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Milaneschi, Y.* ; Arnold, M. ; Kastenmüller, G. ; Dehkordi, S.M.* ; Krishnan, R.R.* ; Dunlop, B.W.* ; Rush, A.J.* ; Penninx, B.W.J.H.* ; Kaddurah-Daouk, R.*

Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression.

J. Affect. Disord. 307, 254-263 (2022)

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Background: Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. Methods: Summary statistics were obtained from large GWAS: the Fenland Study (N = 9363), and the Psychiatric Genomics Consortium (246,363 depression cases and 561,190 controls). Two-sample Mendelian randomization analyses tested the potential causal link of 15 endogenous acylcarnitines with depression. Results: In univariable analyses, genetically-predicted lower levels of short-chain acylcarnitines C2 (odds ratio [OR] 0.97, 95% confidence intervals [CIs] 0.95–1.00) and C3 (OR 0.97, 95%CIs 0.96–0.99) and higher levels of medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.01–1.06) and C10 (OR 1.04, 95%CIs 1.02–1.06) were associated with increased depression risk. No reverse potential causal role of depression genetic liability on acylcarnitines levels was found. Multivariable analyses showed that the association with depression was driven by the medium-chain acylcarnitines C8 (OR 1.04, 95%CIs 1.02–1.06) and C10 (OR 1.04, 95%CIs 1.02–1.06), suggesting a potential causal role in the risk of depression. Causal estimates for C8 (OR = 1.05, 95%CIs = 1.02–1.07) and C10 (OR = 1.05, 95%CIs = 1.02–1.08) were confirmed in follow-up analyses using genetic instruments derived from a GWAS meta-analysis including up to 16,841 samples. Discussion: Accumulation of medium-chain acylcarnitines is a signature of inborn errors of fatty acid metabolism and age-related metabolic conditions. Our findings point to a link between altered mitochondrial energy production and depression pathogenesis. Acylcarnitine metabolism represents a promising access point for the development of novel therapeutic approaches for depression.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Acylcarnitines ; Causality ; Depression ; Genomics ; Mendelian Randomization ; Metabolomics

ISSN (print) / ISBN 0165-0327

e-ISSN 1573-2517

Journal Journal of Affective Disorders

Quellenangaben Volume: 307, Pages: 254-263

Publisher Elsevier

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)