Yuri Milaneschi1, Matthias Arnold2, Gabi Kastenmüller3, Siamak Mahmoudian Dehkordi4, Ranga R Krishnan5, Boadie W Dunlop6, A John Rush7, Brenda W J H Penninx8, Rima Kaddurah-Daouk9. 1. Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, The Netherlands; Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress program, Amsterdam, The Netherlands; Amsterdam Neuroscience, Complex Trait Genetics, Amsterdam, The Netherlands. Electronic address: y.milaneschi@amsterdamumc.nl. 2. Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA. 3. Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. 4. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA. 5. Department of Psychiatry, Rush Medical College, Chicago, IL, USA. 6. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA. 7. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke-National University of Singapore, Singapore; Department of Psychiatry, Texas Tech University, Health Sciences Center, Permian Basin, TX, USA. 8. Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Amsterdam Public Health, Mental Health program, Amsterdam, The Netherlands. 9. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute of Brain Sciences, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA.
Abstract
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.
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.
Authors: Christopher R Brydges; Sudeepa Bhattacharyya; Siamak Mahmoudian Dehkordi; Yuri Milaneschi; Brenda Penninx; Rick Jansen; Bruce S Kristal; Xianlin Han; Matthias Arnold; Gabi Kastenmüller; Mandakh Bekhbat; Helen S Mayberg; W Edward Craighead; A John Rush; Oliver Fiehn; Boadie W Dunlop; Rima Kaddurah-Daouk Journal: Brain Behav Immun Date: 2022-02-04 Impact factor: 19.227
Authors: Jelena Brasanac; Stefanie Gamradt; Christian Otte; Yuri Milaneschi; Anna S Monzel; Martin Picard; Stefan M Gold Journal: Mol Psychiatry Date: 2022-02-18 Impact factor: 13.437
Authors: Siamak MahmoudianDehkordi; Sudeepa Bhattacharyya; Christopher R Brydges; Wei Jia; Oliver Fiehn; A John Rush; Boadie W Dunlop; Rima Kaddurah-Daouk Journal: Front Neurosci Date: 2022-07-20 Impact factor: 5.152