{"title":"Reverse phase protein array-based investigation of mitochondrial genes reveals alteration of glutaminolysis in the parahippocampal cortex of people who died by suicide.","authors":"Fanni Dóra, Tamara Hajdu, Éva Renner, Krisztina Paál, Alán Alpár, Miklós Palkovits, Christos Chinopoulos, Arpád Dobolyi","doi":"10.1038/s41398-024-03137-x","DOIUrl":"10.1038/s41398-024-03137-x","url":null,"abstract":"<p><p>A moderating hub between resting state networks (RSNs) and the medial temporal lobe (MTL) is the parahippocampal cortex (PHC). Abnormal activity has been reported in depressed patients and suicide attempters in this region. Alterations in neuronal mitochondrial function may contribute to depression and suicidal behavior. However, little is known about the underlying molecular level changes in relevant structures. Specifically, expressional changes related to suicide have not been reported in the PHC. In this study, we compared the protein expression levels of genes encoding tricarboxylic acid (TCA) cycle enzymes in the PHC of adult individuals who died by suicide by reverse phase protein array (RPPA), which was corroborated by qRT-PCR at the mRNA level. Postmortem human brain samples were collected from 12 control and 10 suicidal individuals. The entorhinal cortex, which is topographically anterior to the PHC in the parahippocampal gyrus, and some other cortical brain regions were utilized for comparison. The results of the RPPA analysis revealed that the protein levels of DLD, OGDH, SDHB, SUCLA2, and SUCLG2 subunits were significantly elevated in the PHC but not in other cortical brain regions. In accordance with these findings, the mRNA levels of the respective subunits were also increased in the PHC. The subunits with altered levels are implicated in enzyme complexes involved in the oxidative decarboxylation branch of glutamine catabolism. These data suggest a potential role of glutaminolysis in the pathophysiology of suicidal behavior in the PHC.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"479"},"PeriodicalIF":5.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Decreased prefrontal glutamatergic function is associated with a reduced astrocyte-related gene expression in treatment-resistant depression.","authors":"Masataka Wada, Shinichiro Nakajima, Shiori Honda, Mayuko Takano, Keita Taniguchi, Saki Homma, Risako Ueda, Yui Tobari, Yu Mimura, Shinya Fujii, Masaru Mimura, Yoshihiro Noda","doi":"10.1038/s41398-024-03186-2","DOIUrl":"10.1038/s41398-024-03186-2","url":null,"abstract":"<p><p>Glutamatergic dysfunction is involved in the pathophysiology of treatment-resistant depression (TRD). However, few physiological studies have evaluated its pathophysiology in vivo in individuals with TRD. Transcranial magnetic stimulation-electroencephalography (TMS-EEG) techniques can assess intracortical facilitation (ICF), which reflects glutamatergic neurophysiological function in specific cortical regions. The objectives of this study were (1) to compare glutamatergic receptor-mediated function as indexed with ICF TMS-EEG in the dorsolateral prefrontal cortex (DLPFC) between participants with TRD and healthy controls (HCs) and (2) to explore the relationships between cell-specific gene expression levels and the group difference in glutamatergic neural propagation using virtual histology approach. Sixty participants with TRD and thirty HCs were examined with ICF TMS-EEG measure (80 single-pulse TMS and paired-pulse ICF) in the left DLPFC. Both sensor and source-level ICF measures were computed to compare them between the TRD and HC groups. Furthermore, we conducted spatial correlation analyses interregionally between ICF glutamatergic activity and cell-specific gene expression levels employing the Allen Human Brain Atlas dataset. DLPFC-ICF at the sensor level was not significantly different between the two groups, whereas DLPFC-ICF at the source level was reduced in the TRD group compared with the HC group (p = 0.026). Moreover, the reduced ICF signal propagation of TRD correlated with astrocyte-specific gene expression level (p < 0.0001). The glutamatergic neural activities indexed by ICF in the left DLPFC were decreased in participants with TRD. Additionally, a relative reduction in glutamatergic signal propagation originating from the DLPFC in TRD may be associated with astrocytic abnormality.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"478"},"PeriodicalIF":5.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11589749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sho Oasa, Erdinc Sezgin, Yuelong Ma, David A Horne, Mihajlo D Radmilović, Tijana Jovanović-Talisman, Rémi Martin-Fardon, Vladana Vukojević, Lars Terenius
