Publications by authors named "Caroline M Nievergelt"

161 Publications

Prospective examination of pre-trauma anhedonia as a risk factor for post-traumatic stress symptoms.

Eur J Psychotraumatol 2022 19;13(1):2015949. Epub 2022 Jan 19.

Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla, CA, USA.

Background: Anhedonia, the reduction of pleasure and reward-seeking behaviour, is a transdiagnostic symptom with well-described neural circuit mediators. Although typically observed during disease state, extant hypotheses suggest that anhedonia may also be an early risk factor for development of psychopathology. Understanding the contribution of anhedonia to the trauma-response trajectory may bolster inferences about biological mechanisms contributing to pre-trauma risk versus trauma-related symptom expression, knowledge of which could aid in targeted interventions.

Objective: Using a prospective, longitudinal design in a population at risk for trauma disorders, we tested the hypothesis that anhedonia may be a pre-trauma risk factor for post-traumatic stress disorder (PTSD) symptoms.

Methods: Adult male participants from the Marine Resilience Study ( = 2,593) were assessed across three time-points (pre-deployment, 3-month and 6-month post-deployment). An anhedonia factor was extracted from self-report instruments pre-trauma and tested for its relationship with development of PTSD re-experiencing symptoms after deployment.

Results: Higher pre-deployment anhedonia predicted increased PTSD intrusive re-experiencing symptoms at 3- and 6-months post-deployment when controlling for pre-trauma PTSD and depression symptoms. Depression symptoms were not significant predictors of subsequent PTSD intrusive re-experiencing symptoms. Anhedonia at 3 mo also robustly predicted maintenance of PTSD intrusive re-experiencing symptoms at the 6 mo time point.

Conclusions: Pre-deployment anhedonia may be a pre-trauma risk factor for PTSD, not simply a state-dependent effect of trauma exposure and PTSD symptom expression. Anhedonia may contribute to persistence and/or chronicity of re-experiencing symptoms after the emergence of PTSD symptoms.
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http://dx.doi.org/10.1080/20008198.2021.2015949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8774051PMC
January 2022

Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress.

Mol Psychiatry 2022 Jan 7. Epub 2022 Jan 7.

Genomics Program, College of Public Health, University of South Florida, Tampa, FL, USA.

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
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http://dx.doi.org/10.1038/s41380-021-01398-2DOI Listing
January 2022

Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume.

Transl Psychiatry 2021 Dec 16;11(1):637. Epub 2021 Dec 16.

VA Boston Healthcare System, Jamaica Plain, MA, USA.

The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10), thalamus (p = 7.46 × 10), caudate (p = 1.97 × 10), putamen (p = 1.7 × 10), and nucleus accumbens (p = 1.99 × 10). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = -0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10) or PTSD (rs10861272; p = 1.78 × 10) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.
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http://dx.doi.org/10.1038/s41398-021-01707-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677780PMC
December 2021

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

Biol Psychiatry 2021 Sep 28. Epub 2021 Sep 28.

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; McLean Hospital, Belmont, Massachusetts.

Background: 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.
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http://dx.doi.org/10.1016/j.biopsych.2021.09.020DOI Listing
September 2021

Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients.

Transl Psychiatry 2021 Nov 29;11(1):606. Epub 2021 Nov 29.

Institute of Human Genetics, University of Bonn and Department of Genomics, Life & Brain Center, Bonn, Germany.

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLiGen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
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http://dx.doi.org/10.1038/s41398-021-01702-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630000PMC
November 2021

Association of polygenic risk scores, traumatic life events and coping strategies with war-related PTSD diagnosis and symptom severity in the South Eastern Europe (SEE)-PTSD cohort.

J Neural Transm (Vienna) 2021 Nov 27. Epub 2021 Nov 27.

Department of Psychiatry, University Clinical Center, Sarajevo, Bosnia and Herzegovina.

Objectives: Posttraumatic stress disorder (PTSD) is triggered by extremely stressful environmental events and characterized by high emotional distress, re-experiencing of trauma, avoidance and hypervigilance. The present study uses polygenic risk scores (PRS) derived from the UK Biobank (UKBB) mega-cohort analysis as part of the PGC PTSD GWAS effort to determine the heritable basis of PTSD in the South Eastern Europe (SEE)-PTSD cohort. We further analyzed the relation between PRS and additional disease-related variables, such as number and intensity of life events, coping, sex and age at war on PTSD and CAPS as outcome variables.

