genomic Copy Number ◽  
Subcortical Brain ◽  
Genomic Copy ◽  
The Uk

scholarly journals Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank

2019 ◽  
Vol 214 (5) ◽  
pp. 297-304 ◽  
Author(s):  
Kimberley M. Kendall ◽  
Matthew Bracher-Smith ◽  
Harry Fitzpatrick ◽  
Amy Lynham ◽  
Elliott Rees ◽  
...  
Keyword(s):  
Cognitive Performance ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Cognitive Test ◽  
Carrier Status ◽  
Cognitive Tests ◽  
Uk Biobank ◽  
The Uk

BackgroundRare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.AimsWe aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.MethodWe called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.ResultsMost CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.ConclusionsCNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.Declaration of interestNone.

scholarly journals Development and validation of decision rules models to stratify coronary artery disease, diabetes, and hypertension risk in preventive care: cohort study of returning UK Biobank participants

2021 ◽  
Author(s):  
José Castela Forte ◽  
Pytrik Folkertsma ◽  
Rahul Gannamani ◽  
Sridhar Kumaraswamy ◽  
Sarah Mount ◽  
...  
Keyword(s):  
Lifestyle Intervention ◽  
Genetic Risk ◽  
Risk Group ◽  
Decision Rules ◽  
High Risk Group ◽  
Risk Scores ◽  
Uk Biobank ◽  
Physical Measurements ◽  
The Uk

AbstractBackgroundA wide range of predictive models exist that predict risk of common lifestyle conditions. However, these have not focused on identifying pre-clinical higher risk groups that would benefit from lifestyle interventions and do not include genetic risk scores. In this study, we developed, validated, and compared the performance of three decision rule algorithms including biomarkers, physical measurements and genetic risk scores for incident coronary artery disease (CAD), diabetes (T2D), and hypertension in the general population against commonly used clinical risk scoring tools.Methods and findingsOf all individuals recruited between 2006 and 2010 from the UK Biobank study for whom re-measurement data were available, 60782 were included in the analyses (mean age 56.3 (7.59), 51.2% female). Follow-up data were available until 2016. Three decision rules models with three risk strata were developed and tested for an association with incident disease. Hazard ratios (HR with 95% confidence interval) for incident CAD, T2D, and hypertension were calculated from survival models. Model performance in discriminating between higher risk individuals suitable for lifestyle intervention and individuals at low risk was assessed using the area under the receiver operating characteristic curve (AUROC).From the initial baseline measurement until the follow-up re-measurements, 500 incident CAD cases, 1005 incident T2D cases, and 2379 incident hypertension cases were ascertained. The higher risk group in the decision rules model had a 40-, 40.9-, and 21.6-fold increase in risk of CAD, T2D, and hypertension, respectively (P < 0.001 for all), and the risk increased significantly between the three strata for all three conditions (P < 0.05). Risk stratification based on decision rules identified both a low risk group which would not have benefited from lifestyle intervention (only 1.3% incident disease across all models), as well as a high risk group where 72%, 81.5%, and 74% of those who developed disease within 8 years would have been recommended lifestyle intervention. Based on genetic risk alone, we identified not only a high risk group, but also a group at elevated risk for all health conditions. This study was limited by the restricted number of participants with follow-up data, and the lack of ethnic diversity in the UK Biobank cohort.ConclusionIn this analysis of returning UK Biobank participants, we found that decision rule models comprising blood biomarkers, physical measurements, and polygenic risk scores were superior at identifying individuals likely to benefit from lifestyle intervention for three of the most common lifestyle-related chronic health conditions compared to commonly used clinical risk scores.

scholarly journals Schizophrenia-associated genomic copy number variants and subcortical brain volumes in the UK Biobank

2018 ◽  
Author(s):  
Anthony Warland ◽  
Kimberley M Kendall ◽  
Elliott Rees ◽  
George Kirov ◽  
Xavier Caseras
Keyword(s):  
Copy Number ◽  
Copy Number Variants ◽  
Risk Groups ◽  
Clinical Samples ◽  
Uk Biobank ◽  
Subcortical Structures ◽  
Brain Volumes ◽  
Subcortical Brain ◽  
Heritable Disorder ◽  
The Uk

AbstractSchizophrenia is a highly heritable disorder for which anatomical brain alterations have been repeatedly reported in clinical samples. Unaffected at-risk groups have also been studied in an attempt to identify brain changes that do not reflect reverse causation or treatment effects. However, no robust associations have been observed between neuroanatomical phenotypes and known genetic risk factors for schizophrenia. We tested subcortical brain volume differences between 49 unaffected participants carrying at least one of the 12 copy number variants associated with schizophrenia in UK Biobank and 9,063 individuals who did not carry any of the 93 copy number variants reported to be pathogenic. Our results show that CNV carriers have reduced volume in some of the subcortical structures previously shown to be reduced in schizophrenia. Moreover, these associations were partially accounted for by the association between pathogenic copy number variants and cognitive impairment, which is one of the features of schizophrenia.