{"title":"Naltrexone blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane.","authors":"Sho Oasa, Erdinc Sezgin, Yuelong Ma, David A Horne, Mihajlo D Radmilović, Tijana Jovanović-Talisman, Rémi Martin-Fardon, Vladana Vukojević, Lars Terenius","doi":"10.1038/s41398-024-03172-8","DOIUrl":"10.1038/s41398-024-03172-8","url":null,"abstract":"<p><p>Naltrexone (NTX), a homolog of the opiate antidote naloxone, is an orally active long-acting general opioid receptor antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of few FDA-approved medications for treatment of alcohol use disorder (AUD). While it was early on established that NTX acts by blocking the binding of endogenous opioid peptide ligands released by alcohol, experimental evidence emerged that could not be fully accounted for by this explanation alone, suggesting that NTX may have additional modes of action. Mu- and kappa-opioid receptors (MOP and KOP, respectively) are structurally related G-protein-coupled receptors (GPCRs), but they are anatomically differently distributed and functionally distinct, often mediating opposite responses, with MOP typically promoting euphoria and reward, while KOP is associated with dysphoria and aversive states. While the actions of NTX on MOP are extensively characterized, the interactions with KOP are not. Here, we used sensitive fluorescence-based methods with single-molecule sensitivity to study in live cells the influence of alcohol (ethanol, EtOH) on KOP and the interaction between KOP and NTX. Our data show that alcohol, at relevant concentrations (10-40 mM), alters KOP interactions with the lipid environment in the plasma membrane. The counteracting effects of NTX are exerted by both its canonical action on KOP and its hitherto unrevealed effects on the lateral dynamics and organization of lipids in the plasma membrane. The KOP-specific antagonist LY2444296, in clinical trial for major depressive disorder (MDD), blocks KOP but does not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may in part be due to direct actions on KOP and in part due to its effect on the surrounding lipid environment.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"477"},"PeriodicalIF":5.8,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yiran Li, Tian Xie, Melissa Vos, Harold Snieder, Catharina A Hartman
{"title":"Shared genetic architecture and causality between autism spectrum disorder and irritable bowel syndrome, multisite pain, and fatigue.","authors":"Yiran Li, Tian Xie, Melissa Vos, Harold Snieder, Catharina A Hartman","doi":"10.1038/s41398-024-03184-4","DOIUrl":"10.1038/s41398-024-03184-4","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) often co-occurs with functional somatic syndromes (FSS), such as irritable bowel syndrome (IBS), multisite pain, and fatigue. However, the underlying genetic mechanisms and causality have not been well studied. Using large-scale genome-wide association study (GWAS) data, we investigated the shared genetic architecture and causality between ASD and FSS. Specifically, we first estimated genetic correlations and then conducted a multi-trait analysis of GWAS (MTAG) to detect potential novel genetic variants for single traits. Afterwards, polygenic risk scores (PRS) of ASD were derived from GWAS and MTAG to examine the associations with phenotypes in the large Dutch Lifelines cohort. Finally, we performed Mendelian randomization (MR) to evaluate the causality. We observed positive genetic correlations between ASD and FSS (IBS: r<sub>g</sub> = 0.27, adjusted p = 2.04 × 10<sup>-7</sup>; multisite pain: r<sub>g</sub> = 0.13, adjusted p = 1.10 × 10<sup>-3</sup>; fatigue: r<sub>g</sub> = 0.33, adjusted p = 5.21 × 10<sup>-9</sup>). Leveraging these genetic correlations, we identified 3 novel genome-wide significant independent loci for ASD by conducting MTAG, mapped to NEDD4L, MFHAS1, and RP11-10A14.4. PRS of ASD derived from both GWAS and MTAG were associated with ASD and FSS in Lifelines, and MTAG-derived PRS showed a bigger effect size, larger explained variance, and smaller p-values. We did not observe significant causality using MR. Our study found genetic associations between ASD and FSS, specifically with IBS, multisite pain, and fatigue. These findings suggest that a shared genetic architecture may partly explain the co-occurrence between ASD and FSS. Further research is needed to investigate the causality between ASD and FSS due to current limited statistical power of the GWASs.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"476"},"PeriodicalIF":5.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xia Liu, Zongxin Ling, Yiwen Cheng, Lingbin Wu, Li Shao, Jie Gao, Wenhui Lei, Zhangcheng Zhu, Wenwen Ding, Qinghai Song, Longyou Zhao, Guolin Jin
{"title":"Oral fungal dysbiosis and systemic immune dysfunction in Chinese patients with schizophrenia.","authors":"Xia Liu, Zongxin Ling, Yiwen Cheng, Lingbin Wu, Li Shao, Jie Gao, Wenhui Lei, Zhangcheng Zhu, Wenwen Ding, Qinghai Song, Longyou Zhao, Guolin Jin","doi":"10.1038/s41398-024-03183-5","DOIUrl":"10.1038/s41398-024-03183-5","url":null,"abstract":"<p><p>Oral microbial dysbiosis contributes to the development of schizophrenia (SZ). While numerous studies have investigated alterations in the oral bacterial microbiota among SZ patients, investigations into the fungal microbiota, another integral component of the oral microbiota, are scarce. In this cross-sectional study, we enrolled 118 Chinese patients with SZ and 97 age-matched healthy controls (HCs) to evaluate the oral fungal microbiota from tongue coating samples using internal transcribed spacer 1 amplicon sequencing and assess host immunity via multiplex immunoassays. Our findings revealed that SZ patients exhibited reduced fungal richness and significant differences in β-diversity compared to HCs. Within the oral fungal communities, we identified two distinct fungal clusters (mycotypes): Candida and Malassezia, with SZ patients showing increased Malassezia and decreased Candida levels. These key functional oral fungi may serve as potential diagnostic biomarkers for SZ. Furthermore, SZ patients displayed signs of immunological dysfunction, characterized by elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α, and chemokines including MIP-1α and MCP-1. Importantly, Malassezia mycotype correlated positively with peripheral pro-inflammatory cytokines, while Candida mycotype exhibited a negative correlation with these cytokines. In conclusion, we have demonstrated, for the first time, the presence of altered oral fungal communities and systemic immune dysfunction in Chinese SZ patients compared to HCs, providing novel insights into the potential role of oral fungi as biomarkers and the broader implications for understanding SZ pathogenesis.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"475"},"PeriodicalIF":5.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yukitoshi Izumi, Angela M Reiersen, Eric J Lenze, Steven J Mennerick, Charles F Zorumski
{"title":"Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids.","authors":"Yukitoshi Izumi, Angela M Reiersen, Eric J Lenze, Steven J Mennerick, Charles F Zorumski","doi":"10.1038/s41398-024-03185-3","DOIUrl":"10.1038/s41398-024-03185-3","url":null,"abstract":"<p><p>In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that contain GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, even though both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"474"},"PeriodicalIF":5.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giles W Story, Sam Ereira, Stephanie Valle, Samuel R Chamberlain, Jon E Grant, Raymond J Dolan
{"title":"A computational signature of self-other mergence in Borderline Personality Disorder.","authors":"Giles W Story, Sam Ereira, Stephanie Valle, Samuel R Chamberlain, Jon E Grant, Raymond J Dolan","doi":"10.1038/s41398-024-03170-w","DOIUrl":"10.1038/s41398-024-03170-w","url":null,"abstract":"<p><p>A tendency to merge mental representations of self and other is thought to underpin the intense and unstable relationships that feature in Borderline Personality Disorder (BPD). However, clinical theories of BPD do not specify, in computational terms, how the perspectives of self and other might become confused. To address this question, we used a probabilistic false belief task (p-FBT) to examine how individuals with BPD (N = 38) and matched controls from the general population (N = 74) selectively assigned beliefs to self or other. The p-FBT requires participants to track a gradually changing quantity, whilst also predicting another person's belief about that quantity. We found that