Methods: Association of PRS, number and intensity of life events, coping, sex and age on PTSD were calculated using logistic regression in a total of 321 subjects with current and remitted PTSD and 337 controls previously subjected to traumatic events but not having PTSD. In addition, PRS and other disease-related variables were tested for association with PTSD symptom severity, measured by the Clinician Administrated PTSD Scale (CAPS) by liner regression. To assess the relationship between the main outcomes PTSD diagnosis and symptom severity, each of the examined variables was adjusted for all other PTSD related variables.

Results: The categorical analysis showed significant polygenic risk in patients with remitted PTSD and the total sample, whereas no effects were found on symptom severity. Intensity of life events as well as the individual coping style were significantly associated with PTSD diagnosis in both current and remitted cases. The dimensional analyses showed as association of war-related frequency of trauma with symptom severity, whereas the intensity of trauma yielded significant results independently of trauma timing in current PTSD.

Conclusions: The present PRS application in the SEE-PTSD cohort confirms modest but significant polygenic risk for PTSD diagnosis. Environmental factors, mainly the intensity of traumatic life events and negative coping strategies, yielded associations with PTSD both categorically and dimensionally with more significant p-values. This suggests that, at least in the present cohort of war-related trauma, the association of environmental factors and current individual coping strategies with PTSD psychopathology was stronger than the polygenic risk.
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http://dx.doi.org/10.1007/s00702-021-02446-5DOI Listing
November 2021

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

Bipolar Disord 2021 Nov 26. Epub 2021 Nov 26.

University of Michigan, Ann Arbor, Michigan, USA.

Background: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties.

Methods: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed.

Results: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania.

Conclusions: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. Clinical Trials Registry: NCT0127253.
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http://dx.doi.org/10.1111/bdi.13162DOI Listing
November 2021

Reply to: On powerful GWAS in admixed populations.

Nat Genet 2021 12 25;53(12):1634-1635. Epub 2021 Nov 25.

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41588-021-00975-zDOI Listing
December 2021

Disentangling sex differences in the shared genetic architecture of posttraumatic stress disorder, traumatic experiences, and social support with body size and composition.

Neurobiol Stress 2021 Nov 17;15:100400. Epub 2021 Sep 17.

Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, 06516, USA.

There is a well-known association of traumatic experiences and posttraumatic stress disorder (PTSD) with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand the genetic underpinnings of this complex relationship, we investigated genome-wide datasets informative of African and European ancestries from the Psychiatric Genomic Consortium, the UK Biobank, the GIANT Consortium, and the Million Veteran Program. We used genome-wide association statistics to estimate sex-specific genetic correlations ( ) of traumatic experiences, social support, and PTSD with multiple anthropometric traits. After multiple testing corrections (false discovery rate, FDR q < 0.05), we observed 58 significant relationships in females (e.g., childhood physical abuse and body mass index, BMI  = 0.245, p = 3.88 × 10) and 21 significant relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage;  = 0.405, p = 4.42 × 10). We performed causal inference analyses of these genetic overlaps using Mendelian randomization and latent causal variable approaches. Multiple female-specific putative causal relationships were observed linking body composition/size with PTSD (e.g., leg fat percentage→PTSD; beta = 0.319, p = 3.13 × 10), traumatic experiences (e.g., childhood physical abuse→waist circumference; beta = 0.055, p = 5.07 × 10), and childhood neglect (e.g., "someone to take you to doctor when needed as a child"→BMI; beta = -0.594, p = 1.09 × 10). In males, we observed putative causal effects linking anthropometric-trait genetic liabilities to traumatic experiences (e.g., BMI→childhood physical abuse; beta = 0.028, p = 8.19 × 10). Some of these findings were replicated in individuals of African descent although the limited sample size available did not permit us to conduct a sex-stratified analysis in this ancestry group. In conclusion, our findings provide insights regarding sex-specific causal networks linking anthropometric traits to PTSD, traumatic experiences, and social support
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http://dx.doi.org/10.1016/j.ynstr.2021.100400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477211PMC
November 2021

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Sci Rep 2021 09 8;11(1):17823. Epub 2021 Sep 8.

Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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http://dx.doi.org/10.1038/s41598-021-97140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426488PMC
September 2021

Dissociable impact of childhood trauma and deployment trauma on affective modulation of startle.

Neurobiol Stress 2021 Nov 26;15:100362. Epub 2021 Jun 26.

VA Center of Excellence for Stress and Mental Health (CESAMH), USA.

Trauma disorders are often associated with alterations in aversive anticipation and disruptions in emotion/fear circuits. Heightened or blunted anticipatory responding to negative cues in adulthood may be due to differential trauma exposure during development, and previous trauma exposure in childhood may also modify effects of subsequent trauma in adulthood. The aim of the current investigation was to examine the contributions of childhood trauma on affective modulation of startle before and after trauma exposure in adulthood (a combat deployment). Adult male participants from the Marine Resilience Study with (n = 1145) and without (n = 1312) a history of reported childhood trauma completed an affective modulation of startle task to assess aversive anticipation. Affective startle response was operationalized by electromyography (EMG) recording of the orbicularis oculi muscle in response to acoustic stimuli when anticipating positive and negative affective images. Startle responses to affective images were also assessed. Testing occurred over three time-points; before going on a 7 month combat deployment and 3 and 6 months after returning from deployment. Startle response when anticipating negative images was greater compared to pleasant images across all three test periods. Across all 3 time points, childhood trauma was consistently associated with significantly blunted startle when anticipating negative images, suggesting reliable effects of childhood trauma on aversive anticipation. Conversely, deployment trauma was associated with increased startle reactivity post-deployment compared to pre-deployment, which was independent of childhood trauma and image valence. These results support the hypothesis that trauma exposure during development vs. adulthood may have dissociable effects on aversive anticipation and arousal mechanisms. Further study in women and across more refined age groups is needed to test generalizability and identify potential developmental windows for these differential effects.
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http://dx.doi.org/10.1016/j.ynstr.2021.100362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259305PMC
November 2021

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Front Neurosci 2021 23;15:678503. Epub 2021 Jun 23.

Department of Psychiatry, Case Western Reserve University, Cleveland, OH, United States.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European ( = 70,870) and African ( = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, < 1E-20; DBP: β = 1.32, SE = 0.04, < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (β = -1.46, SE = 0.44, = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.
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http://dx.doi.org/10.3389/fnins.2021.678503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262489PMC
June 2021

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.

Nat Genet 2021 06 17;53(6):817-829. Epub 2021 May 17.

Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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http://dx.doi.org/10.1038/s41588-021-00857-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192451PMC
June 2021

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

Bipolar Disord 2021 Dec 5;23(8):821-831. Epub 2021 May 5.

University of Michigan, Ann Arbor, MI, USA.

Background: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response.

Methods: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse.

Results: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness.

Conclusions: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.
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http://dx.doi.org/10.1111/bdi.13078DOI Listing
December 2021

Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach.

Lancet Psychiatry 2021 05 16;8(5):373-386. Epub 2021 Mar 16.

Department of Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands; Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands.

Background: Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene-environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, we aimed to delineate the sources of gene-environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health.

Methods: We did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank (n=143 473), Psychiatric Genomics Consortium (n=26 290), Avon Longitudinal Study of Parents and Children (n=8346), Adolescent Brain Cognitive Development Study (n=5400), and Generation R (n=1905). We included individuals who had phenotypic and genetic data available. We investigated single nucleotide polymorphism heritability and genetic correlations among different subtypes, operationalisations, and reports of childhood maltreatment. Family-based and population-based polygenic score analyses were done to elucidate gene-environment correlation mechanisms. We used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions.

Findings: Our meta-analysis of genome-wide association studies (N=185 414) identified 14 independent loci associated with childhood maltreatment (13 novel). We identified high genetic overlap (genetic correlations 0·24-1·00) among different maltreatment operationalisations, subtypes, and reporting methods. Within-family analyses provided some support for active and reactive gene-environment correlation but did not show the absence of passive gene-environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration).

