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

Publication ,  Journal Article
Milaneschi, Y; Arnold, M; Kastenmüller, G; Dehkordi, SM; Krishnan, RR; Dunlop, BW; Rush, AJ; Penninx, BWJH; Kaddurah-Daouk, R ...
Published in: J Affect Disord
June 15, 2022

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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Published In

J Affect Disord

DOI

EISSN

1573-2517

Publication Date

June 15, 2022

Volume

307

Start / End Page

254 / 263

Location

Netherlands

Related Subject Headings

  • Psychiatry
  • Humans
  • Genomics
  • Depression
  • Causality
  • Carnitine
  • 52 Psychology
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 17 Psychology and Cognitive Sciences
 

Citation

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Milaneschi, Y., Arnold, M., Kastenmüller, G., Dehkordi, S. M., Krishnan, R. R., Dunlop, B. W., … Mood Disorders Precision Medicine Consortium (MDPMC), . (2022). Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression. J Affect Disord, 307, 254–263. https://doi.org/10.1016/j.jad.2022.03.070
Milaneschi, Yuri, Matthias Arnold, Gabi Kastenmüller, Siamak Mahmoudian Dehkordi, Ranga R. Krishnan, Boadie W. Dunlop, A John Rush, Brenda W. J. H. Penninx, Rima Kaddurah-Daouk, and Rima Mood Disorders Precision Medicine Consortium (MDPMC). “Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression.J Affect Disord 307 (June 15, 2022): 254–63. https://doi.org/10.1016/j.jad.2022.03.070.
Milaneschi Y, Arnold M, Kastenmüller G, Dehkordi SM, Krishnan RR, Dunlop BW, et al. Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression. J Affect Disord. 2022 Jun 15;307:254–63.
Milaneschi, Yuri, et al. “Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression.J Affect Disord, vol. 307, June 2022, pp. 254–63. Pubmed, doi:10.1016/j.jad.2022.03.070.
Milaneschi Y, Arnold M, Kastenmüller G, Dehkordi SM, Krishnan RR, Dunlop BW, Rush AJ, Penninx BWJH, Kaddurah-Daouk R, Mood Disorders Precision Medicine Consortium (MDPMC). Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression. J Affect Disord. 2022 Jun 15;307:254–263.
Journal cover image

Published In

J Affect Disord

DOI

EISSN

1573-2517

Publication Date

June 15, 2022

Volume

307

Start / End Page

254 / 263

Location

Netherlands

Related Subject Headings

  • Psychiatry
  • Humans
  • Genomics
  • Depression
  • Causality
  • Carnitine
  • 52 Psychology
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
  • 17 Psychology and Cognitive Sciences