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1.
Artigo em Inglês | MEDLINE | ID: mdl-34750568

RESUMO

Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modeling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance-specific Ns range: 82,707-435,563) while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk-taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk-taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for the genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology.

2.
Mol Psychiatry ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34725455

RESUMO

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-American US veterans (N = 1326). Results revealed that 8.8% (n = 115) of veterans developed new-onset SI, 4.0% (n = 52) had chronic SI, 3.4% (n = 31) had remitted SI, and 83.8% (n = 1128) denied SI over the study period. Suicidality PRSstandardized was positively associated with chronic SI (relative risk ratio [RRR] = 4.54, 95% confidence interval [CI] = 1.01-20.48) and new-onset SI (RRR = 2.97, 95%CI = 1.22-7.23), and negatively associated with remitted SI (RRR = 0.12, 95% CI = 0.02-0.60). Among veterans with higher suicidality PRS, those with higher baseline dispositional optimism had a lower likelihood of chronic SI (RRR = 0.67, 95% CI = 0.49-0.91) and higher likelihood of remitted SI (RRR = 1.98, 95% CI = 1.18-3.31). Among veterans with higher suicidality PRS, those with higher baseline levels of social support were less likely to develop new-onset SI (RRR = 0.95, 95% CI = 0.92-0.99). These interaction effects were enriched for genes implicated in neuron recognition and development, while the PRS main effect was enriched for genes involved in mannosylation. Collectively, results of this study suggest that suicidality PRS is linked prospectively to symptomatic courses of SI, and that dispositional optimism and social support moderate these associations. Interventions targeting these modifiable psychosocial factors may help mitigate risk of SI in veterans with high polygenic risk for suicidality.

3.
Transl Psychiatry ; 11(1): 586, 2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34775470

RESUMO

Alcohol drinking and tobacco smoking are hazardous behaviors associated with a wide range of adverse health outcomes. In this study, we explored the association of polygenic risk scores (PRS) related to drinks per week, age of smoking initiation, smoking initiation, cigarettes per day, and smoking cessation with 433 psychiatric and behavioral traits in 4498 children and young adults (aged 8-21) of European ancestry from the Philadelphia neurodevelopmental cohort. After applying a false discovery rate multiple testing correction accounting for the number of PRS and traits tested, we identified 36 associations related to psychotic symptoms, emotion and age recognition social competencies, verbal reasoning, anxiety-related traits, parents' education, and substance use. These associations were independent of the genetic correlations among the alcohol-drinking and tobacco-smoking traits and those with cognitive performance, educational attainment, risk-taking behaviors, and psychopathology. The removal of participants endorsing substance use did not affect the associations of each PRS with psychiatric and behavioral traits identified as significant in the discovery analyses. Gene-ontology enrichment analyses identified several neurobiological processes underlying mechanisms of the PRS associations we report. In conclusion, we provide novel insights into the genetic overlap of smoking and drinking behaviors in children and young adults, highlighting their independence from psychopathology and substance use.

4.
Drug Alcohol Depend ; 229(Pt B): 109047, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34710713

RESUMO

BACKGROUND: The Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA) was developed to assess substance-use disorders and other psychiatric traits. We translated the SSADDA into Chinese and evaluated its inter-rater reliability and concurrent validity in diagnosing DSM-IV methamphetamine (MA) dependence and DSM-5 MA-use disorder (MUD). METHODS: The sample comprised 231 participants who were interviewed using the Chinese SSADDA and the Mini-International Neuropsychiatric Interview (Chinese MINI) for concurrent validation. Of the 231 participants, 191 were interviewed by two different interviewers two weeks apart. We evaluated the inter-rater reliability and concurrent validity of the diagnoses using percent agreement and Cohen's kappa coefficient (κ). Cohen's linear weighted kappa was used to assess the reliability of DSM-5 MUD severity. RESULTS: It showed good inter-rater reliability and no significant differences among the DSM-5 MUD (κ = 0.71), DSM-IV MA abuse or dependence (κ = 0.72), and the DSM-IV diagnoses of MA dependence (κ = 0.66) and abuse (κ = 0.68) tested separately. The weighted kappa was 0.67 across the three DSM-5 MUD severity levels. The reliability of each individual diagnostic criterion for DSM-5 MUD ranged from fair to excellent (κ = 0.41-0.80), except for "repeated attempts to quit/control use" (κ = 0.38). The concurrent validity based on MINI-derived diagnoses ranged from good to excellent (κ = 0.65-0.78). CONCLUSIONS: This study shows that the Chinese version of SSADDA has good reliability and validity among Chinese MA users.

5.
Drug Alcohol Depend ; 229(Pt B): 109115, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34710714

RESUMO

BACKGROUND: Machine learning (ML) models are beginning to proliferate in psychiatry, however machine learning models in psychiatric genetics have not always accounted for ancestry. Using an empirical example of a proposed genetic test for OUD, and exploring a similar test for tobacco dependence and a simulated binary phenotype, we show that genetic prediction using ML is vulnerable to ancestral confounding. METHODS: We utilize five ML algorithms trained with 16 brain reward-derived "candidate" SNPs proposed for commercial use and examine their ability to predict OUD vs. ancestry in an out-of-sample test set (N = 1000, stratified into equal groups of n = 250 cases and controls each of European and African ancestry). We rerun analyses with 8 random sets of allele-frequency matched SNPs. We contrast findings with 11 genome-wide significant variants for tobacco smoking. To document generalizability, we generate and test a random phenotype. RESULTS: None of the 5 ML algorithms predict OUD better than chance when ancestry was balanced but were confounded with ancestry in an out-of-sample test. In addition, the algorithms preferentially predicted admixed subpopulations. Random sets of variants matched to the candidate SNPs by allele frequency produced similar bias. Genome-wide significant tobacco smoking variants were also confounded by ancestry. Finally, random SNPs predicting a random simulated phenotype show that the bias attributable to ancestral confounding could impact any ML-based genetic prediction. CONCLUSIONS: Researchers and clinicians are encouraged to be skeptical of claims of high prediction accuracy from ML-derived genetic algorithms for polygenic traits like addiction, particularly when using candidate variants.

6.
Neurobiol Stress ; 15: 100400, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34611531

RESUMO

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 (r g ) 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 r g relationships in females (e.g., childhood physical abuse and body mass index, BMI r g  = 0.245, p = 3.88 × 10-10) and 21 significant r g relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage; r g  = 0.405, p = 4.42 × 10-10). 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 × 10-9), traumatic experiences (e.g., childhood physical abuse→waist circumference; beta = 0.055, p = 5.07 × 10-4), and childhood neglect (e.g., "someone to take you to doctor when needed as a child"→BMI; beta = -0.594, p = 1.09 × 10-5). 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 × 10-3). 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.

7.
Nat Neurosci ; 24(10): 1367-1376, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34446935

RESUMO

Behaviors and disorders related to self-regulation, such as substance use, antisocial behavior and attention-deficit/hyperactivity disorder, are collectively referred to as externalizing and have shared genetic liability. We applied a multivariate approach that leverages genetic correlations among externalizing traits for genome-wide association analyses. By pooling data from ~1.5 million people, our approach is statistically more powerful than single-trait analyses and identifies more than 500 genetic loci. The loci were enriched for genes expressed in the brain and related to nervous system development. A polygenic score constructed from our results predicts a range of behavioral and medical outcomes that were not part of genome-wide analyses, including traits that until now lacked well-performing polygenic scores, such as opioid use disorder, suicide, HIV infections, criminal convictions and unemployment. Our findings are consistent with the idea that persistent difficulties in self-regulation can be conceptualized as a neurodevelopmental trait with complex and far-reaching social and health correlates.


Assuntos
Comportamento Aditivo/genética , Estudos de Associação Genética , Autocontrole , Transtorno do Deficit de Atenção com Hiperatividade/genética , Comportamento Aditivo/psicologia , Sintomas Comportamentais/genética , Sintomas Comportamentais/psicologia , Biologia Computacional , Crime/psicologia , Estudo de Associação Genômica Ampla , Infecções por HIV/genética , Infecções por HIV/psicologia , Humanos , Metanálise como Assunto , Herança Multifatorial , Análise Multivariada , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/psicologia , Reprodutibilidade dos Testes , Suicídio , Desemprego
8.
Psychol Med ; : 1-9, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231451

RESUMO

BACKGROUND: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. METHODS: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. RESULTS: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). CONCLUSIONS: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

9.
Nat Rev Genet ; 22(11): 712-729, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34211176

RESUMO

Substance use disorders (SUDs) are conditions in which the use of legal or illegal substances, such as nicotine, alcohol or opioids, results in clinical and functional impairment. SUDs and, more generally, substance use are genetically complex traits that are enormously costly on an individual and societal basis. The past few years have seen remarkable progress in our understanding of the genetics, and therefore the biology, of substance use and abuse. Various studies - including of well-defined phenotypes in deeply phenotyped samples, as well as broadly defined phenotypes in meta-analysis and biobank samples - have revealed multiple risk loci for these common traits. A key emerging insight from this work establishes a biological and genetic distinction between quantity and/or frequency measures of substance use (which may involve low levels of use without dependence), versus symptoms related to physical dependence.


Assuntos
Estudo de Associação Genômica Ampla , Transtornos Relacionados ao Uso de Substâncias/genética , Alcoolismo/metabolismo , Alcoolismo/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Epigenômica , Humanos , