Biology subjects

Bracher-Smith, M.

Publications and source records attributed to Bracher-Smith, M..

3 recordsLinked to original sources

bioRxiv2018

The role of rare copy number variants in depression

The role of large, rare copy number variants (CNVs) in neurodevelopmental disorders is well-established,1-5 but their contribution to common psychiatric disorders, such as depression, remains unclear. We have previously shown that a substantial proportion of CNV enrichment in schizophrenia is explained by CNVs associated with neurodevelopmental disorders.6, 7 Depression shares genetic risk with schizophrenia8, 9 and is frequently comorbid with neurodevelopmental disorders10, 11, suggesting to us the hypothesis that if CNVs play a role in depression, neurodevelopmental CNVs are those most likely to be associated. We confirmed this in UK Biobank by showing that neurodevelopmental CNVs were associated with depression (24,575 cases, 5.87%; OR=1.36, 95% CI 1.22-1.51, p=1.61x10-8), whilst finding no evidence implicating other CNVs. Four individual neurodevelopmental CNVs increased risk of depression (1q21.1 duplication, PWS duplication, 16p13.11 deletion, 16p11.2 duplication). The association between neurodevelopmental CNVs and depression was partially explained by social deprivation but not by education attainment or physical illness.

neuroscience↗

bioRxiv2018

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

BackgroundCopy 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.\n\nMethodsThe 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.\n\nResults396,725 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.\n\nConclusionsCarriers 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.

genetics↗

bioRxiv2018

Medical consequences of pathogenic CNVs in adults: Analysis of the UK Biobank.

BackgroundGenomic copy number variants (CNVs) increase risk for early-onset neurodevelopmental disorders but their impact on medical outcomes in later life is poorly understood. The UK Biobank, with half a million well-phenotyped adults, presents an opportunity to study the medical consequences of CNV in middle and old age.\n\nMethodsWe called 54 CNVs associated with clinical phenotypes or genomic disorders, including their reciprocal deletions or duplications, in all Biobank participants. We used logistic regression analysis to test CNVs for associations with 58 common medical phenotypes.\n\nFindingsCNV carriers had an increased risk of developing 37 of the 58 phenotypes at nominal levels of statistical significance, with 19 associations surviving Bonferroni correction (p<8{middle dot}6x10-4). Tests of each of the 54 CNVs for association with each of the 58 phenotypes identified 18 associations that survived Bonferroni correction (p<1{middle dot}6x10-5) and a further 57 that were associated at a false discovery rate (FDR) threshold of 0{middle dot}1. Thirteen CNVs had three or more significant associations at FDR=0{middle dot}1, with the largest number of phenotypes (N=15) found for deletions at 16p11{middle dot}2. The most common CNVs (frequency 0{middle dot}5-0{middle dot}7%) have no or minimal impact on medical outcomes in adults.\n\nInterpretationSome of the 54 tested CNVs have profound effects on physical health, even in people who have largely escaped early neurodevelopmental outcomes. Our work provides clinicians with a morbidity map of potential outcomes among carriers of these CNVs.\n\nFundingMRC UK, Wellcome Trust UK

genomics↗