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1. Momentary Depression Severity Prediction in Patients With Acute Depression Who Undergo Sleep Deprivation Therapy: Speech-Based Machine Learning Approach

Author

Lisa-Marie Hartnagel, Daniel Emden, Jerome C Foo, Fabian Streit, Stephanie H Witt, Josef Frank, Matthias F Limberger, Sara E Schmitz, Maria Gilles, Marcella Rietschel, Tim Hahn, Ulrich W Ebner-Priemer, and Lea Sirignano

Subjects
Psychology, BF1-990
Abstract

Abstract BackgroundMobile devices for remote monitoring are inevitable tools to support treatment and patient care, especially in recurrent diseases such as major depressive disorder. The aim of this study was to learn if machine learning (ML) models based on longitudinal speech data are helpful in predicting momentary depression severity. Data analyses were based on a dataset including 30 inpatients during an acute depressive episode receiving sleep deprivation therapy in stationary care, an intervention inducing a rapid change in depressive symptoms in a relatively short period of time. Using an ambulatory assessment approach, we captured speech samples and assessed concomitant depression severity via self-report questionnaire over the course of 3 weeks (before, during, and after therapy). We extracted 89 speech features from the speech samples using the Extended Geneva Minimalistic Acoustic Parameter Set from the Open-Source Speech and Music Interpretation by Large-Space Extraction (audEERING) toolkit and the additional parameter speech rate. ObjectiveWe aimed to understand if a multiparameter ML approach would significantly improve the prediction compared to previous statistical analyses, and, in addition, which mechanism for splitting training and test data was most successful, especially focusing on the idea of personalized prediction. MethodsTo do so, we trained and evaluated a set of >500 ML pipelines including random forest, linear regression, support vector regression, and Extreme Gradient Boosting regression models and tested them on 5 different train-test split scenarios: a group 5-fold nested cross-validation at the subject level, a leave-one-subject-out approach, a chronological split, an odd-even split, and a random split. ResultsIn the 5-fold cross-validation, the leave-one-subject-out, and the chronological split approaches, none of the models were statistically different from random chance. The other two approaches produced significant results for at least one of the models tested, with similar performance. In total, the superior model was an Extreme Gradient Boosting in the odd-even split approach (RP ConclusionsOverall, our analyses highlight that ML fails to predict depression scores of unseen patients, but prediction performance increased strongly compared to our previous analyses with multilevel models. We conclude that future personalized ML models might improve prediction performance even more, leading to better patient management and care.

Published
2024
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2. Haplotype phasing of CYP2D6: an allelic ratio method using Agena MassARRAY data

Author

Megana Thamilselvan, Cheryl Mather, Yabing Wang, Jerome C. Foo, and Katherine J. Aitchison

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Pharmacogenomics aims to use the genetic information of an individual to personalize drug prescribing. There is evidence that pharmacogenomic testing before prescription may prevent adverse drug reactions, increase efficacy, and reduce cost of treatment. CYP2D6 is a key pharmacogene of relevance to multiple therapeutic areas. Indeed, there are prescribing guidelines available for medications based on CYP2D6 enzyme activity as deduced from CYP2D6 genetic data. The Agena MassARRAY system is a cost-effective method of detecting genetic variation that has been clinically applied to other genes. However, its clinical application to CYP2D6 has to date been limited by weaknesses such as the inability to determine which haplotype was present in more than one copy for individuals with more than two copies of the CYP2D6 gene. We report application of a new protocol for CYP2D6 haplotype phasing of data generated from the Agena MassARRAY system. For samples with more than two copies of the CYP2D6 gene for which the prior consensus data specified which one was present in more than one copy, our protocol was able to conduct CYP2D6 haplotype phasing resulting in 100% concordance with the prior data. In addition, for three reference samples known to have more than two copies of CYP2D6 but for which the exact number of CYP2D6 genes was unknown, our protocol was able to resolve the number for two out of the three of these, and estimate the likely number for the third. Finally, we demonstrate that our method is applicable to CYP2D6 hybrid tandem configurations.

Published
2024
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3. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Author

Antonino Glaviano, Aaron S. C. Foo, Hiu Y. Lam, Kenneth C. H. Yap, William Jacot, Robert H. Jones, Huiyan Eng, Madhumathy G. Nair, Pooyan Makvandi, Birgit Geoerger, Matthew H. Kulke, Richard D. Baird, Jyothi S. Prabhu, Daniela Carbone, Camilla Pecoraro, Daniel B. L. Teh, Gautam Sethi, Vincenzo Cavalieri, Kevin H. Lin, Nathalie R. Javidi-Sharifi, Eneda Toska, Matthew S. Davids, Jennifer R. Brown, Patrizia Diana, Justin Stebbing, David A. Fruman, and Alan P. Kumar

Subjects
PI3K/AKT/mTORC pathway, Pan PI3K inhibitors, Isoform-specific PI3K inhibitors, Dual PI3K/mTOR inhibitors, AKT inhibitors, Allosteric mTOR inhibitors, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Published
2023
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4. Sex- and age-specific effects on the development of addiction and compulsive-like drinking in rats

Author

Jerome C. Foo, Ivan Skorodumov, Rainer Spanagel, and Marcus W. Meinhardt

Subjects
Sex differences, Age differences, Alcohol deprivation effect, Addiction research, Compulsive drinking, Quinine taste adulteration, Medicine, Physiology, QP1-981
Abstract

Abstract Background Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction and preclinical and clinical evidence suggests that sex is an important factor influencing disease dynamics in alcohol dependence. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest. Methods Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system, acquiring high-resolution data to study changes over the course of addictive behavior as well as compulsive-like drinking in cohorts of adolescent vs. adult as well as male vs. female rats. Results Female rats drank more alcohol than male rats during the whole experiment, drinking much more weak alcohol (5%) and similar amounts of stronger alcohol solutions (10%, 20%); female rats also consumed more alcohol than male rats during quinine taste adulteration. Increased consumption in females compared to males was driven by larger access sizes of alcohol. Differences in circadian patterns of movement were observed between groups. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). Conclusions Our results suggest that there are sex-specific drinking patterns, not only in terms of total amount consumed, but specifically in terms of solution preference and access size. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior, and can inform the preclinical development of models of addiction, drug development and exploration of options for new treatments.

Published
2023
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5. Impulsivity, decision‐making, and risk behavior in bipolar disorder and major depression from bipolar multiplex families

Author

Almudena Ramírez‐Martín, Lea Sirignano, Fabian Streit, Jerome C. Foo, Andreas J. Forstner, Josef Frank, Markus M. Nöthen, Jana Strohmaier, Stephanie H. Witt, Fermin Mayoral‐Cleries, Berta Moreno‐Küstner, Marcella Rietschel, and Jose Guzmán‐Parra

Subjects
bipolar disorder, bipolar multiplex families, decision‐making, impulsivity, major depression disorder, risk behavior, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Objectives Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision‐making, and risk‐taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision‐making, and risk‐taking behavior in BD and MDD patients from bipolar multiplex families. Methods Eighty‐two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision‐making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. Results Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision‐making was associated with both mood disorders (BD and MDD). In risk‐taking behavior, no significant impairment was found in any group. Limitations As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. Conclusions Our findings show that alterations of cognitive domains—while present in both disorders—are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders.

Published
2024
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6. Speech Features as Predictors of Momentary Depression Severity in Patients With Depressive Disorder Undergoing Sleep Deprivation Therapy: Ambulatory Assessment Pilot Study

Author

Lisa-Marie Wadle, Ulrich W Ebner-Priemer, Jerome C Foo, Yoshiharu Yamamoto, Fabian Streit, Stephanie H Witt, Josef Frank, Lea Zillich, Matthias F Limberger, Ayimnisagul Ablimit, Tanja Schultz, Maria Gilles, Marcella Rietschel, and Lea Sirignano

Subjects
Psychology, BF1-990
Abstract

BackgroundThe use of mobile devices to continuously monitor objectively extracted parameters of depressive symptomatology is seen as an important step in the understanding and prevention of upcoming depressive episodes. Speech features such as pitch variability, speech pauses, and speech rate are promising indicators, but empirical evidence is limited, given the variability of study designs. ObjectivePrevious research studies have found different speech patterns when comparing single speech recordings between patients and healthy controls, but only a few studies have used repeated assessments to compare depressive and nondepressive episodes within the same patient. To our knowledge, no study has used a series of measurements within patients with depression (eg, intensive longitudinal data) to model the dynamic ebb and flow of subjectively reported depression and concomitant speech samples. However, such data are indispensable for detecting and ultimately preventing upcoming episodes. MethodsIn this study, we captured voice samples and momentary affect ratings over the course of 3 weeks in a sample of patients (N=30) with an acute depressive episode receiving stationary care. Patients underwent sleep deprivation therapy, a chronotherapeutic intervention that can rapidly improve depression symptomatology. We hypothesized that within-person variability in depressive and affective momentary states would be reflected in the following 3 speech features: pitch variability, speech pauses, and speech rate. We parametrized them using the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS) from open-source Speech and Music Interpretation by Large-Space Extraction (openSMILE; audEERING GmbH) and extracted them from a transcript. We analyzed the speech features along with self-reported momentary affect ratings, using multilevel linear regression analysis. We analyzed an average of 32 (SD 19.83) assessments per patient. ResultsAnalyses revealed that pitch variability, speech pauses, and speech rate were associated with depression severity, positive affect, valence, and energetic arousal; furthermore, speech pauses and speech rate were associated with negative affect, and speech pauses were additionally associated with calmness. Specifically, pitch variability was negatively associated with improved momentary states (ie, lower pitch variability was linked to lower depression severity as well as higher positive affect, valence, and energetic arousal). Speech pauses were negatively associated with improved momentary states, whereas speech rate was positively associated with improved momentary states. ConclusionsPitch variability, speech pauses, and speech rate are promising features for the development of clinical prediction technologies to improve patient care as well as timely diagnosis and monitoring of treatment response. Our research is a step forward on the path to developing an automated depression monitoring system, facilitating individually tailored treatments and increased patient empowerment.

