Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids

Davyson, Eleanor; Shen, Xueyi; Gadd, Danni A; Bernabeu, Elena; Hillary, Robert F.; McCartney, Daniel L.; Adams, Mark; Marioni, Riccardo E.; McIntosh, Andrew M.

doi:10.1016/j.biopsych.2023.01.027

Cited by 23 publications

(25 citation statements)

References 91 publications

(102 reference statements)

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“…The FADS locus (includes FADS1, FADS2 and FADS3 ) is the most pleiotropic regulator of peripheral metabolite levels, with significant genetic associations for 79 metabolites, including 75 lipid species 25 . Furthermore, there is also evidence to suggest that peripheral lipid dysregulation caused by the FADS locus is causal in MDD 81 . FADS1 has also been identified through TWAS as a depression risk gene within the brain and we describe alterations in FADS1 co-expression networks in the prefrontal cortex associated with MDD and suicidality.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic convergence of depression and suicidality on astrocyte fatty acid metabolism

Fitzgerald

O’Toole

Pokhvisneva

et al. 2023

Preprint

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Genome-wide association studies (GWAS) show conceptual promise to identify novel mechanisms of major depressive disorder (MDD), but have not yet achieved this potential. One explanation is that MDD risk acts through complex expression networks, and GWAS-identified genes represent important components of these networks but in isolation are insufficient for their functional annotation. In this study, we aimed to identify and characterize the expression networks through which GWAS-identified MDD risk genes operate. We generated and characterized seeded co-expression networks of 252 MDD risk genes over 11 brain regions. We used principal component regression and Mendelian randomization to identify a relation between the networks of two such genes (FADS1 and ZKSCAN8) and suicidal ideation. These networks were primarily expressed in astrocytes, enriched for functions related to fatty acid metabolism, and could define MDD-altered astrocyte states. We then identified FGFR3 to EPHA4 signaling as a putative downstream effector of these astrocyte states on synaptic function. Finally through transcriptomic and genetic analyses, we identify PPARA as a putative therapeutic target of these mechanisms in MDD. Our study defines a tractable pathway to translate genetic findings into therapeutically actionable mechanisms.

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Section: Discussionmentioning

confidence: 99%

Mechanistic convergence of depression and suicidality on astrocyte fatty acid metabolism

Fitzgerald

O’Toole

Pokhvisneva

et al. 2023

Preprint

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“…Finally, our study focused only on the European population. Genetic adaptation and variation of fatty acid composition have been demonstrated in the Inuit, African, South Asian, East Asian, and European populations [23,[107][108][109]. Differences in prevalence [110,111] and genetic risk factors [89] of psychiatric disorders were also demonstrated across ethnic groups.…”

Section: Figure S9mentioning

confidence: 99%

“…Previous studies have leveraged genetic information to investigate the connections between PUFAs and brain disorders ( Supplementary Table S1 ), such as the application of Mendelian randomization (MR) to statistically infer causal relationships. For instance, a recent MR study suggested that decreased docosahexaenoic acid (DHA) and increased omega-6 to omega-3 ratio have causal links with MDD, and it further identified the fatty acid desaturase ( FADS ) gene cluster as a common genetic signal [23]. In an experimental study, mice with Fads1/2 genes knockout were used to simulate the effect of BIP risk allele on Fads1/2 activity, revealing significant changes in lipid profile and behavioral alterations [24].…”

Section: Introductionmentioning

confidence: 99%

“…In an experimental study, mice with Fads1/2 genes knockout were used to simulate the effect of BIP risk allele on Fads1/2 activity, revealing significant changes in lipid profile and behavioral alterations [24]. However, current genetic studies primarily concentrate on specific brain disorders (e.g., MDD [23, 25], SCZ [26, 27], and BIP [24, 28]) or a limited number of genes, such as FADS [23, 24, 26, 28] and ELOVL2/5 [26]. Therefore, it is necessary to explore the broader genomic landscape to ascertain additional genetic determinants that underlie the connection between PUFAs and brain disorders.…”

Section: Introductionmentioning

confidence: 99%

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Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders

Xu,

Sun,

Francis

et al. 2023

Preprint

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The neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2) and rs4818766 (ADARB1). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.

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“…Circulating blood metabolites typically exhibit significant heritabilities (3), although substantial variability exists in estimates depending upon the particular metabolite assayed (2,(4)(5)(6). Genome-wide association studies (GWAS) have identified hundreds of quantitative trait loci robustly associated with serum/plasma levels of a wide range of metabolites (1,2,(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Perhaps unsurprisingly, the genetic variants reported in these studies have often mapped to genes that encode enzymes, metabolite transporters, and regulators of metabolism (6).…”

mentioning

confidence: 99%

A Genome-Wide Association Study of Serum Metabolite Profiles in Septic Shock Patients

Daubney,

D’Urso,

Cuellar-Partida

et al. 2024

Critical Care Explorations

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OBJECTIVES: We sought to assess whether genetic associations with metabolite concentrations in septic shock patients could be used to identify pathways of potential importance for understanding sepsis pathophysiology. DESIGN: Retrospective multicenter cohort studies of septic shock patients. SETTING: All participants who were admitted to 27 participating hospital sites in three countries (Australia, New Zealand, and the United Kingdom) were eligible for inclusion. PATIENTS: Adult, critically ill, mechanically ventilated patients with septic shock (n = 230) who were a subset of the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial (ClinicalTrials.gov number: NCT01448109). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A genome-wide association study was conducted for a range of serum metabolite levels for participants. Genome-wide significant associations (p ≤ 5 × 10–8) were found for the two major ketone bodies (3-hydroxybutyrate [rs2456680] and acetoacetate [rs2213037] and creatinine (rs6851961). One of these single-nucleotide polymorphisms (SNPs) (rs2213037) was located in the alcohol dehydrogenase cluster of genes, which code for enzymes related to the metabolism of acetoacetate and, therefore, presents a plausible association for this metabolite. None of the three SNPs showed strong associations with risk of sepsis, 28- or 90-day mortality, or Acute Physiology and Chronic Health Evaluation score (a measure of sepsis severity). CONCLUSIONS: We suggest that the genetic associations with metabolites may reflect a starvation response rather than processes involved in sepsis pathophysiology. However, our results require further investigation and replication in both healthy and diseased cohorts including those of different ancestry.

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Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids

Cited by 23 publications

References 91 publications

Mechanistic convergence of depression and suicidality on astrocyte fatty acid metabolism

Mechanistic convergence of depression and suicidality on astrocyte fatty acid metabolism

Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders

A Genome-Wide Association Study of Serum Metabolite Profiles in Septic Shock Patients

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