Interpretation: Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment. Family-based analyses point to a role of active and reactive gene-environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. Our study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects.

Funding: Wellcome Trust, UK Medical Research Council, Horizon 2020, National Institute of Mental Health, and National Institute for Health Research Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2215-0366(20)30569-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055541PMC
May 2021

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response: preliminary studies.

Mol Psychiatry 2021 07 5;26(7):3383-3394. Epub 2021 Mar 5.

VA San Diego Healthcare System, San Diego, CA, USA.

Bipolar disorder (BD) is a neuropsychiatric illness defined by recurrent episodes of mania/hypomania, depression and circadian rhythm abnormalities. Lithium is an effective drug for BD, but 30-40% of patients fail to respond adequately to treatment. Previous work has demonstrated that lithium affects the expression of "clock genes" and that lithium responders (Li-R) can be distinguished from non-responders (Li-NR) by differences in circadian rhythms. However, circadian rhythms have not been evaluated in BD patient neurons from Li-R and Li-NR. We used induced pluripotent stem cells (iPSCs) to culture neuronal precursor cells (NPC) and glutamatergic neurons from BD patients characterized for lithium responsiveness and matched controls. We identified strong circadian rhythms in Per2-luc expression in NPCs and neurons from controls and Li-R, but NPC rhythms in Li-R had a shorter circadian period. Li-NR rhythms were low amplitude and profoundly weakened. In NPCs and neurons, expression of PER2 was higher in both BD groups compared to controls. In neurons, PER2 protein levels were higher in BD than controls, especially in Li-NR samples. In single cells, NPC and neuron rhythms in both BD groups were desynchronized compared to controls. Lithium lengthened period in Li-R and control neurons but failed to alter rhythms in Li-NR. In contrast, temperature entrainment increased amplitude across all groups, and partly restored rhythms in Li-NR neurons. We conclude that neuronal circadian rhythm abnormalities are present in BD and most pronounced in Li-NR. Rhythm deficits in BD may be partly reversible through stimulation of entrainment pathways.
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http://dx.doi.org/10.1038/s41380-021-01048-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418615PMC
July 2021

A 7 Tesla Amygdalar-Hippocampal Shape Analysis of Lithium Response in Bipolar Disorder.

Front Psychiatry 2021 16;12:614010. Epub 2021 Feb 16.

Department of Psychiatry and Behavioral Science, Johns Hopkins School of Medicine, Baltimore, MD, United States.

Research to discover clinically useful predictors of lithium response in patients with bipolar disorder has largely found them to be elusive. We demonstrate here that detailed neuroimaging may have the potential to fill this important gap in mood disorder therapeutics. Lithium treatment and bipolar disorder have both been shown to affect anatomy of the hippocampi and amygdalae but there is no consensus on the nature of their effects. We aimed to investigate structural surface anatomy changes in amygdala and hippocampus correlated with treatment response in bipolar disorder. Patients with bipolar disorder ( = 14) underwent lithium treatment, were classified by response status at acute and long-term time points, and scanned with 7 Tesla structural MRI. Large Deformation Diffeomorphic Metric Mapping was applied to detect local differences in hippocampal and amygdalar anatomy between lithium responders and non-responders. Anatomy was also compared to 21 healthy comparison participants. A patch of the ventral surface of the left hippocampus was found to be significantly atrophied in non-responders as compared to responders at the acute time point and was associated at a trend-level with long-term response status. We did not detect an association between response status and surface anatomy of the right hippocampus or amygdala. To the best of our knowledge, this is the first shape analysis of hippocampus and amygdala in bipolar disorder using 7 Tesla MRI. These results can inform future work investigating possible neuroimaging predictors of lithium response in bipolar disorder.
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http://dx.doi.org/10.3389/fpsyt.2021.614010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920967PMC
February 2021

Tractor uses local ancestry to enable the inclusion of admixed individuals in GWAS and to boost power.

Nat Genet 2021 02 18;53(2):195-204. Epub 2021 Jan 18.

Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African-European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants.
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http://dx.doi.org/10.1038/s41588-020-00766-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867648PMC
February 2021

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Nat Commun 2020 11 24;11(1):5965. Epub 2020 Nov 24.

Brown University, Psychiatry and Human Behavior, Department of Pediatric Research, Providence, RI, USA.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
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http://dx.doi.org/10.1038/s41467-020-19615-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686485PMC
November 2020

Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry.

JAMA Otolaryngol Head Neck Surg 2020 11;146(11):1015-1025

Research Service, Veterans Affairs San Diego Healthcare System, San Diego, California.

Importance: Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished.

Objective: To identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits.

Design, Setting, And Participants: A GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020.

Main Outcomes And Measures: Estimates of single nucleotide variation (SNV)-based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed.

Results: Of 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (β = 0.133; P = .003) and years of education had a protective effect (β = -0.322, P = <.001) on tinnitus, whereas tinnitus and hearing loss inferred a bidirectional association (β = 0.072, P = .001 and β = 1.546, P = <.001, respectively).

Conclusions And Relevance: This large GWAS characterizes the genetic architecture of tinnitus, demonstrating modest but significant heritability and a polygenic profile with multiple significant risk loci and genes. Genetic correlation and inferred causation between tinnitus and major depressive disorder, educational level, and hearing impairment were identified, consistent with clinical and neuroimaging evidence. These findings may guide gene-based diagnostic and therapeutic approaches to this pervasive disorder.
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http://dx.doi.org/10.1001/jamaoto.2020.2920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516809PMC
November 2020

Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.

Cell Rep 2020 06;31(9):107716

SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town 7700, South Africa.

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
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http://dx.doi.org/10.1016/j.celrep.2020.107716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359754PMC
June 2020

The association between lithium use and neurocognitive performance in patients with bipolar disorder.

Neuropsychopharmacology 2020 09 29;45(10):1743-1749. Epub 2020 Apr 29.

NORMENT, Division of Psychiatry, Haukeland University Hospital and Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.
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http://dx.doi.org/10.1038/s41386-020-0683-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419515PMC
September 2020

Association of Race and Major Adverse Cardiac Events (MACE): The Atherosclerosis Risk in Communities (ARIC) Cohort.

J Aging Res 2020 21;2020:7417242. Epub 2020 Mar 21.

Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California, USA.

Background And Aims: To evaluate the association of self-reported race with major adverse cardiac events (MACE) and modification of this association by paraoxonase gene (1, 2, and 3) single nucleotide polymorphisms (SNPs).

Methods: Included in this longitudinal study were 12,770 black or white participants from the Atherosclerosis Risk in Communities (ARIC) cohort who completed a baseline visit (1987-1989) with genotyping. Demographic, behavioral, and health information was obtained at baseline. MACE was defined as first occurrence of myocardial infarction, stroke, or CHD-related death through 2004. Cox proportional hazards regression was used to evaluate the association between race and MACE after adjustment for age, gender, and other demographic and cardiovascular risk factors such as diabetes and hypertension. Modification of the association between SNPs and MACE was also assessed.

Results: Blacks comprised 24.6% of the ARIC cohort; overall, 14.0% of participants developed MACE. Compared with whites, blacks had 1.24 times greater hazard of MACE (OR = 1.24,95%CI = 1.10,1.39) than whites after adjusting for age, gender, BMI, cigarette and alcohol use, educational and marital status, and aspirin use. This association became nonsignificant after further adjustment for high cholesterol, diabetes, and hypertension. None of the evaluated SNPs met the significance level ( < 0.001) after Bonferroni correction for multiple comparisons.

Conclusions: No association between race and MACE was identified after adjusting for high cholesterol, diabetes, and hypertension, suggesting that comorbidities are major determinants of MACE; medical intervention with focus on lifestyle and health management could ameliorate the development of MACE. Further studies are needed to confirm this observation.
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http://dx.doi.org/10.1155/2020/7417242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114773PMC
March 2020

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Mol Psychiatry 2021 06 16;26(6):2457-2470. Epub 2020 Mar 16.

Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
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http://dx.doi.org/10.1038/s41380-020-0689-5DOI Listing
June 2021

Dissecting the genetic association of C-reactive protein with PTSD, traumatic events, and social support.

Neuropsychopharmacology 2021 05 16;46(6):1071-1077. Epub 2020 Mar 16.

Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, 06516, USA.

Inflammatory markers like C-reactive protein (CRP) have been associated with post-traumatic stress disorder (PTSD) and traumatic experiences, but the underlying mechanisms are unclear. We investigated the relationship among serum CRP, PTSD, and traits related to traumatic events and social support using genetic association data from the Psychiatric Genomics Consortium (23,185 PTSD cases and 151,309 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization (MR) analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg = 0.16, p = 0.026) and traits related to traumatic events, and the presence of social support (-0.28 < rg < 0.20; p < 0.008). We observed a bidirectional association between CRP and PTSD (CRP → PTSD: β = 0.065, p = 0.015; PTSD → CRP: β = 0.008, p = 0.009). CRP also showed a negative association with the "felt loved as a child" trait (UKB, β = -0.017, p = 0.008). Owing to the known association of socioeconomic status (SES) on PTSD, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: β = -0.22, p = 1.57 × 10; multivariate MR: β = -0.17, p = 0.005) and deprivation index (univariate MR: β = 0.38, p = 1.63 × 10; multivariate MR: β = 0.27, p = 0.016) were driving the causal estimates of "felt loved as a child" and CRP on PTSD. The present findings highlight a bidirectional genetic association between PTSD and CRP, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk.
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http://dx.doi.org/10.1038/s41386-020-0655-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115274PMC
May 2021

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci.

Clin Epigenetics 2020 03 14;12(1):46. Epub 2020 Mar 14.

Arq, Psychotrauma Reseach Expert Group, Diemen, NH, Netherlands.

Background: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD).

Methods: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72).

Results: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10, p = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10, p = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10, p = 0.042).

Conclusions: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.
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http://dx.doi.org/10.1186/s13148-020-0820-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071645PMC
March 2020

Genomic influences on self-reported childhood maltreatment.

Transl Psychiatry 2020 01 27;10(1):38. Epub 2020 Jan 27.

US Army Medical Research and Materiel Command, Fort Detrick, MD, USA.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10, FOXP1; rs10262462, p = 3.24 × 10, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r = 0.0025; p = 1.8 × 10). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r = 0.70, p = 4.65 × 10), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.
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http://dx.doi.org/10.1038/s41398-020-0706-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026037PMC
January 2020

Author Correction: A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

Sci Rep 2020 Feb 14;10(1):2996. Epub 2020 Feb 14.

Departments of Medicine, Pharmacology, Psychiatry, and Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-59785-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021692PMC
February 2020

Longitudinal epigenome-wide association studies of three male military cohorts reveal multiple CpG sites associated with post-traumatic stress disorder.

Clin Epigenetics 2020 01 13;12(1):11. Epub 2020 Jan 13.

Department of Psychiatry and Neuropsychology, School for Mental health and Neuroscience, Maastricht University, Maastricht, Limburg, Netherlands.

Background: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.

Results: Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.

Conclusions: This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.
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http://dx.doi.org/10.1186/s13148-019-0798-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958602PMC
January 2020

Molecular genetic overlap between posttraumatic stress disorder and sleep phenotypes.

Sleep 2020 04;43(4)

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, VA.

Study Objectives: Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes).

Methods: Genetic correlations were estimated utilizing linkage disequilibrium score regression (LDSC), an approach that uses GWAS summary statistics to compute genetic correlations across traits, and Mendelian randomization (MR) analyses were conducted to follow up on significant correlations.

Results: Significant, moderate genetic correlations were found between insomnia symptoms (rg range 0.36-0.49), oversleeping (rg range 0.32-0.44), undersleeping (rg range 0.48-0.49), and PTSD. In contrast, there were mixed results for continuous sleep duration and daytime sleepiness phenotypes, and chronotype was not correlated with PTSD. MR analyses did not provide evidence for casual effects of sleep phenotypes on PTSD.

Conclusion: Sleep phenotypes, particularly insomnia symptoms and extremes of sleep duration, have shared genetic etiology with PTSD, but causal relationships were not identified. This highlights the importance of further investigation into the overlapping influences on these phenotypes as sample sizes increase and new methods to investigate directionality and causality become available.
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http://dx.doi.org/10.1093/sleep/zsz257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157187PMC
April 2020
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