Published
2024
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7. Higher throughput workflow with sensitive, reliable and automatic quantification of myelination in vitro suitable for drug screening

Author

Sybille Seiler, Ciril Marius Wälti, Vanessa de Barros, Shahar Barbash, and Lynette C. Foo

Subjects
Medicine, Science
Abstract

Abstract Multiple sclerosis (MS) is the most common demyelinating autoimmune disease of the central nervous system (CNS). Immune-mediated myelin and axonal damage that is accompanied by chronic axonal loss causing destruction of the myelin sheaths are hallmarks of MS. While great strides have been made in understanding the molecular underpinnings of re-/myelination, currently no remyelination therapy is available for MS. As myelination is a complex process that is not fully understood, we sought to develop a systematic, reliable, automated and quantitative higher throughput screening method. We aimed to quantitate myelin sheaths in vitro with high sensitivity at the single cell level suitable for testing small compound libraries. To this end, we miniaturised in vitro retinal ganglion cell-oligodendrocyte precursor cell (RGC–OPC) co-cultures into a multi-well plate format. This allowed us to maintain the reciprocal interaction of live axons and oligodendrocytes (OLs) to ensure compact myelin formation. To quantify our co-cultures, we developed a novel computer vision algorithm to precisely measure myelination. We demonstrated efficacy of our system with known pro-differentiating compounds BQ3020 and XAV939 which exhibited robust, efficient, and dose dependent effects on myelination. Through this combination of experimental and technical advances, we have developed a method allowing systematic and reliable testing of remyelinating compound efficacy.

Published
2023
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8. Perception from students regarding online synchronous interactive teaching in the clinical year during COVID-19 pandemic

Author

Billy H. H. Cheung, Dominic C. C. Foo, Kent Man Chu, Michael Co, and Lok Sze Lee

Subjects
Online teaching, Online synchronous education, Medical education, Undergraduate education, Special aspects of education, LC8-6691, Medicine
Abstract

Abstract Aim The global pandemic of COVID-19 has led to extensive practice of online learning. Our main objective is to compare different online synchronous interactive learning activities to evaluate students’ perceptions. Moreover, we also aim to identify factors influencing their perceptions in these classes. Methods A cross-sectional, questionnaire-based study focusing on clinical year medical students’ perceptions and feedback was conducted between February 2021 –June 2021 at the University of Hong Kong. Online learning activities were divided into bedside teaching, practical skill session, problem-based learning (PBL) or tutorial, and lecture. A questionnaire based on the Dundee Ready Education Environment Measure (DREEM) was distributed to 716 clinical year students to document their perceptions. Results One hundred responses were received with a response rate of 15.4% (110/716, including 96 from bedside teaching, 67 from practical skill session, 104 from PBL/tutorial, and 101 from lecture). For the mean score of the DREEM-extracted questionnaire, online PBL/tutorial scored the highest (2.72 ± 0.54), while bedside scored the lowest (2.38 ± 0.68, p = 0.001). Meanwhile, there was no significant difference when we compared different school years (p = 0.39), age (p = 0.37), gender (p = 1.00), year of internet experience (

Published
2023
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9. Recovering non-Maxwellian particle velocity distribution functions from collective Thomson-scattered spectra

Author

B. C. Foo, D. B. Schaeffer, and P. V. Heuer

Subjects
Physics, QC1-999
Abstract

Collective optical Thomson scattering (TS) is a diagnostic commonly used to characterize plasma parameters. These parameters are typically extracted by a fitting algorithm that minimizes the difference between a measured scattered spectrum and an analytic spectrum calculated from the velocity distribution function (VDF) of the plasma. However, most existing TS analysis algorithms assume that the VDFs are Maxwellian, and applying an algorithm that makes this assumption does not accurately extract the plasma parameters of a non-Maxwellian plasma due to the effect of non-Maxwellian deviations on the TS spectra. We present new open-source numerical tools for forward modeling analytic spectra from arbitrary VDFs and show that these tools are able to more accurately extract plasma parameters from synthetic TS spectra generated by non-Maxwellian VDFs compared to standard TS algorithms. Estimated posterior probability distributions of fits to synthetic spectra for a variety of example non-Maxwellian VDFs are used to determine uncertainties in the extracted plasma parameters and show that correlations between parameters can significantly affect the accuracy of fits in plasmas with non-Maxwellian VDFs.

Published
2023
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10. Depression and bipolar disorder subtypes differ in their genetic correlations with biological rhythms

Author

Lea Sirignano, Fabian Streit, Josef Frank, Lea Zillich, Stephanie H. Witt, Marcella Rietschel, and Jerome C. Foo

Subjects
Medicine, Science
Abstract

Abstract Major Depression and Bipolar Disorder Type I (BIP-I) and Type II (BIP-II), are characterized by depressed, manic, and hypomanic episodes in which specific changes of physical activity, circadian rhythm, and sleep are observed. It is known that genetic factors contribute to variation in mood disorders and biological rhythms, but unclear to what extent there is an overlap between their underlying genetics. In the present study, data from genome-wide association studies were used to examine the genetic relationship between mood disorders and biological rhythms. We tested the genetic correlation of depression, BIP-I, and BIP-II with physical activity (overall physical activity, moderate activity, sedentary behaviour), circadian rhythm (relative amplitude), and sleep features (sleep duration, daytime sleepiness). Genetic correlations of depression, BIP-I, and BIP-II with biological rhythms were compared to discover commonalities and differences. A gene-based analysis tested for associations of single genes and common circadian genes with mood disorders. Depression was negatively correlated with overall physical activity and positively with sedentary behaviour, while BIP-I showed associations in the opposite direction. Depression and BIP-II had negative correlations with relative amplitude. All mood disorders were positively correlated with daytime sleepiness. Overall, we observed both genetic commonalities and differences across mood disorders in their relationships with biological rhythms: depression and BIP-I differed the most, while BIP-II was in an intermediate position. Gene-based analysis suggested potential targets for further investigation. The present results suggest shared genetic underpinnings for the clinically observed associations between mood disorders and biological rhythms. Research considering possible joint mechanisms may offer avenues for improving disease detection and treatment.

Published
2022
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11. Epigenetic signatures in antidepressant treatment response: a methylome-wide association study in the EMC trial

Author

J. Engelmann, L. Zillich, J. Frank, S. Wagner, M. Cetin, D. P. Herzog, M. B. Müller, A. Tadic, J. C. Foo, L. Sirignano, D. F. Braus, N. Dahmen, S. Sordon, M. Riemenschneider, C. Spaniol, G. Gasparoni, M. Rietschel, S. H. Witt, K. Lieb, and F. Streit

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Although the currently available antidepressants are well established in the treatment of the major depressive disorder (MDD), there is strong variability in the response of individual patients. Reliable predictors to guide treatment decisions before or in an early stage of treatment are needed. DNA-methylation has been proven a useful biomarker in different clinical conditions, but its importance for mechanisms of antidepressant response has not yet been determined. 80 MDD patients were selected out of >500 participants from the Early Medication Change (EMC) cohort with available genetic material based on their antidepressant response after four weeks and stratified into clear responders and age- and sex-matched non-responders (N = 40, each). Early improvement after two weeks was analyzed as a secondary outcome. DNA-methylation was determined using the Illumina EPIC BeadChip. Epigenome-wide association studies were performed and differentially methylated regions (DMRs) identified using the comb-p algorithm. Enrichment was tested for hallmark gene-sets and in genome-wide association studies of depression and antidepressant response. No epigenome-wide significant differentially methylated positions were found for treatment response or early improvement. Twenty DMRs were associated with response; the strongest in an enhancer region in SORBS2, which has been related to cardiovascular diseases and type II diabetes. Another DMR was located in CYP2C18, a gene previously linked to antidepressant response. Results pointed towards differential methylation in genes associated with cardiac function, neuroticism, and depression. Linking differential methylation to antidepressant treatment response is an emerging topic and represents a step towards personalized medicine, potentially facilitating the prediction of patients’ response before treatment.

Published
2022
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12. Multi-omics signatures of alcohol use disorder in the dorsal and ventral striatum

Author

Lea Zillich, Eric Poisel, Josef Frank, Jerome C. Foo, Marion M. Friske, Fabian Streit, Lea Sirignano, Stefanie Heilmann-Heimbach, André Heimbach, Per Hoffmann, Franziska Degenhardt, Anita C. Hansson, Georgy Bakalkin, Markus M. Nöthen, Marcella Rietschel, Rainer Spanagel, and Stephanie H. Witt

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDR

Published
2022
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13. Identifying the Common Genetic Basis of Antidepressant Response

Author

Oliver Pain, Karen Hodgson, Vassily Trubetskoy, Stephan Ripke, Victoria S. Marshe, Mark J. Adams, Enda M. Byrne, Adrian I. Campos, Tania Carrillo-Roa, Annamaria Cattaneo, Thomas D. Als, Daniel Souery, Mojca Z. Dernovsek, Chiara Fabbri, Caroline Hayward, Neven Henigsberg, Joanna Hauser, James L. Kennedy, Eric J. Lenze, Glyn Lewis, Daniel J. Müller, Nicholas G. Martin, Benoit H. Mulsant, Ole Mors, Nader Perroud, David J. Porteous, Miguel E. Rentería, Charles F. Reynolds, III, Marcella Rietschel, Rudolf Uher, Eleanor M. Wigmore, Wolfgang Maier, Naomi R. Wray, Katherine J. Aitchison, Volker Arolt, Bernhard T. Baune, Joanna M. Biernacka, Guido Bondolfi, Katharina Domschke, Masaki Kato, Qingqin S. Li, Yu-Li Liu, Alessandro Serretti, Shih-Jen Tsai, Gustavo Turecki, Richard Weinshilboum, Andrew M. McIntosh, Cathryn M. Lewis, Siegfried Kasper, Joseph Zohar, Stuart Montgomery, Diego Albani, Gianluigi Forloni, Panagiotis Ferentinos, Dan Rujescu, Julien Mendlewicz, Manuel Mattheisen, Maciej Trzaskowski, Abdel Abdellaoui, Esben Agerbo, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Tim B. Bigdeli, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Jonathan R.I. Coleman, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Ian J. Deary, Franziska Degenhardt, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Per Hoffmann, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Hougaard, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Michael J. Owen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Jianxin Shi, Stanley I. Shyn, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Hreinn Stefansson, Stacy Steinberg, Fabian Streit, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Stephanie H. Witt, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Klaus Berger, Dorret I. Boomsma, Sven Cichon, Udo Dannlowski, E.J.C. de Geus, J. Raymond DePaulo, Enrico Domenici, Tõnu Esko, Hans J. Grabe, Steven P. Hamilton, Andrew C. Heath, Kenneth S. Kendler, Stefan Kloiber, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Preben Bo Mortensen, Bertram Müller-Myhsok, Merete Nordentoft, Markus M. Nöthen, Michael C. O’Donovan, Sara A. Paciga, Nancy L. Pedersen, Brenda W.J.H. Penninx, Roy H. Perlis, James B. Potash, Martin Preisig, Catherine Schaefer, Thomas G. Schulze, Jordan W. Smoller, Kari Stefansson, Henning Tiemeier, Henry Völzke, Myrna M. Weissman, Thomas Werge, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, and Patrick F. Sullivan

Subjects
Antidepressant response, Depression, Genetics, GWAS, MDD, Polygenic score, Psychiatry, RC435-571
Abstract

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Published
2022
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14. Borderline personality disorder and the big five: molecular genetic analyses indicate shared genetic architecture with neuroticism and openness

Author

Fabian Streit, Stephanie H. Witt, Swapnil Awasthi, Jerome C. Foo, Martin Jungkunz, Josef Frank, Lucía Colodro-Conde, Guy Hindley, Olav B. Smeland, Tolou Maslahati, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Nikolaus Kleindienst, Annette Hartmann, Ina Giegling, Lea Zillich, Lea Sirignano, Eric Poisel, Chi-Hua Chen, Markus M. Nöthen, Arian Mobascher, Dan Rujescu, Klaus Lieb, Stefan Roepke, Christian Schmahl, Martin Bohus, Stephan Ripke, Marcella Rietschel, and Ole A. Andreassen

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality—the “Big Five”. In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2543) and GWAS on the Big Five (N = 76,551–122,886, Neuroticism N = 390,278). Polygenic scores (PGS) were calculated to test the association of the genetic disposition for the personality traits with BPD case-control status. Significant positive genetic correlations of BPD were found with Neuroticism (rg = 0.34, p = 6.3*10−5) and Openness (rg = 0.24, p = 0.036), but not with the other personality traits (all | rg | 0.30). A cluster and item-level analysis showed positive genetic correlations of BPD with the Neuroticism clusters “Depressed Affect” and “Worry”, and with a broad range of Neuroticism items (N = 348,219–376,352). PGS analyses confirmed the genetic correlations, and found an independent contribution of the personality traits to BPD risk. The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the “Big Five” are needed to further explore the role of personality traits in the etiology of BPD.

Published
2022
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15. The interplay of family history of depression and early trauma: associations with lifetime and current depression in the German national cohort (NAKO)

Author

Fabian Streit, Maja P. Völker, Johanna Klinger-König, Lea Zillich, Josef Frank, Iris Reinhard, Jerome C. Foo, Stephanie H. Witt, Lea Sirignano, Heiko Becher, Nadia Obi, Oliver Riedel, Stefanie Do, Stefanie Castell, Max J. Hassenstein, André Karch, Andreas Stang, Börge Schmidt, Tamara Schikowski, Anna Stahl-Pehe, Hermann Brenner, Laura Perna, Karin Halina Greiser, Rudolf Kaaks, Karin B. Michels, Claus-Werner Franzke, Annette Peters, Beate Fischer, Julian Konzok, Rafael Mikolajczyk, Amand Führer, Thomas Keil, Julia Fricke, Stefan N. Willich, Tobias Pischon, Henry Völzke, Claudia Meinke-Franze, Markus Loeffler, Kerstin Wirkner, Klaus Berger, Hans J. Grabe, and Marcella Rietschel

Subjects
depression, childhood trauma, family history, genetics, abuse, neglect, Infectious and parasitic diseases, RC109-216
Abstract

IntroductionFamily history of depression and childhood maltreatment are established risk factors for depression. However, how these factors are interrelated and jointly influence depression risk is not well understood. The present study investigated (i) if childhood maltreatment is associated with a family history of depression (ii) if family history and childhood maltreatment are associated with increased lifetime and current depression, and whether both factors interact beyond their main effects, and (iii) if family history affects lifetime and current depression via childhood maltreatment.MethodsAnalyses were based on a subgroup of the first 100,000 participants of the German National Cohort (NAKO), with complete information (58,703 participants, mean age = 51.2 years, 53% female). Parental family history of depression was assessed via self-report, childhood maltreatment with the Childhood Trauma Screener (CTS), lifetime depression with self-reported physician's diagnosis and the Mini-International Neuropsychiatric Interview (MINI), and current depressive symptoms with the depression scale of the Patient Health Questionnaire (PHQ-9). Generalized linear models were used to test main and interaction effects. Mediation was tested using causal mediation analyses.ResultsHigher frequencies of the childhood maltreatment measures were found in subjects reporting a positive family history of depression. Family history and childhood maltreatment were independently associated with increased depression. No statistical interactions of family history and childhood maltreatment were found for the lifetime depression measures. For current depressive symptoms (PHQ-9 sum score), an interaction was found, with stronger associations of childhood maltreatment and depression in subjects with a positive family history. Childhood maltreatment was estimated to mediate 7%–12% of the effect of family history on depression, with higher mediated proportions in subjects whose parents had a depression onset below 40 years. Abuse showed stronger associations with family history and depression, and higher mediated proportions of family history effects on depression than neglect.DiscussionThe present study confirms the association of childhood maltreatment and family history with depression in a large population-based cohort. While analyses provide little evidence for the joint effects of both risk factors on depression beyond their individual effects, results are consistent with family history affecting depression via childhood maltreatment to a small extent.

Published
2023
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16. DNA methylation in cocaine use disorder–An epigenome-wide approach in the human prefrontal cortex

Author

Eric Poisel, Lea Zillich, Fabian Streit, Josef Frank, Marion M. Friske, Jerome C. Foo, Naguib Mechawar, Gustavo Turecki, Anita C. Hansson, Markus M. Nöthen, Marcella Rietschel, Rainer Spanagel, and Stephanie H. Witt

Subjects
cocaine, DNA methylation, addiction, epigenetics, EWAS, prefrontal cortex, Psychiatry, RC435-571
Abstract

BackgroundCocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue.MethodsWe investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of Brodmann area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study (EWAS) and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology (GO) enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age.ResultsWhile no cytosine-phosphate-guanine (CpG) site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identified Neuropeptide FF Receptor 2 (NPFFR2) and Kalirin RhoGEF Kinase (KALRN) for which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction (PPI) networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such as Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit (JUN). In BA9, we observed a trend toward epigenetic age acceleration (EAA) in individuals with CUD remaining stable even after adjustment for covariates.ConclusionResults from our study highlight that CUD is associated with epigenome-wide differences in DNAm levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex (PFC). Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.

Published
2023
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17. Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort

Author

Thao Nguyen, Lea Zillich, Metin Cetin, Alisha S. M. Hall, Jerome C. Foo, Lea Sirignano, Josef Frank, Tabea S. Send, Maria Gilles, Marcella Rietschel, Michael Deuschle, Stephanie H. Witt, and Fabian Streit

Subjects
children, covid-19, emotional well-being, hpa axis, polygenic risk score, prenatal stress, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7–10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020–October 2020; November 2020–February 2021). Associations of the children’s and mothers’ well-being with maternal perceived stress, of the children’s well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children’s but not the mothers’ emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children’s emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

Published
2023
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18. Methylome-wide change associated with response to electroconvulsive therapy in depressed patients

Author

Lea Sirignano, Josef Frank, Laura Kranaster, Stephanie H. Witt, Fabian Streit, Lea Zillich, Alexander Sartorius, Marcella Rietschel, and Jerome C. Foo

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Electroconvulsive therapy (ECT) is a quick-acting and powerful antidepressant treatment considered to be effective in treating severe and pharmacotherapy-resistant forms of depression. Recent studies have suggested that epigenetic mechanisms can mediate treatment response and investigations about the relationship between the effects of ECT and DNA methylation have so far largely taken candidate approaches. In the present study, we examined the effects of ECT on the methylome associated with response in depressed patients (n = 34), testing for differentially methylated CpG sites before the first and after the last ECT treatment. We identified one differentially methylated CpG site associated with the effect of ECT response (defined as >50% decrease in Hamilton Depression Rating Scale score, HDRS), TNKS (q

Published
2021
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19. Ethnicity influences the gut microbiota of individuals sharing a geographical location: a cross-sectional study from a middle-income country

Author

Jacky Dwiyanto, M. H. Hussain, D. Reidpath, K. S. Ong, A. Qasim, S. W. H. Lee, S. M. Lee, S. C. Foo, C. W. Chong, and Sadequr Rahman

Subjects
Medicine, Science
Abstract

Abstract No studies have investigated the influence of ethnicity in a multi-ethnic middle-income country with a long-standing history of co-habitation. Stool samples from 214 Malaysian community members (46 Malay, 65 Chinese, 49 Indian, and 54 Jakun) were collected. The gut microbiota of the participants was investigated using 16S amplicon sequencing. Ethnicity exhibited the largest effect size across participants (PERMANOVA Pseudo-F = 4.24, R2 = 0.06, p = 0.001). Notably, the influence of ethnicity on the gut microbiota was retained even after controlling for all demographic, dietary factors and other covariates which were significantly associated with the gut microbiome (PERMANOVA Pseudo-F = 1.67, R2 = 0.02, p = 0.002). Our result suggested that lifestyle, dietary, and uncharacterized differences collectively drive the gut microbiota variation across ethnicity, making ethnicity a reliable proxy for both identified and unidentified lifestyle and dietary variation across ethnic groups from the same community.

Published
2021
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20. Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families

Author

Jose Guzman-Parra, Fabian Streit, Andreas J. Forstner, Jana Strohmaier, Maria José González, Susana Gil Flores, Francisco J. Cabaleiro Fabeiro, Francisco del Río Noriega, Fermin Perez Perez, Jesus Haro González, Guillermo Orozco Diaz, Yolanda de Diego-Otero, Berta Moreno-Kustner, Georg Auburger, Franziska Degenhardt, Stefanie Heilmann-Heimbach, Stefan Herms, Per Hoffmann, Josef Frank, Jerome C. Foo, Lea Sirignano, Stephanie H. Witt, Sven Cichon, Fabio Rivas, Fermín Mayoral, Markus M. Nöthen, Till F. M. Andlauer, and Marcella Rietschel

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.

Published
2021
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21. Occult Kidney Dysfunction in Children With Transfusion-Dependent Thalassemia

Author

Nurwahida Mohd Zikre, Nor A. Muhamad, Caroline S. Y. Eng, Nur E. Zailanalhuddin, Charles D. Lai, Jen C. Foo, Suet L. Yap, Hany Ariffin, and Karmila Abu Bakar

Subjects
thalassemia, nephropathy, transfusion-dependent, ferritin, iron chelator, Pediatrics, RJ1-570
Abstract

Background: Thalassemia is the commonest hemoglobinopathy in Southeast Asia. Kidney dysfunction is an underreported sequelae in children with thalassemia. We conducted a retrospective study to identify the prevalence of and predisposing factors for kidney dysfunction in children with transfusion-dependent thalassemia (TDT).Method: Abnormal kidney function was defined as children with a glomerular filtration rate (GFR) of 20 ml/min/1.73 m2 or presence of nephrotic range proteinuria within 3 years of commencing regular (every ≤6 weeks) red cell transfusion. Data analyzed were age at diagnosis of thalassemia, number of transfusion-years, iron chelation therapy, serum ferritin, and pre-transfusion hemoglobin levels.Results: Eighty-one children were studied. Mean age was 11.72 ± 5.275 years. Thirty out of 81 (37%) demonstrated abnormal kidney function. Evidence of glomerular hyperfiltration was seen in 29/81 patients (25.85%) at their last clinic visit. This fraction was doubled [48/81 (59.3%)] when the cohort was tracked back by 3 years from the last clinic encounter. Age at diagnosis (RR, 1.157; 95% CI, 1.014–1.319; p = 0.03) and duration of receiving transfusions (RR, 0.984; 95% CI, 0.974–0.994; p = 0.001) were associated with increased risk of developing abnormal kidney function.Conclusion: Abnormal kidney function in children with TDT may be overlooked by medical personnel without active screening measures. Children receiving regular red cell transfusions require systematic surveillance to enable early detection of kidney dysfunction and timely implementation of appropriate therapeutic interventions.

Published
2021
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22. Clinical Outcomes of 3D-Printed Bioresorbable Scaffolds for Bone Tissue Engineering—A Pilot Study on 126 Patients for Burrhole Covers in Subdural Hematoma

Author

Emma M. S. Toh, Ashiley A. Thenpandiyan, Aaron S. C. Foo, John J. Y. Zhang, Mervyn J. R. Lim, Chun Peng Goh, Nivedh Dinesh, Srujana V. Vedicherla, Ming Yang, Kejia Teo, Tseng Tsai Yeo, and Vincent D. W. Nga

Subjects
chronic subdural hemorrhage, burrhole cover, cosmetic outcomes, polycaprolactone, bioresorbable, Biology (General), QH301-705.5
Abstract

Burrhole craniostomy is commonly performed for subdural hematoma (SDH) evacuation, but residual scalp depressions are often cosmetically suboptimal for patients. OsteoplugTM, a bioresorbable polycaprolactone burrhole cover, was introduced by the National University Hospital, Singapore, in 2006 to cover these defects, allowing osseous integration and vascular ingrowth. However, the cosmetic and safety outcomes of OsteoplugTM-C—the latest (2017) iteration, with a chamfered hole for subdural drains—remain unexplored. Data were collected from a single institution from April 2017 to March 2021. Patient-reported aesthetic outcomes (Aesthetic Numeric Analog (ANA)) and quality of life (EQ-5D-3L including Visual Analog Scale (VAS)) were assessed via telephone interviews. Clinical outcomes included SDH recurrence, postoperative infections, and drain complications. OsteoplugTM-C patients had significantly higher satisfaction and quality of life compared to those without a burrhole cover (ANA: 9 [7, 9] vs. 7 [5, 8], p = 0.019; VAS: 85 [75, 90] vs. 70 [50, 80], p = 0.021), and the absence of a burrhole cover was associated with poorer aesthetic outcomes after multivariable adjustment (adjusted OR: 4.55, 95% CI: 1.09–22.68, p = 0.047). No significant differences in other clinical outcomes were observed between OsteoplugTM-C, OsteoplugTM, or no burrhole cover. Our pilot study supports OsteoplugTM-C and its material polycaprolactone as suitable adjuncts to burrhole craniostomy, improving cosmetic outcomes while achieving comparable safety outcomes.

Published
2022
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23. Cyclin-dependent kinase 9 is required for the survival of adult Drosophila melanogaster glia

Author

Lynette C. Foo

Subjects
Medicine, Science
Abstract

Abstract Neuronal and glial progenitor cells exist in the adult Drosophila brain. The primarily glial progenitor cells rely on a microRNA, mir-31a, to inhibit the expression of a predicted E3 ubiquitin ligase, CG16947. Erroneous inheritance of CG16947 by the progeny when the neural progenitor cell divides leads to death of the progeny, however how CG16947 achieves glial cell death is unknown. I have identified the interacting partner of CG16947 to be cdk9. I show that reduction of cdk9 expression in glia causes glial loss; highlighting the importance of cdk9 in mediating the survival of glia. Further, glial loss observed in mir-31a mutants was prevented with adult-specific expression of cdk9 in glia. I provide biochemical evidence that the binding of CG16947 to cdk9 causes its degradation. Taken together, this data shows that cdk9 plays a role in the survival of adult glia in the Drosophila brain. Thus, a fine balance exists between mir-31a and CG16947 expression in the progenitor cells that in turn regulates the levels of cdk9 in the progeny. This serves to allow the progenitor cells to regulate the number of glia in the adult brain.

Published
2017
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24. Quantitative lung ultrasound detects dynamic changes in lung recruitment in the preterm lamb

Author

Arun Sett, Gillian W. C. Foo, Kelly R. Kenna, Rebecca J. Sutton, Elizabeth J. Perkins, Magdy Sourial, Sheryle R. Rogerson, Brett J. Manley, Peter G. Davis, Prue M. Pereira-Fantini, and David G. Tingay

Subjects
Pediatrics, Perinatology and Child Health
Abstract

Background Lung ultrasound (LUS) may not detect small, dynamic changes in lung volume. Mean greyscale measurement using computer-assisted image analysis (Q-LUSMGV) may improve the precision of these measurements. Methods Preterm lambs (n = 40) underwent LUS of the dependent or non-dependent lung during static pressure–volume curve mapping. Total and regional lung volumes were determined using the super-syringe technique and electrical impedance tomography. Q-LUSMGV and gold standard measurements of lung volume were compared in 520 images. Results Dependent Q-LUSMGV moderately correlated with total lung volume (rho = 0.60, 95% CI 0.51–0.67) and fairly with right whole (rho = 0.39, 0.27–0.49), central (rho = 0.38, 0.27–0.48), ventral (rho = 0.41, 0.31–0.51) and dorsal regional lung volumes (rho = 0.32, 0.21–0.43). Non-dependent Q-LUSMGV moderately correlated with total lung volume (rho = 0.57, 0.48–0.65) and fairly with right whole (rho = 0.43, 0.32–0.52), central (rho = 0.46, 0.35–0.55), ventral (rho = 0.36, 0.25–0.47) and dorsal lung volumes (rho = 0.36, 0.25–0.47). All correlation coefficients were statistically significant. Distinct inflation and deflation limbs, and sonographic pulmonary hysteresis occurred in 95% of lambs. The greatest changes in Q-LUSMGV occurred at the opening and closing pressures. Conclusion Q-LUSMGV detected changes in total and regional lung volume and offers objective quantification of LUS images, and may improve bedside discrimination of real-time changes in lung volume. Impact Lung ultrasound (LUS) offers continuous, radiation-free imaging that may play a role in assessing lung recruitment but may not detect small changes in lung volume. Mean greyscale image analysis using computer-assisted quantitative LUS (Q-LUSMGV) moderately correlated with changes in total and regional lung volume. Q-LUSMGV identified opening and closing pressure and pulmonary hysteresis in 95% of lambs. Computer-assisted image analysis may enhance LUS estimation of lung recruitment at the bedside. Future research should focus on improving precision prior to clinical translation.

Published
2022
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25. Alcohol solution strength preference predicts compulsive‐like drinking behavior in rats

Author

Jerome C. Foo, Marcus W. Meinhardt, Ivan Skorodumov, and Rainer Spanagel

Subjects
Psychiatry and Mental health, Alcohol Drinking, Ethanol, Quinine, Recurrence, Compulsive Behavior, Animals, Water, Medicine (miscellaneous), Toxicology, Rats
Abstract

Understanding compulsive drinking behavior is key to improving outcomes in the treatment of addiction. In the present study, we investigated compulsive-like drinking in alcohol-addicted rats using the alcohol deprivation effect (ADE) model of relapse behavior, which involves repeated deprivation and reintroduction phases; the latter approximate relapse.High-resolution longitudinal drinking and locomotor data were measured while rats (n = 30) underwent a four-bottle (water, 5%, 10%, 20% alcohol v/v) free-choice ADE paradigm. Alcohol bottles were adulterated with the bitter compound quinine during a reintroduction phase to test for compulsive behavior. We characterized how drinking and locomotor behavior during ADE + quinine differed from a regular ADE and how, at the individual level, behavioral parameters extracted from the regular ADE related to compulsive-like drinking. Associations of drinking with locomotor activity were also examined.In the ADE with quinine, we observed reduced consumption of alcohol and a shift to preference for stronger alcohol. Quinine acted by decreasing both the access size and frequency of drinking of 5% alcohol while increasing the frequency of consumption of 20% alcohol. Preference for higher alcohol concentrations prior to the quinine challenge was associated with greater compulsive-like drinking behavior; higher baseline consumption of 20% alcohol correlated with more drinking of quinine-adulterated solutions while high frequency and amount of 5% alcohol consumption at baseline were correlated with being more strongly affected by quinine. Associations between locomotor activity and drinking behavior were observed at the hourly level. These associations reflected changing preferences across experimental phases.Drinking patterns, and specifically solution preference, may offer insights into the presentation of compulsive-like drinking. The findings provide a preclinical basis for observations from epidemiological studies that link higher risk and burden of alcohol-related disease to stronger alcohol concentrations and encourage further translational studies to better understand the underlying mechanisms.

Published
2022
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26. Association between number of confidants and adolescent anxiety/depression: A school-based study

Author

Asuka Nishida, Jerome C. Foo, Satoshi Yamaguchi, Fumiharu Togo, Shinji Shimodera, Atsushi Nishida, Yuji Okazaki, and Sasaki Tsukasa

Abstract

Background Having no or few confidants is found to be associated with more severe mental health problems and a higher prevalence of depression in adults, but research examining this association in adolescents is scarce. Social relationships may be particularly critical during adolescence, as it is an important developmental period during which vulnerability to mental health problems increases. The present study examined the relationship between having no or few confidants and anxiety/depressive symptoms in adolescents. Methods Cross-sectional self-report data from 17,829 Japanese students (49.7% boys) in public junior and senior high schools were analyzed. Associations between anxiety/depressive symptoms (12-item General Health Questionnaire; score range: 0–12) and the number of confidants (None, 1–3, or ≥ 4) were examined using multilevel regression analyses. The analyses were stratified by gender and school level (junior/senior high), and adjusted for experiences of physical abuse and bullying. Results Having 1–3 or no confidants was associated with more anxiety/depressive symptoms, compared to having ≥ 4 confidants (p

Published
2023
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28. Sex and age specific effects on the development of addiction and compulsive-like drinking in rats

Author

Jerome C. Foo, Ivan Skorodumov, Rainer Spanagel, and Marcus W. Meinhardt

Abstract

Biological factors are known to influence disease trajectories and treatment effectiveness in alcohol addiction. One important biological factor influencing disease dynamics in alcohol use disorder is sex, as preclinical and clinical evidence suggests that gender influences disease trajectories in subjects with alcohol use disorder. Another critical factor is age at first intoxicating drink, which has been identified as a risk factor for later alcohol binging. Preclinical research allows prospective monitoring of rodents throughout the lifespan, providing very detailed information that cannot be acquired in humans. Lifetime monitoring in rodents can be conducted under highly controlled conditions, during which one can systematically introduce multiple biological and environmental factors that impact behaviors of interest.Here, we used the alcohol deprivation effect (ADE) rat model of alcohol addiction in a computerized drinkometer system to study disease dynamics and transition points of addictive behavior in cohorts of adolescent vs. adult as well as male vs. female rats in direct comparison. Early age of onset of drinking (postnatal day 40) in male rats had surprisingly little impact on the development of drinking behavior and compulsivity (quinine taste adulteration) when compared to rats that started drinking during early adulthood (postnatal day 72). However, female rats showed a stronger resistance to quinine taste adulteration after a history of ADEs, indicative of more pronounced compulsive behavior in females as compared to male rats. Specifically, female rats exhibit during quinine taste adulteration a higher frequency of drinking events and a larger access size, especially from the 20% alcohol solution, resulting in fast intoxication despite taste aversion in a relapse-like situation. Our results suggest that drinking patterns, and specifically solution preference as well as access size, provide a valuable indication into determining compulsive drinking. These findings provide a better understanding of sex and age factors involved in the development of drinking behavior that are important in preclinical development of models of addiction, drug development and exploration options for new treatments.

Published
2022
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29. Polygenic risk scores for nicotine use and family history of smoking are associated with smoking behaviour

Author

Jerome C. Foo, Fabian Streit, Josef Frank, Norman Zacharias, Lea Zillich, Lea Sirignano, Maja P. Völker, Peter Nürnberg, Thomas Wienker, Michael Wagner, Markus Nöthen, Michael Nothnagel, Henrik Walter, Bernd Lenz, Rainer Spanagel, Falk Kiefer, Georg Winterer, Marcella Rietschel, and Stephanie H. Witt

Abstract

IntroductionFormal genetics studies show that smoking is influenced by genetic factors; exploring this on the molecular level can offer deeper insight into the etiology of smoking behaviours.MethodsSummary statistics from the GWAS and Sequencing Consortium of Alcohol and Nicotine (GSCAN) Consortium were used to calculate polygenic risk scores (PRS) in a sample of ∼2,200 smokers/never-smokers. The association of PRS for Smoking Initiation (i.e. Lifetime Smoking; SI-PRS) with smoking status, and PRS for Cigarettes per Day (CpD-PRS) and Smoking Cessation (SC-PRS) with Fagerström Test for Nicotine Dependence (FTND) score were examined, as were distinct/additive effects of parental smoking on smoking status.ResultsSI-PRS explained 6.65% of variance (Nagelkerke-R2) in smoking status (p=1.71×10−24). In smokers, CpD-PRS (R2=3.15%, p=1.82×10−8) and SC-PRS (R2=2.01%; p=7.18×10−6) were associated with FTND score. Parental smoking alone explained R2=3.06% (p=2.43×10−12) of smoking status, and 1.39% when added to the most informative SI-PRS model (total R²=8.04%).ConclusionThese results show the potential utility of molecular genetic data for research investigating smoking prevention. The fact that PRS explains more variance than family history highlights progress from formal to molecular genetics; the overlap and increased predictive value when using both suggests the importance of combining these approaches.ImplicationsThis study underlines the value of using PRS to predict smoking status/behaviour. It highlights the importance of molecular genetic methods in research investigating smoking prevention and points to the necessity of combining family history and molecular genetic data.

Published
2022
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30. Epigenome-wide association study of alcohol use disorder in five brain regions

Author

Marion M. Friske, Marcella Rietschel, Lea Sirignano, Jerome C. Foo, Josef Frank, Markus M. Nöthen, Anita C. Hansson, Fabian Streit, Lea Zillich, Stephanie H. Witt, Per Hoffmann, Stefanie Heilmann-Heimbach, Rainer Spanagel, Franziska Degenhardt, and Helene Dukal

Subjects
Oncology, medicine.medical_specialty, Alcohol Drinking, Medizin, Caudate nucleus, Biology, Epigenesis, Genetic, Epigenome, Internal medicine, mental disorders, medicine, Humans, Brodmann area 9, Anterior cingulate cortex, Pharmacology, Putamen, Ventral striatum, Weighted correlation network analysis, Brain, Human brain, DNA Methylation, Alcoholism, Psychiatry and Mental health, medicine.anatomical_structure, Differentially methylated regions, Genome-Wide Association Study
Abstract

Alcohol use disorder (AUD) is closely linked to the brain regions forming the neurocircuitry of addiction. Postmortem human brain tissue enables the direct study of the molecular pathomechanisms of AUD. This study aims to identify these mechanisms by examining differential DNA-methylation between cases with severe AUD (n = 53) and controls (n = 58) using a brain-region-specific approach, in which sample sizes ranged between 46 and 94. Samples of the anterior cingulate cortex (ACC), Brodmann Area 9 (BA9), caudate nucleus (CN), ventral striatum (VS), and putamen (PUT) were investigated. DNA-methylation levels were determined using the Illumina HumanMethylationEPIC Beadchip. Epigenome-wide association analyses were carried out to identify differentially methylated CpG-sites and regions between cases and controls in each brain region. Weighted correlation network analysis (WGCNA), gene-set, and GWAS-enrichment analyses were performed. Two differentially methylated CpG-sites were associated with AUD in the CN, and 18 in VS (q q n = 6), VS (n = 18), and ACC (n = 1). In the VS, the WGCNA-module showing the strongest association with AUD was enriched for immune-related pathways. This study is the first to analyze methylation differences between AUD cases and controls in multiple brain regions and consists of the largest sample to date. Several novel CpG-sites and regions implicated in AUD were identified, providing a first basis to explore epigenetic correlates of AUD.

Published
2021
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32. DNA Methylation in Cocaine Use Disorder – An Epigenome-wide Approach in the Human Prefrontal Cortex

Author

Eric Poisel, Lea Zillich, Fabian Streit, Josef Frank, Marion M Friske, Jerome C Foo, Naguib Mechawar, Gustavo Turecki, Anita C Hansson, Markus M Nöthen, Marcella Rietschel, Rainer Spanagel, and Stephanie H Witt

Abstract

Cocaine use disorder (CUD) is characterized by a loss of control over drug intake and is associated with structural, functional, and molecular alterations in the brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes as observed in CUD. Most evidence of cocaine-associated epigenetic changes comes from animal studies while only a few studies have been performed using human tissue. We investigated epigenome-wide DNA methylation signatures of CUD in human postmortem brain tissue of Brodmann Area 9 (BA9). A total of N = 42 BA9 brain samples were obtained from N = 21 individuals with CUD and N = 21 individuals without a CUD diagnosis. We performed an epigenome-wide association study and analyzed CUD-associated differentially methylated regions (DMRs). To assess the functional role of CUD-associated differential methylation, we performed Gene Ontology enrichment analyses and characterized co-methylation networks using a weighted correlation network analysis. We further investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age. While no CpG site was associated with CUD at epigenome-wide significance in BA9, we detected a total of 20 CUD-associated DMRs. After annotation of DMRs to genes, we identifiedNPFFR2andKALRNfor which a previous role in the behavioral response to cocaine in rodents is known. Three of the four identified CUD-associated co-methylation modules were functionally related to neurotransmission and neuroplasticity. Protein-protein interaction networks derived from module hub genes revealed several addiction-related genes as highly connected nodes such asCACNA1C, NR3C1, andJUN. In BA9, we observed a trend toward epigenetic age acceleration in individuals with CUD remaining stable even after adjustment for covariates. Results from our study highlight that CUD is associated with epigenome-wide differences in DNA methylation levels in BA9 particularly related to synaptic signaling and neuroplasticity. This supports findings from previous studies that report on the strong impact of cocaine on neurocircuits in the human prefrontal cortex. Further studies are needed to follow up on the role of epigenetic alterations in CUD focusing on the integration of epigenetic signatures with transcriptomic and proteomic data.

Published
2022
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33. Early-Onset Signet-Ring Cell Adenocarcinoma of the Colon: A Case Report and Review of the Literature

Author

Maliha Khan, Krittiya Korphaisarn, Aneeqa Saif, Wai C. Foo, and Scott Kopetz

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in the United States. While a decline has been observed in the older population, the occurrence of CRC in the adolescent and young adult (AYA) population has increased over the past two decades. The histopathologic characteristics and clinical behavior of CRC in AYA patients have been shown to be distinct from those of CRC in older adults. The rarer subtypes of CRC such as mucinous adenocarcinoma and signet-ring cell carcinoma are associated with a poorer prognosis compared to the more common subtypes. Here we report a case of a 20-year-old man who was diagnosed with stage IVB (T4 N2 M1, with peritoneal carcinomatosis) signet-ring cell adenocarcinoma of the colon. The scarcity of information on these rarer subtypes merits further study and investigation.