scholarly journals Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

2021 ◽  
Author(s):  
Chaoyue Wang ◽  
Aurea B. Martins-Bach ◽  
Fidel Alfaro-Almagro ◽  
Gwenaëlle Douaud ◽  
Johannes C. Klein ◽  
...  
Keyword(s):  
Magnetic Susceptibility ◽  
Brain Imaging ◽  
Added Value ◽  
Therapeutic Interventions ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Brain Health ◽  
Brain Functions ◽  
The Uk

A key aim of epidemiological neuroscience studies is the identification of novel markers to assess brain health and evaluate the efficacy of therapeutic interventions. A broad range of tissue constituents associated with healthy brain functions and diseases (e.g., iron, myelin and calcium) are characterised by unique magnetic properties, motivating the development of measurements sensitive to these effects. Quantitative susceptibility mapping (QSM) is an emerging MRI technique which enables in vivo quantification of tissue magnetic susceptibility, providing the opportunity to identify such markers. In this study, we developed a robust QSM modelling pipeline and evaluated the potential of QSM in a cohort of 35,885 subjects (ages 45-82), alongside extensive genetic and phenotypic associations as part of UK Biobank. Our analysis identified a rich set of distinctive phenotypic and genetic associations with QSM. This included phenotypic associations with body iron, diet, alcohol and diseases, and genetic associations related to a broad range of biological functions including iron, calcium homeostasis, myelination, extracellular matrix. Importantly, we found that QSM and T2* have unique patterns of associations, demonstrating the added value in including QSM IDPs in the UK Biobank brain imaging resource, with considerable promise to identify novel in vivo brain health markers.

scholarly journals The effect of schizophrenia-associated CNVs on other psychiatric disorders

BJPsych Open ◽  
2021 ◽  
Vol 7 (S1) ◽  
pp. S248-S249
Author(s):  
Lily Farakish
Keyword(s):  
Psychiatric Disorders ◽  
Copy Number Variants ◽  
Clinical Importance ◽  
Carrier Status ◽  
Uk Biobank ◽  
Online Resource ◽  
Icd 10 ◽  
Heritable Disorder ◽  
Rare Genetic Variants ◽  
The Uk

AimsSchizophrenia is a highly heritable disorder, sharing genetic roots with other psychiatric disorders from both common and rare genetic variants. Copy number variants (CNVs) are one of the rare causes which increase the risk of a variety of psychiatric, medical and physical phenotypes. The role of schizophrenia-associated CNVs is becoming of increasingly scientific and clinical importance in the field of psychiatry, with new CNV-phenotype relationships opening perspectives for understanding the aetiology of psychiatric disorders. This paper aims to investigate whether 13 schizophrenia (SZ)-associated CNVs or any SZ-CNV-carrier status increase the risk for 9 psychiatric phenotypes, reduce levels of happiness, change duration of sleep, and increase the index of multiple deprivation.MethodThe study includes 421,268 participants of British or Irish descent (aged 40–69 years), containing 418,036 controls and 3232 schizophrenia-associated CNV carriers. The data are secondary from the UK Biobank, an online resource containing data on array-genotyped participants with their specific phenotypic information. Prior to analysis, CNV selection led to the exclusion of any CNV with less than 5 hits in the UK Biobank population. Incidence of each phenotype was based on self-reported diagnoses, questionnaires or hospital ICD-10 diagnoses, with a minimum of 500 cases. Both binary logistic and linear regression were used to assess the incidence of these phenotypes in relation to the CNVs, adjusted for age, sex, and ethnicity as potential cofounders.ResultOverall, 12/13 CNVs were nominally associated with at least one phenotype, including 114/168 possible associations and 54 undetectable associations as not every CNV carrier displayed one of the chosen phenotypes. 41 associations were statistically significant (p < 0.05) and 13 survived Bonferroni Correction (p < 2.98 × 10-4). All significant associations met the expected change except 15q11.2 deletion and any CNV carrier status which showed a decrease in likelihood of addiction.ConclusionThese findings suggest schizophrenia-associated CNV can affect range of psychiatric phenotypes. By building on existing reports, understanding the widespread effects of CNVs in the aetiology and pathogenicty of psychiatric disorders may overtime aid in strengthening our search for more targetted, effective treatments.Many thanks to Professor George Kirov for supervising and supporting this project.

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