BPD participants showed less selectivity in belief assignment compared with controls (Cohen's d = 0.64). Behaviourally, participants with BPD tended to predict that others' beliefs resembled their own. Modelling analysis revealed that BPD participants were prone to generalise their own learning signals to others. Furthermore, this generalising tendency correlated with BPD symptomatology across participants, even when controlling for demographic factors and affective psychopathology. Our results support a computational account of self-other mergence, based on a generalisation of learning across agents. Self-other generalisation in learning purports to explain key clinical features of BPD, and suggests a potential transdiagnostic marker of mentalising capability.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"473"},"PeriodicalIF":5.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Association of polygenic liabilities for schizophrenia and bipolar disorder with educational attainment and cognitive aging.","authors":"Chi-Shin Wu, Chia-Lin Hsu, Mei-Chen Lin, Mei-Hsin Su, Yen-Feng Lin, Chia-Yen Chen, Po-Chang Hsiao, Yi-Jiun Pan, Pei-Chun Chen, Yen-Tsung Huang, Shi-Heng Wang","doi":"10.1038/s41398-024-03182-6","DOIUrl":"10.1038/s41398-024-03182-6","url":null,"abstract":"<p><p>To elucidate the specific and shared genetic background of schizophrenia (SCZ) and bipolar disorder (BPD), this study explored the association of polygenic liabilities for SCZ and BPD with educational attainment and cognitive aging. Among 106,806 unrelated community participants from the Taiwan Biobank, we calculated the polygenic risk score (PRS) for SCZ (PRS<sub>SCZ</sub>) and BPD (PRS<sub>BPD</sub>), shared PRS between SCZ and BPD (PRS<sub>SCZ+BPD</sub>), and SCZ-specific PRS (PRS<sub>SCZvsBPD</sub>). Based on the sign-concordance of the susceptibility variants with SCZ/BPD, PRS<sub>SCZ</sub> was split into PRS<sub>SCZ_concordant</sub>/PRS<sub>SCZ_discordant</sub>, and PRS<sub>BPD</sub> was split into PRS<sub>BPD_concordant</sub>/PRS<sub>BPD_discordant</sub>. Ordinal logistic regression models were used to estimate the association with educational attainment. Linear regression models were used to estimate the associations with cognitive aging (n = 27,005), measured by the Mini-Mental State Examination (MMSE), and with MMSE change (n = 6194 with mean follow-up duration of 3.9 y) in individuals aged≥ 60 years. PRS<sub>SCZ,</sub> PRS<sub>BPD</sub>, and PRS<sub>SCZ+BPD</sub> were positively associated with educational attainment, whereas PRS<sub>SCZvsBPD</sub> was negatively associated with educational attainment. PRS<sub>SCZ</sub> was negatively associated with MMSE, while PRS<sub>BPD</sub> was positively associated with MMSE. The concordant and discordant parts of polygenic liabilities have contrasting association, PRS<sub>SCZ_concordant</sub> and PRS<sub>BPD_concordant</sub> mainly determined these effects mentioned above<sub>.</sub> PRS<sub>SCZvsBPD</sub> predicted decreases in the MMSE scores. Using a large collection of community samples, this study provided evidence for the contrasting effects of polygenic architecture in SCZ and BPD on educational attainment and cognitive aging and suggested that SCZ and BPD were not genetically homogeneous.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"472"},"PeriodicalIF":5.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11569198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marianna Piras, Jue Lin, Marie Catherine Sadler, Setareh Ranjbar, Claire Grosu, Nermine Laaboub, Martin Preisig, Franziska Gamma, Kerstin Jessica Plessen, Armin von Gunten, Philippe Conus, Zoltan Kutalik, Chin B Eap
{"title":"Psychotropic-induced weight gain and telomere length: results from a one-year longitudinal study and a large population-based cohort.","authors":"Marianna Piras, Jue Lin, Marie Catherine Sadler, Setareh Ranjbar, Claire Grosu, Nermine Laaboub, Martin Preisig, Franziska Gamma, Kerstin Jessica Plessen, Armin von Gunten, Philippe Conus, Zoltan Kutalik, Chin B Eap","doi":"10.1038/s41398-024-03177-3","DOIUrl":"10.1038/s41398-024-03177-3","url":null,"abstract":"<p><p>Weight-inducing psychotropic treatments are risk factors for age-related diseases such as cardiovascular disorders, which are associated with both inflammation and telomere length shortening. With a longitudinal design, the present study evaluates telomere length trajectories after 1 year of