Published
2017
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34. Translational approach to understanding momentary factors associated with alcohol consumption

Author

Jinhyuk Kim, Jerome C. Foo, and Valentina Vengeliene

Subjects
0301 basic medicine, Pharmacology, Consumption (economics), Motivation, Alcohol Drinking, Drinking motives, Stressor, Craving, Anxiety, Individual risk, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Pharmacological interventions, medicine, Humans, Cues, medicine.symptom, Substance use, Psychology, Review Articles, Alcohol consumption, 030217 neurology & neurosurgery, Clinical psychology
Abstract

Multiple interindividual and intra‐individual factors underlie variability in drinking motives, challenging clinical translatability of animal research and limiting treatment success of substance use‐related problems. Intra‐individual variability refers to time‐dependent continuous and discrete changes within the individual and in substance use research is studied as momentary variation in the internal states (craving, stressed, anxious, impulsive and tired) and response to external triggers (stressors, drug‐associated environmental cues and social encounters). These momentary stimuli have a direct impact on behavioural decisions and may be triggers and predictors of substance consumption. They also present potential targets for real‐time behavioural and pharmacological interventions. In this review, we provide an overview of the studies demonstrating different momentary risk factors associated with increased probability of alcohol drinking in humans and changes in alcohol seeking and consumption in animals. The review also provides an overview of pharmacological interventions related to every individual risk factor.

Published
2020
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35. Integrated clinico-molecular profiling of appendiceal adenocarcinoma reveals a unique grade-driven entity distinct from colorectal cancer

Author

Michael J. Overman, Keith Fournier, Jennifer L. Guerra, Cathy Eng, Wai C. Foo, Alexandre A. Jácome, Melissa W. Taggart, Aurelio Matamoros, John Paul Shen, Kenna R. Shaw, Kanwal Pratap Singh Raghav, and Christopher P. Scally

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Colorectal cancer, Concordance, Disease, Adenocarcinoma, Gastroenterology, Article, Tumour biomarkers, 03 medical and health sciences, Gastrointestinal cancer, 0302 clinical medicine, Internal medicine, Overall survival, GNAS complex locus, Chromogranins, GTP-Binding Protein alpha Subunits, Gs, Medicine, Humans, 030304 developmental biology, Aged, Retrospective Studies, 0303 health sciences, biology, business.industry, Poorly differentiated, High-Throughput Nucleotide Sequencing, Middle Aged, Appendiceal Adenocarcinoma, medicine.disease, Genes, ras, Oncology, Appendiceal Neoplasms, 030220 oncology & carcinogenesis, Mutation, biology.protein, Female, Neoplasm Grading, Tumor Suppressor Protein p53, business, Colorectal Neoplasms
Abstract

Background Appendiceal adenocarcinoma (AA) is an orphan disease with unique clinical attributes but often treated as colorectal cancer (CRC). Understanding key molecular differences between AA and CRC is critical. Methods We performed retrospective analyses of AA patients (N = 266) with tumour and/or blood next-generation sequencing (NGS) (2013–2018) with in-depth clinicopathological annotation. Overall survival (OS) was examined. For comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes (CMS) and mutations (N = 3283) were used. Results Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS (4.2% vs. 60.9%, P RAS (56.2%), GNAS (28.1%) and TP53 (26.9%) were most frequent mutations. Well/moderately differentiated tumours harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more GNAS mutations (28.1% vs. 2.0%) (P Conclusion Integrated clinico-molecular profiling of AA identified key molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a predominantly grade-driven biology that trumps mutations.

Published
2020

36. A quasi‐cluster randomized controlled trial of a classroom‐based mental health literacy educational intervention to promote knowledge and help‐seeking/helping behavior in adolescents

Author

Tsukasa Sasaki, Norihito Oshima, Kumiko Onuma, Shuntaro Ando, Yasutaka Ojio, Satoshi Usami, Jerome C. Foo, Fumiharu Togo, Emiko Michigami, Satoshi Yamaguchi, and Taruto Fuyama

Subjects
Male, Adolescent, Social Psychology, education, Helping behavior, 050109 social psychology, Academic achievement, law.invention, Help-Seeking Behavior, Japan, Randomized controlled trial, law, Surveys and Questionnaires, Intervention (counseling), Developmental and Educational Psychology, Humans, 0501 psychology and cognitive sciences, Students, Mental health literacy, Curriculum, School Health Services, Medical education, Schools, Mental Disorders, 05 social sciences, Mental health, Help-seeking, Health Literacy, Psychiatry and Mental health, Mental Health, Pediatrics, Perinatology and Child Health, Female, School Teachers, Psychology, Program Evaluation, 050104 developmental & child psychology
Abstract

School-based education is a potentially effective approach for improving mental health literacy (MHL) in adolescents. This study evaluated the effects of the "Short MHL Program (SMHLP)", a brief (50 min), school teacher-led program, on MHL in adolescents in a quasi-cluster randomized controlled trial.A total of 975 high school first graders (age 15-16) in Japan were allocated to classes such that gender and academic achievement ratios were almost equivalent at the time of admission to the high school. They were assigned at the class level to the SMHLP (n = 364 from 10 classes) or a control group (n = 611 from 17 classes). The program consisted of a 50-minute session and was delivered by a school teacher. The students completed a self-report questionnaire at 3 time points: pre-, (immediately) post- and 2-month follow-up. Outcomes included "Knowledge about mental health/illnesses", "Recognition of the necessity to seek help", "Intention to seek help", and "Intention of helping peers". Mixed effects modeling was employed for analyses.Scores of all outcomes were significantly improved in the intervention group compared to the control group post-intervention (p.001). These improvements were maintained at 2-months follow-up for all outcomes (p.001-.05). Questionnaire scores did not differ between groups at baseline.The effect of the SMHLP was confirmed in grade 10 students. Brief, yet effective programs can be a viable option to promote understanding of mental health problems and have the potential to be incorporated into regular school curriculum. ".

Published
2020
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37. Single nuclei RNAseq stratifies multiple sclerosis patients into three distinct white matter glia responses

Author

Will Macnair, Daniela Calini, Eneritz Agirre, Julien Bryois, Sarah Jäkel, Petra Kukanja, Nadine Stokar-Regenscheit, Virginie Ott, Lynette C. Foo, Ludovic Collin, Sven Schippling, Eduard Urich, Erik Nutma, Manuel Marzin, Sandra Amor, Roberta Magliozzi, Elyas Heidari, Mark D. Robinson, Charles ffrench-Constant, Gonçalo Castelo-Branco, Anna Williams, and Dheeraj Malhotra

Abstract

The lack of understanding as to the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies and biomarkers. Here, to address this gap, we analysed 740,000 single nuclei RNAseq profiles of 165 samples of white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 55 MS patients and 28 controls. We find that gene expression changes in response to MS are highly cell-type specific in WM and GM lesions but are largely shared within an individual cell-type across lesions, following a continuum rather than discrete lesion-specific molecular programs. The major biological determinants of variability in gene expression in MS samples relate to individual patient effects, rather than to lesion types or other metadata. Using multi-omics factor analysis (MOFA+), we identify three subgroups of MS patients with distinct oligodendrocyte composition and WM glial gene expression signatures, suggestive of engagement of different pathological/regenerative processes. The discovery of these three patterns significantly advances our mechanistic understanding of progressive MS, provides a framework to use molecular biomarkers to stratify patients for best therapeutic approaches for progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients.

Published
2022
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39. Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort

Author

Thao Nguyen, Lea Zillich, Metin Cetin, Alisha S.M. Hall, Jerome C. Foo, Lea Sirignano, Josef Frank, Tabea S. Send, Maria Gilles, Marcella Rietschel, Michael Deuschle, Stephanie H. Witt, and Fabian Streit

Abstract

The COVID-19 pandemic severely affected the lives of families, and the well-being of children and their parent. Prenatal stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and genetic factors might influence individuals’ well-being in the presence of a major stressor such as the COVID-19 pandemic.The present work is part of an ongoing birth cohort study and aims to investigate maternal perceived stress, early childhood HPA axis activity, and polygenic risk scores (PRSs) as predictors of emotional well-being during the COVID-19 pandemic. All participants are part of the ongoing birth cohort study POSEIDON. Emotional well-being of children (n=263) and mothers (n=241) was assessed during the COVID-19 pandemic using the CRISIS questionnaire in two waves between June 2020 and February 2021. Associations of well-being with previously assessed maternal perceived stress, children’s salivary and morning urine cortisol at 45 months, PRSs for depression, schizophrenia, loneliness were investigated.A positive association between the children’s and mothers’ emotional well-being was found. Lower emotional well-being was observed in both children and mothers during the pandemic compared to before. Children’s emotional well-being improved over the course of the pandemic. Prenatally assessed maternal perceived stress was associated with a decrease in children’s but not in the mothers’ well-being. Cortisol measures and PRSs were not significantly associated with emotional wellbeing.The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

Published
2022
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40. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author

Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep

Subjects
0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Published
2022
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41. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. Waldman, John-Anker Zwart, John I. Nurnberger, Arianna Di Florio, Roger A.H. Adan, Tetsuya Ando, Harald Aschauer, Jessica H. Baker, Vladimir Bencko, Andreas Birgegård, Joseph M. Boden, Ilka Boehm, Claudette Boni, Vesna Boraska Perica, Katharina Buehren, Roland Burghardt, Laura Carlberg, Matteo Cassina, Maurizio Clementi, Roger D. Cone, Philippe Courtet, James J. Crowley, Unna N. Danner, Oliver S.P. Davis, Martina de Zwaan, George Dedoussis, Daniela Degortes, Janiece E. DeSocio, Danielle M. Dick, Christian Dina, Monika Dmitrzak-Weglarz, Elisa Docampo Martinez, Laramie E. Duncan, Karin Egberts, Morten Mattingsdal, Sara McDevitt, Ingrid Meulenbelt, Nadia Micali, James Mitchell, Karen Mitchell, Palmiero Monteleone, Alessio Maria Monteleone, Melissa A. Munn-Chernoff, Benedetta Nacmias, Marie Navratilova, Ioanna Ntalla, Julie K. O’Toole, Leonid Padyukov, Aarno Palotie, Jacques Pantel, Hana Papezova, Richard Parker, John F. Pearson, Stefan Ehrlich, Geòrgia Escaramís, Thomas Espeseth, Xavier Estivill, Anne Farmer, Angela Favaro, Krista Fischer, James A.B. Floyd, Manuel Föcker, Lenka Foretova, Monica Forzan, Christopher S. Franklin, Giovanni Gambaro, Johanna Giuranna, Paola Giusti-Rodríquez, Fragiskos Gonidakis, Scott Gordon, Monica Gratacos Mayora, Sébastien Guillaume, Ken B. Hanscombe, Konstantinos Hatzikotoulas, Johannes Hebebrand, Sietske G. Helder, Anjali K. Henders, Beate Herpertz-Dahlmann, Wolfgang Herzog, Anke Hinney, L. John Horwood, Christopher Hübel, Liselotte V. Petersen, Kirstin L. Purves, Anu Raevuori, Ted Reichborn-Kjennerud, Valdo Ricca, Samuli Ripatti, Franziska Ritschel, Marion Roberts, Filip Rybakowski, Paolo Santonastaso, André Scherag, Ulrike Schmidt, Nicholas J. Schork, Alexandra Schosser, Jochen Seitz, Lenka Slachtova, P. Eline Slagboom, Margarita C.T. Slof-Op ‘t Landt, Agnieszka Slopien, Nicole Soranzo, Sandro Sorbi, Lorraine Southam, Vidar W. Steen, Laura M. Huckins, James I. Hudson, Hartmut Imgart, Hidetoshi Inoko, Vladimir Janout, Jennifer Jordan, Antonio Julià, Gursharan Kalsi, Deborah Kaminská, Jaakko Kaprio, Leila Karhunen, Andreas Karwautz, Martien J.H. Kas, Martin A. Kennedy, Anna Keski-Rahkonen, Kirsty Kiezebrink, Youl-Ri Kim, Katherine M. Kirk, Lars Klareskog, Gun Peggy S. Knudsen, Janne T. Larsen, Stephanie Le Hellard, Virpi M. Leppä, Paul Lichtenstein, Bochao Danae Lin, Astri Lundervold, Jurjen Luykx, Mario Maj, Katrin Mannik, Sara Marsal, Garret D. Stuber, Jin P. Szatkiewicz, Ioanna Tachmazidou, Elena Tenconi, Alfonso Tortorella, Federica Tozzi, Artemis Tsitsika, Marta Tyszkiewicz-Nwafor, Konstantinos Tziouvas, Annemarie A. van Elburg, Eric F. van Furth, Tracey D. Wade, Gudrun Wagner, Esther Walton, H. Erich Wichmann, Elisabeth Widen, Shuyang Yao, Eleftheria Zeggini, Stephanie Zerwas, Stephan Zipfel, Martin Jungkunz, Lydie Dietl, Cornelia E. Schwarze, Norbert Dahmen, Björn H. Schott, Arian Mobascher, Silvia Crivelli, Michelle F. Dennis, Phillip D. Harvey, Bruce W. Carter, Jennifer E. Huffman, Daniel Jacobson, Ravi Madduri, Maren K. Olsen, John Pestian, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean Beckham, Kyong-Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James Breeling, Grant Huang, J.P. Casas Romero, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Saiju Pyarajan, Elizabeth Hauser, Yan Sun, Hongyu Zhao, Peter Wilson, Rachel McArdle, Louis Dellitalia, Kristin Mattocks, John Harley, Clement J. Zablocki, Jeffrey Whittle, Frank Jacono, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark Hamner, Roy Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair Ballas, Douglas Ivins, Stephen Mastorides, Jonathan Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Florez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel Aguayo, David Cohen, Satish Sharma, Suthat Liangpunsakul, Kris Ann Oursler, Mary Whooley, Sunil Ahuja, Joseph Constans, Paul Meyer, Jennifer Greco, Michael Rauchman, Richard Servatius, Melinda Gaddy, Agnes Wallbom, Timothy Morgan, Todd Stapley, Scott Sherman, George Ross, Philip Tsao, Patrick Strollo, Edward Boyko, Laurence Meyer, Samir Gupta, Mostaqul Huq, Joseph Fayad, Adriana Hung, Jack Lichy, Robin Hurley, Brooks Robey, Robert Striker, Dietl, Lydie, Schwarze, Cornelia E., Dahmen, Norbert, Schott, Björn H., Nöthen, Markus M., Ripke, Stephan, Mobascher, Arian, Rujescu, Dan, Lieb, Klaus, Roepke, Stefan, Schmahl, Christian, Bohus, Martin, Rietschel, Marcella, Crivelli, Silvia, Dennis, Michelle F., Harvey, Phillip D., Carter, Bruce W., Huffman, Jennifer E., Jacobson, Daniel, Madduri, Ravi, Olsen, Maren K., Pestian, John, Gaziano, J. Michael, Muralidhar, Sumitra, Ramoni, Rachel, Beckham, Jean, Chang, Kyong-Mi, O'Donnell, Christopher J., Tsao, Philip S., Breeling, James, Huang, Grant, Romero, J. P. 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M., Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan T. F., Bigdeli, Tim B., Binder, Elisabeth B., Bryois, Julien, Buttenschøn, Henriette N., Bybjerg-Grauholm, Jonas, Cai, Na, Castelao, Enrique, Christensen, Jane Hvarregaard, Clarke, Toni-Kim, Coleman, Jonathan R. I., Colodro-Conde, Lucía, Couvy-Duchesne, Baptiste, Craddock, Nick, Crawford, Gregory E., Davies, Gail, Degenhardt, Franziska, Derks, Eske M., Direk, Nese, Dolan, Conor V., Dunn, Erin C., Eley, Thalia C., Escott-Price, Valentina, Hassan Kiadeh, Farnush Farhadi, Finucane, Hilary K., Foo, Jerome C., Forstner, Andreas J., Frank, Josef, Gaspar, Héléna A., Gill, Michael, Goes, Fernando S., Gordon, Scott D., Weinsheimer, Shantel Marie, Wellmann, Jürgen, Willemsen, Gonneke, Witt, Stephanie H., Wu, Yang, Xi, Hualin S., Yang, Jian, Zhang, Futao, Arolt, Volker, Baune, Bernhard T., Berger, Klaus, Boomsma, Dorret I., Cichon, Sven, Dannlowski, Udo, de Geus, E. J. C., DePaulo, J. 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Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022
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42. Multi-Omics Signatures of Alcohol Use Disorder in the Dorsal and Ventral Striatum

Author

Georgy Bakalkin, Eric Poisel, Josef Frank, Markus M. Nöthen, Stephanie H. Witt, Fabian Streit, Stefanie Heilmann-Heimbach, Marcella Rietschel, Per Hoffmann, Jerome C. Foo, André Heimbach, Anita C. Hansson, Lea Zillich, Lea Sirignano, Rainer Spanagel, Marion M. Friske, and Franziska Degenhardt

Subjects
medicine.anatomical_structure, Putamen, mental disorders, Ventral striatum, medicine, Caudate nucleus, Weighted correlation network analysis, Genome-wide association study, Striatum, Human brain, Biology, Neuroscience, Gene
Abstract

Alcohol Use Disorder (AUD) is a major contributor to global mortality and morbidity. Postmortem human brain tissue enables the investigation of molecular mechanisms of AUD in the neurocircuitry of addiction. We aimed to identify differentially expressed (DE) genes in the ventral and dorsal striatum between individuals with AUD and controls, and to integrate the results with findings from genome- and epigenome-wide association studies (GWAS/EWAS) to identify functionally relevant molecular mechanisms of AUD. DNA-methylation and gene expression (RNA-seq) data was generated from postmortem brain samples of 48 individuals with AUD and 51 controls from the ventral striatum (VS) and the dorsal striatal regions caudate nucleus (CN) and putamen (PUT). We identified DE genes using DESeq2, performed gene-set enrichment analysis (GSEA), and tested enrichment of DE genes in results of GWASs using MAGMA. Weighted correlation network analysis (WGCNA) was performed for DNA-methylation and gene expression data and gene overlap was tested. Differential gene expression was observed in the dorsal (FDRARHGEF15 gene was upregulated in all three brain regions. GSEA in CN and VS pointed towards cell-structure associated GO-terms and in PUT towards immune pathways. The WGCNA modules most strongly associated with AUD showed strong enrichment for immune response and inflammation pathways. Our integrated analysis of multi-omics data sets provides further evidence for the importance of immune-and inflammation-related processes in AUD.

Published
2021
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43. Borderline Personality Disorder and the Big Five: Molecular Genetic Analyses Indicate Shared Genetic Architecture with Neuroticism and Openness

Author

Eric Poisel, Ole A. Andreassen, Tolou Maslahati, Stephan Ripke, Lucía Colodro-Conde, Norbert Dahmen, Olav B. Smeland, Guy Hindley, Marcella Rietschel, Björn H. Schott, Stefan Roepke, Jerome C. Foo, Cornelia E. Schwarze, Arian Mobascher, Josef Frank, Markus M. Nöthen, Christian Schmahl, Martin Jungkunz, Fabian Streit, Chi-Hua Chen, Ina Giegling, Lea Sirignano, Dan Rujescu, Annette M. Hartmann, Martin Bohus, Lea Zillich, Klaus Lieb, Swapnil Awasthi, and Stephanie H. Witt

Subjects
medicine, Openness to experience, Psychology, medicine.disease, Neuroticism, Borderline personality disorder, Genetic architecture, Clinical psychology
Abstract

Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD). Twin studies assessing borderline personality symptoms/features in the general population indicate that genetic factors underlying these symptoms/features are shared in part with the personality traits of the Five Factor Model (FFM) of personality – the “Big Five". In the present study, the genetic overlap of BPD with the Big Five -Openness to Experience, Conscientiousness, Extraversion, Agreeableness and Neuroticism- was assessed. Linkage disequilibrium score regression was used to calculate genetic correlations between a genome-wide association study (GWAS) in central European populations on BPD (N = 2,543) and GWAS on the “Big Five” (N = 76,551–122,886, Neuroticism N = 390,278). Significant positive genetic correlations were found between BPD and the traits Neuroticism (rg=.34, p=6.3*10−5) and Openness (rg=.24, p=.036), but not between BPD and the other personality traits (all |rg|p>.30). A cluster and item-level analysis showed positive correlations with the Neuroticism clusters “Depressed Affect” and “Worry”, and with a broad range of Neuroticism items (N = 348,219 – 376,352). The observed associations indicate a partially shared genetic background of BPD and the personality traits Neuroticism and Openness. Larger GWAS of BPD and the “Big Five” are needed to further explore the role of personality traits in the etiology of this disorder.

