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Cited by 16Genetic Associations and EpidemiologyLipoproteins and Cardiovascular HealthSchizophrenia research and treatment

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

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Hay, Rachel, Cullen, Breda, Graham, Nicholas, Lyall, Donald M., Aman, Alisha, Pell, Jill P., Ward, Joey, Smith, Daniel J., Strawbridge, Rona J.·2022·European Journal of Human Genetics
DOI 10.1038/s41431-022-01107-9PMC PMC9712543
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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.

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Metadata

Authors
Hay, R., Cullen, B., Graham, N., Lyall, D. M., Aman, A., Pell, J. P., Ward, J., Smith, D. J., & Strawbridge, R. J.
Affiliations
  • University of Glasgow (GB)
  • Karolinska Institutet (SE)
Corresponding author
Strawbridge, Rona J.
ORCID
Venue
European Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-05-02
Volume
30
Issue
12
Pages
1380-1390
ISSN
  • 1018-4813 (ISSN-L)
  • 1476-5438
DOI
10.1038/s41431-022-01107-9
PMC
PMC9712543
OpenAlex
W4225276706
Cited by
16
References
5
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 2
FWCI
2.10
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Human Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • PsyArXiv (OSF Preprints) (submittedVersion, cc-by)
  • PsyArXiv (OSF Preprints) (submittedVersion)
Funders
  • Wellcome Trust
  • UK Research and Innovation (MR/S003061/1)
  • British Heart Foundation
  • University of Glasgow
  • Northwest Regional Development Agency
  • Medical Research Council (MR/S003061/1, MC_PC_17217, MC_PC_17228)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
PCSK9, severe mental illness, cardiovascular disease, metabolic disorders, mood instability, neuroticism, abdominal obesity, venous thrombosis, systolic blood pressure, lipid homeostasis, polygenic risk score, genetic overlap
MeSH terms
Proprotein Convertase 9, Cardiovascular Diseases, United Kingdom, Humans, Lipids, Phenotype, Biological Specimen Banks, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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