Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility

Smeeth, Demelza; Dima, Danai; Jones, Lisa; Jones, Ian; Craddock, Nick; Rietschel, Marcella; Maier, Wolfgang; Korszun, Ania; Rice, John P.; Mors, Ole; Preisig, Martin; Uher, Rudolf; Lewis, Cathryn M.; Thuret, Sandrine; Powell, Timothy R.

doi:10.1016/j.psyneuen.2019.04.011

Cited by 18 publications

(11 citation statements)

References 85 publications

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“…45 Another study explored the association between PRS for 4 reproductive hormones (estradiol, progesterone, prolactin, and testosterone) and subfield volumetry in a sample of MDD with an average age of 50 ± 8.1. 46 The study reported that PRS for estradiol predicted reduced volumes of the right and left subiculum (right: Although GRS-AD correlated strongly with the percentage change in thickness across the whole hippocampal complex (β = −0.25, p = 0.048) and ERC (β = −0.35, p = 0.009), no significant results were found between the risk scores and thickness in any specific hippocampal subfield.…”

Section: Polygenic Risk Scoresmentioning

confidence: 93%

Genetic Influences on Hippocampal Subfields

et al. 2021

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There is clear evidence that hippocampal subfield volumes have partly distinct genetic determinants associated with specific biological processes. The identification of genetic correlates of hippocampal subfield volumes may help to elucidate the mechanisms of neurologic diseases, as well as aging and neurodegenerative processes. However, despite the emerging interest in this area of research, the current knowledge of the genetic architecture of hippocampal subfields has not yet been consolidated. We aimed to provide a review of the current evidence from genetic studies of hippocampal subfields, highlighting current priorities and upcoming challenges. The limited number of studies investigating the influential genetic effects on hippocampal subfields, a lack of replicated results and longitudinal designs, and modest sample sizes combined with insufficient standardization of protocols are identified as the most pressing challenges in this emerging area of research.

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Section: Polygenic Risk Scoresmentioning

confidence: 93%

Genetic Influences on Hippocampal Subfields

et al. 2021

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“…Considering the limited evidence for the role of these metabolites in the mechanism underpinning the antiinflammatory and neurogenic activities of ω-3 PUFAs in the context of depression, we used our aforementioned, validated in vitro model of 'depression in a dish' [13,20,21,[29][30][31][32][33] exposing immortalised human hippocampal progenitor cell line HPC0A07/03C to candidate 'depressogenic' cytokines, IL1β, IL6 and IFN-α, resulting in a reduction in neurogenesis and an increase in neuronal apoptosis [13,20,21]. In order to identify the lipid species or families of COX-, LOX-or CYP450-derived mediators putatively involved in the anti-inflammatory and neuroprotective effects exerted by ω-3 PUFAs, we pre-treated cells with EPA/DHA with or without a selective inhibitor of COX-, LOX-or CYP450 enzymes, and then directly exposed cells to candidate metabolites.…”

Section: Introductionmentioning

confidence: 99%

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis

et al. 2021

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Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1β), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

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“…GWASs from European descents [74] and from the Korean population [47] have identified associations of SNPs related to E2 biosynthesis and ERs with SCZ. More recent GWASs have identified that a genetic risk (E2 polygenic risk score) for higher plasma E2 is negatively associated with hippocampal volume, but not with an increased risk of major depressive disorder or postpartum depression [75]. However, the largest GWAS of anxiety traits to date was able to identify genome-wide significant associations near genes involved with the ERα (ESR1) [76].…”

Section: Genetics Of Schizophrenia and Bipolar Disordermentioning

confidence: 99%

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

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Szabó

Osete

et al. 2021

Cells

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Schizophrenia (SCZ) and bipolar disorder (BIP) are severe mental disorders with a considerable disease burden worldwide due to early age of onset, chronicity, and lack of efficient treatments or prevention strategies. Whilst our current knowledge is that SCZ and BIP are highly heritable and share common pathophysiological mechanisms associated with cellular signaling, neurotransmission, energy metabolism, and neuroinflammation, the development of novel therapies has been hampered by the unavailability of appropriate models to identify novel targetable pathomechanisms. Recent data suggest that neuron–glia interactions are disturbed in SCZ and BIP, and are modulated by estrogen (E2). However, most of the knowledge we have so far on the neuromodulatory effects of E2 came from studies on animal models and human cell lines, and may not accurately reflect many processes occurring exclusively in the human brain. Thus, here we highlight the advantages of using induced pluripotent stem cell (iPSC) models to revisit studies of mechanisms underlying beneficial effects of E2 in human brain cells. A better understanding of these mechanisms opens the opportunity to identify putative targets of novel therapeutic agents for SCZ and BIP. In this review, we first summarize the literature on the molecular mechanisms involved in SCZ and BIP pathology and the beneficial effects of E2 on neuron–glia interactions. Then, we briefly present the most recent developments in the iPSC field, emphasizing the potential of using patient-derived iPSCs as more relevant models to study the effects of E2 on neuron–glia interactions.

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Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility

Cited by 18 publications

References 85 publications

Genetic Influences on Hippocampal Subfields

Genetic Influences on Hippocampal Subfields

Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis

Using iPSC Models to Understand the Role of Estrogen in Neuron–Glia Interactions in Schizophrenia and Bipolar Disorder

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