Published
2021
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44. Interplay between the Genetics of Personality Traits, severe Psychiatric Disorders, and COVID-19 Host Genetics in the Susceptibility to SARS-CoV-2 Infection

Author

Kristina Adorjan, Urs Heilbronner, Marcella Rietschel, Jens Reimer, Detlef E. Dietrich, Heike Anderson-Schmidt, Max Schmauss, Fabian Streit, Monika Budde, Markus Jäger, Chi-Hua Chen, Daniela Reich-Erkelenz, Sabrina K. Schaupp, Janos Kalman, Jerome C. Foo, Bernhardt T. Baune, Markus M. Nöthen, Katrin Gade, Farahnaz Klöhn-Saghatolislam, Eric Poisel, Franziska Degenhardt, Andreas J. Forstner, Volker Arolt, Sergi Papiol, Ashley L. Comes, Carsten Spitzer, Mojtaba Oraki Kohshour, Til Stürmer, Maria Heilbronner, Stephanie H. Witt, Thomas G. Schulze, Manfred Amelang, Stefanie Heilmann-Heimbach, Ole A. Andreassen, Thomas J. Vogl, Carsten Konrad, Eva C. Schulte, Peter Falkai, Andreas J. Fallgatter, Georg Juckel, Jörg Zimmermann, Adrian Loerbroks, Martin von Hagen, Jens Wiltfang, Udo Dannlowski, Fanny Senner, Ion-George Anghelescu, Eva Z. Reininghaus, Fabian U. Lang, Till F. M. Andlauer, and Christian Figge

Subjects
0303 health sciences, medicine.medical_specialty, Linkage disequilibrium, Extraversion and introversion, Genome-wide association study, Biology, Mental health, Genetic correlation, Correlation, 03 medical and health sciences, 0302 clinical medicine, medicine, Big Five personality traits, Psychiatry, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

BackgroundThe SARS-CoV-2 pandemic, with all its impacts on our way of life, is affecting our experiences and mental health. Notably, individuals with mental disorders have been reported to have a higher risk of contracting SARS-CoV-2. Personality traits could represent an important determinant of preventative health behavior and, therefore, the risk of contracting the virus.AimsWe examined overlapping genetic underpinnings between major psychiatric disorders, personality traits, and susceptibility to SARS-CoV-2 infection.MethodsLinkage disequilibrium score regression was used to explore the genetic correlations of COVID-19 susceptibility with psychiatric disorders and personality traits based on data from the largest available respective genome-wide association studies (GWAS). In two cohorts (the PsyCourse (n=1346) and the HeiDE (n=3266) study), polygenic risk scores were used to analyze if a genetic association between, psychiatric disorders, personality traits, and COVID-19 susceptibility exists in individual-level data.ResultsWe observed no significant genetic correlations of COVID-19 susceptibility with psychiatric disorders. For personality traits, there was a significant genetic correlation for COVID-19 susceptibility with extraversion (p=1.47×10-5; rg=0.284). Yet, this was not reflected in individual-level data from the PsyCourse and HeiDE studies.ConclusionsWe identified no significant correlation between genetic risk factors for severe psychiatric disorders and genetic risk for COVID-19 susceptibility. Among the personality traits, extraversion showed evidence for a positive genetic association with COVID-19 susceptibility, in one but not in another setting. Overall, these findings highlight a complex contribution of genetic and non-genetic components in the interaction between COVID-19 susceptibility and personality traits or mental disorders.

Published
2021
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45. A survey of mental health literacy in Japanese high school teachers

Author

Jerome C. Foo, Tsukasa Sasaki, Yuko Kitagawa, Satoshi Yamaguchi, and Fumiharu Togo

Subjects
Male, medicine.medical_specialty, Adolescent, education, RC435-571, behavioral disciplines and activities, Japan, Surveys and Questionnaires, mental disorders, medicine, School teacher, Humans, Psychiatry, Child, Mental health literacy, Depression (differential diagnoses), Panic disorder, Research, medicine.disease, Mental illness, Mental health, Health Literacy, Psychiatry and Mental health, Mental Health, Vignette, Health education, Schizophrenia, Female, School Teachers, Psychology
Abstract

Background School teachers are well-positioned to recognize mental health problems in their students and to help them seek appropriate help. Therefore, teachers need to have high levels of mental health literacy (MHL). In East Asia, however, few studies have examined MHL levels in teachers. In this study, MHL levels were investigated in Japanese teachers. Methods Teachers (n = 665) from 27 Japanese high schools answered a self-administered questionnaire which assessed (a) knowledge about mental health/illnesses, (b) correct recognition of specific illnesses (depression, schizophrenia and panic disorder), (c) confidence in helping students with depressive symptoms, and (d) confidence in teaching mental health knowledge to students. Results The average proportion of correct answers to the knowledge questions (n = 20) was 58.1%. The proportion of those who correctly answered about the presence of a sharp increase of mental illnesses in adolescence was 51.7%. Few teachers correctly answered about the life-time prevalences of major mental illness in general (21.9%), depression (37.8%) and schizophrenia (19.8%). Depression, schizophrenia and panic disorder in vignette were correctly recognized by 54.1, 35.3 and 78.0% of teachers, respectively. Correct recognition was significantly lower in male than in female teachers. Only a small proportion of teachers had confidence in helping depressed students (19.9%) and in teaching mental health knowledge to students (11.1%). Conclusions MHL in Japanese high school teachers appears to be low. Education programs should be developed and implemented to improve teacher MHL with the aim of helping them to support students suffering from mental health problems.

Published
2021

46. Emerging technologies to study glial cells

Author

Julien Muffat, Carole Escartin, Tirzah Kreisel, Emilie Hangen, Nicole Déglon, Nathalie Linck, Sara Regio, Sybille Rion, Inbal Goshen, Lynette C. Foo, Jaime Grutzendler, Hélène Hirbec, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE12-0027,EpiHD,Rôle des mécanismes épigénétiques dans la maladie de Huntington(2017), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
0301 basic medicine, Cell type, [SDV]Life Sciences [q-bio], Oligodendrocyte progenitor, Biology, Viral vector, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, In patient, Induced pluripotent stem cell, Neurons, Microglia, Molecular analysis, Oligodendroglia, 030104 developmental biology, medicine.anatomical_structure, nervous system, Neurology, Cell culture, Astrocytes, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroglia, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Development, physiological functions, and pathologies of the brain depend on tight interactions between neurons and different types of glial cells, such as astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. Assessing the relative contribution of different glial cell types is required for the full understanding of brain function and dysfunction. Over the recent years, several technological breakthroughs were achieved, allowing "glio-scientists" to address new challenging biological questions. These technical developments make it possible to study the roles of specific cell types with medium or high-content workflows and perform fine analysis of their mutual interactions in a preserved environment. This review illustrates the potency of several cutting-edge experimental approaches (advanced cell cultures, induced pluripotent stem cell (iPSC)-derived human glial cells, viral vectors, in situ glia imaging, opto- and chemogenetic approaches, and high-content molecular analysis) to unravel the role of glial cells in specific brain functions or diseases. It also illustrates the translation of some techniques to the clinics, to monitor glial cells in patients, through specific brain imaging methods. The advantages, pitfalls, and future developments are discussed for each technique, and selected examples are provided to illustrate how specific "gliobiological" questions can now be tackled.

Published
2020
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48. Attitudes toward the right to autonomous decision‐making in psychiatric genetic testing: Controversial and context‐dependent

Author

Laura Flatau, Franciska Illes, Noemi Lemme, Jana Strohmaier, Marcella Rietschel, Markus Reitt, Josef Frank, Fabian Streit, Dirk Lanzerath, Stephanie H. Witt, Jerome C. Foo, Dan Rujescu, Thomas G. Schulze, and Franziska Degenhardt

Subjects
Adult, Male, 0301 basic medicine, Genetic Research, medicine.medical_specialty, Bipolar Disorder, media_common.quotation_subject, Decision Making, ambivalence, Genetic Counseling, Context (language use), Disclosure, 030105 genetics & heredity, privacy, Ambivalence, 03 medical and health sciences, Cellular and Molecular Neuroscience, Risk Factors, right to self‐determination, Surveys and Questionnaires, medicine, Humans, Genetic Testing, Bipolar disorder, Psychiatry, Research Articles, Genetics (clinical), Depression (differential diagnoses), Psychiatric genetics, media_common, Genetic testing, Depressive Disorder, Major, medicine.diagnostic_test, Mental Disorders, Genomics, 16. Peace & justice, medicine.disease, Test (assessment), Psychiatry and Mental health, 030104 developmental biology, Attitude, psychiatric genetic testing, right to self-determination, Female, Psychology, Attitude to Health, Autonomy, Research Article
Abstract

Recent breakthroughs in psychiatric genetics have identified genetic risk factors of yet unknown clinical value. A main ethical principal in the context of psychiatric research as well as future clinical genetic testing is the respect for a person's autonomy to decide whether to undergo genetic testing, and whom to grant access to genetic data. However, experience within the psychiatric genetic research setting has indicated controversies surrounding attitudes toward this ethical principal. This study aimed to explore attitudes concerning the right of individuals to self-determine testing and disclosure of results, and to determine whether these attitudes are context-dependent, that is, not directly related to the test result but rather to specific circumstances. N = 160 individuals with major depression or bipolar disorder and n = 29 relatives of individuals with either illness completed an online-questionnaire assessing attitudes toward genetic testing, genetic research, disclosure of results, incidental findings, and access to psychiatric genetic test results. Generally, the right of the person's autonomy was considered very important, but attitudes varied. For example, half of those who considered that children should have the right to refuse psychiatric genetic testing even against their parents' will, also state that they should be tested upon their parents' wishes. Also, the majority of respondents considered the physician entitled to disregard their stated wishes concerning the disclosure of incidental findings in case of good treatment options. Thus, researchers and clinicians must be aware that attitudes toward psychiatric genetic testing are often mutable and should discuss these prior to testing. peerReviewed

Published
2019
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