Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological PsychiatryBackground: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.publishersversionpublishe

Wheelchair Controlled by Eye Movement Using Raspberry Pi for ALS Patients

The mobility of people who have suffered a degenerative disease or an accident is partially or totally reduced, which limits their locomotive independence. Therefore, this paper presents a proposal that facilitates the mobility of people suffering from moderate levels of amyotrophic lateral sclerosis (ALS). A control system has been adapted to an electric wheelchair to provide it with a certain degree of intelligence. The acquisition of multimedia data is done with a small camera adapted to a glasses frame that the person must use. For eye patterns tracking, a recognition system is performed using the LabVIEW software environment. The control system that regulates the movement of the wheelchair was designed on the Raspberry Pi embedded board as a low-cost proposal. Experimental tests and user surveys validate the correct operation of this device. © 2020, Springer Nature Switzerland AG

The effect of post-traumatic stress disorder on refugees' parenting and their children's mental health: a cohort study

Background: Children and adolescents, who account for most of the world's refugees, have an increased prevalence of psychological disorders. The mental health of refugee children is often associated with the severity of post-traumatic stress disorder (PTSD) in their caregivers. Despite the potential for refugee caregivers' PTSD to affect child mental health, little evidence exists concerning the underlying mechanisms of this association. This study tested the effect of refugee caregivers' previous trauma and levels of ongoing stressors on current PTSD, and in turn how this influences parenting behaviour and consequent child psychological health. Methods: This cohort study recruited participants from the Building a New Life in Australia study, a population-based prospective cohort study of refugees admitted to 11 sites in Australia between October, 2013, and February, 2014. Eligible participants were aged 18 years or older and the principal or secondary applicant (ie, the refugee applicant within a migrating family unit) for a humanitarian visa awarded between May, 2013, and December, 2013. Primary caregiver PTSD and postmigration difficulties were assessed at Wave 1 (in 2013), and caregiver PTSD was reassessed at Wave 2 (in 2014). At Wave 3, between October, 2015, and February, 2016, primary caregivers repeated measures of trauma history, postmigration difficulties, probable PTSD, and harsh and warm parenting style, and completed the Strengths and Difficulties Questionnaire for their child. We used path analysis to investigate temporal patterns in PTSD, trauma history, postmigration stressors, parenting style, and children's psychological difficulties. Findings: The current data comprised 411 primary caregivers who provided responses in relation to at least one child (660 children). 394 primary caregivers with 639 children had data on independent variables and were included in the final model. Path analyses revealed that caregivers' trauma history and postmigration difficulties were associated with greater subsequent PTSD, which in turn was associated with greater harsh parenting and in turn, higher levels of child conduct problems (β=0&183;049, p=0&183;0214), hyperactivity (β=0&183;044, p=0&183;0241), emotional symptoms (β=0&183;041, p=0&183;0218), and peer problems (β=0&183;007, p=0&183;047). There was also a direct path from primary caregiver PTSD to children's emotional problems (β=0·144, p=0·0001). Interpretation: PTSD in refugees is associated with harsh parenting styles, leading to adverse effects on their children's mental health. Programmes to enhance refugee children's mental health should account for PTSD in parents and caregivers, and the parenting behaviours that these children are exposed to.National Health and Medical Research Council

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.publishe

The effect of post-traumatic stress disorder on refugees' parenting and their children's mental health: a cohort study

Summary: Background: Children and adolescents, who account for most of the world's refugees, have an increased prevalence of psychological disorders. The mental health of refugee children is often associated with the severity of post-traumatic stress disorder (PTSD) in their caregivers. Despite the potential for refugee caregivers' PTSD to affect child mental health, little evidence exists concerning the underlying mechanisms of this association. This study tested the effect of refugee caregivers' previous trauma and levels of ongoing stressors on current PTSD, and in turn how this influences parenting behaviour and consequent child psychological health. Methods: This cohort study recruited participants from the Building a New Life in Australia study, a population-based prospective cohort study of refugees admitted to 11 sites in Australia between October, 2013, and February, 2014. Eligible participants were aged 18 years or older and the principal or secondary applicant (ie, the refugee applicant within a migrating family unit) for a humanitarian visa awarded between May, 2013, and December, 2013. Primary caregiver PTSD and postmigration difficulties were assessed at Wave 1 (in 2013), and caregiver PTSD was reassessed at Wave 2 (in 2014). At Wave 3, between October, 2015, and February, 2016, primary caregivers repeated measures of trauma history, postmigration difficulties, probable PTSD, and harsh and warm parenting style, and completed the Strengths and Difficulties Questionnaire for their child. We used path analysis to investigate temporal patterns in PTSD, trauma history, postmigration stressors, parenting style, and children's psychological difficulties. Findings: The current data comprised 411 primary caregivers who provided responses in relation to at least one child (660 children). 394 primary caregivers with 639 children had data on independent variables and were included in the final model. Path analyses revealed that caregivers' trauma history and postmigration difficulties were associated with greater subsequent PTSD, which in turn was associated with greater harsh parenting and in turn, higher levels of child conduct problems (β=0·049, p=0·0214), hyperactivity (β=0·044, p=0·0241), emotional symptoms (β=0·041, p=0·0218), and peer problems (β=0·007, p=0·047). There was also a direct path from primary caregiver PTSD to children's emotional problems (β=0·144, p=0·0001). Interpretation: PTSD in refugees is associated with harsh parenting styles, leading to adverse effects on their children's mental health. Programmes to enhance refugee children's mental health should account for PTSD in parents and caregivers, and the parenting behaviours that these children are exposed to. Funding: National Health and Medical Research Council

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease