Genetic analysis of the PCSK9 locus in psychological, psychiatric, metabolic and cardiovascular traits in UK Biobank

Hay, R., Cullen, B. , Graham, N., Lyall, D. M. , Aman, A., Pell, J. P. , Ward, J. , Smith, D. J. and Strawbridge, R. J. (2022) Genetic analysis of the PCSK9 locus in psychological, psychiatric, metabolic and cardiovascular traits in UK Biobank. European Journal of Human Genetics, (doi: 10.1038/s41431-022-01107-9) (PMID:35501368) (Early Online Publication)

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Abstract

The association between severe mental illness (SMI) and cardiovascular and metabolic disease (CMD) is poorly understood. PCSK9 is expressed in systems critical to both SMI and CMD and influences lipid homeostasis and brain function. We systematically investigated relationships between genetic variation within the PCSK9 locus and risk for both CMD and SMI. UK Biobank recruited ~500,000 volunteers and assessed a wide range of SMI and CMD phenotypes. We used genetic data from white British ancestry individuals of UK Biobank. Genetic association analyses were conducted in PLINK, with statistical significance defined by the number of independent SNPs. Conditional analyses and linkage disequilibrium assessed the independence of SNPs and the presence of multiple signals. Two genetic risk scores of lipid-lowering alleles were calculated and used as proxies for putative lipid-lowering effects of PCSK9. PCSK9 variants were associated with central adiposity, venous thrombosis embolism, systolic blood pressure, mood instability, and neuroticism (all p < 1.16 × 10−4). No secondary signals were identified. Conditional analyses and high linkage disequilibrium (r2 = 0.98) indicated that mood instability and central obesity may share a genetic signal. Genetic risk scores suggested that the lipid-lowering effects of PCSK9 may be causal for greater mood instability and higher neuroticism. This is the first study to implicate the PCSK9 locus in mood-disorder symptoms and related traits, as well as the shared pathology of SMI and CMD. PCSK9 effects on mood may occur via lipid-lowering mechanisms. Further work is needed to understand whether repurposing PCSK9-targeting therapies might improve SMI symptoms and prevent CMD.

Item Type:Articles
Additional Information:Funding:The UK Biobank was funded by the Wellcome Trust, Medical Research Council, Department of Health, Scottish Government and Northwest Regional Development Agency. UK Biobank has also had funding from the Welsh Assembly Government and the British Heart Foundation. This project was completed using UK Biobank applications 6553 (PI. RJS) and 7155 (PI. JPP). DJS acknowledges the support of a Lister Prize Fellowship (173096) and MRC Mental Health Data Pathfinder Award (MC_PC_17217). RJS was supported by a UKRI Innovation-HDR-UK Fellowship (MR/S003061/1) and a University of Glasgow Lord Kelvin/Adam Smith Fellowship.
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel and Cullen, Dr Breda and Ward, Dr Joey and Pell, Professor Jill and Strawbridge, Dr Rona and Lyall, Dr Donald and Aman, Alisha and Graham, Dr Nicholas
Authors: Hay, R., Cullen, B., Graham, N., Lyall, D. M., Aman, A., Pell, J. P., Ward, J., Smith, D. J., and Strawbridge, R. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:European Journal of Human Genetics
Publisher:Nature Publishing Group
ISSN:1018-4813
ISSN (Online):1476-5438
Published Online:02 May 2022
Copyright Holders:Copyright © The Author(s) 2022
First Published:First published in European Journal of Human Genetics 2022
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173096Investigating comorbidity between hypertension and bipolar disorder to identify new and repurposed medications for bipolar disorderDaniel SmithLister Institute of Preventive Medicine (LISTININ)Research Prize 2016HW - Mental Health and Wellbeing
302957Mental Health Data PathfinderDaniel SmithMedical Research Council (MRC)MC_PC_17217HW - Mental Health and Wellbeing
302131Understanding the excess risk of cardiometabolic disease in individuals with serious mental illnessJill PellMedical Research Council (MRC)MR/S003061/1HW - Public Health