weight-inducing psychotropic medication, accounting for weight changes and the inflammatory biomarker high-sensitivity C-Reactive Protein (CRP). Among 200 patients, an overall median telomere shortening of -41.2 bp was observed (p = 0.014), which is comparable with the general population's yearly telomere attrition. Linear regression showed on average -93.1 and -58.9 bp of further telomere shortening per five units of BMI for BMI values < or ≥30 kg/m<sup>2</sup>, respectively (p = 0.003 and p = 0.009, respectively). Importantly, the overall telomere shortening was predicted to be increased four-fold among patients with low baseline weight (i.e., 50 kg) and with clinically relevant weight gain (≥ 7%) after 1 year of treatment (interaction term between relevant weight gain and baseline weight: +6.3 bp, p = 0.016). Patients with relevant weight gain showed greater CRP levels (+ 49%; p = 0.016), and a telomere shortening of -36.2 bp (p = 0.010) was estimated whenever CRP level doubled. Mendelian randomization using UKBiobank data showed a causal effect of BMI on telomere shortening, notably stronger among patients receiving weight-inducing psychotropic treatments (n = 9798) than among psychiatric patients without such drugs (n = 16228) and non-psychiatric controls (n = 252932) (beta: -0.37, -0.12, -0.06, respectively; p = 0.004, p < 0.001, p < 0.001, respectively). Ultimately, telomere trajectories were associated with 1 year weight gain and increases in CRP levels, with telomere shortening strongly enhanced by BMI increments among patients receiving weight-inducing psychotropic treatments.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"471"},"PeriodicalIF":5.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ebba Du Rietz, Tian Xie, Rujia Wang, Rosa Cheesman, Miguel Garcia-Argibay, Zihan Dong, Jia Zhang, Jacobien Niebuur, Melissa Vos, Harold Snieder, Henrik Larsson, Catharina A Hartman
{"title":"The contribution of attention-deficit/hyperactivity disorder polygenic load to metabolic and cardiovascular health outcomes: a large-scale population and sibling study.","authors":"Ebba Du Rietz, Tian Xie, Rujia Wang, Rosa Cheesman, Miguel Garcia-Argibay, Zihan Dong, Jia Zhang, Jacobien Niebuur, Melissa Vos, Harold Snieder, Henrik Larsson, Catharina A Hartman","doi":"10.1038/s41398-024-03178-2","DOIUrl":"10.1038/s41398-024-03178-2","url":null,"abstract":"<p><p>Emerging evidence suggests that ADHD is associated with increased risk for metabolic and cardiovascular (cardiometabolic) diseases. However, an understanding of the mechanisms underlying these associations is still limited. In this study we estimated the associations of polygenic scores (PGS) for ADHD with several cardiometabolic diseases and biomarkers. Furthermore, we investigated to what extent the PGS effect was influenced by direct and indirect genetic effects (i.e., shared familial effects). We derived ADHD-PGS in 50,768 individuals aged 18-90 years from the Dutch Lifelines Cohort study. Using generalised estimating equations, we estimated the association of PGS with cardiometabolic diseases, derived from self-report and several biomarkers measured during a physical examination. We additionally ran within-sibling PGS analyses, using fixed effects models, to disentangle direct effects of individuals' own ADHD genetic risk from confounding due to indirect genetic effects of relatives, as well as population stratification. We found that higher ADHD-PGS were statistically significantly associated with several cardiometabolic diseases (R-squared [R<sup>2</sup>] range = 0.03-0.50%) and biomarkers (related to inflammation, blood pressure, lipid metabolism, amongst others) (R<sup>2</sup> range = 0.01-0.16%) (P < 0.05). Adjustment for shared familial factors attenuated the associations between ADHD-PGS and cardiometabolic outcomes (on average 56% effect size reduction), and significant associations only remained for metabolic disease. Overall our findings suggest that increased genetic liability for ADHD confers a small but significant risk increase for cardiometabolic health outcomes in adulthood. These associations were observable in the general population, even in individuals without ADHD diagnosis, and were partly explained by familial factors shared among siblings.</p>","PeriodicalId":23278,"journal":{"name":"Translational Psychiatry","volume":"14 1","pages":"470"},"PeriodicalIF":5.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}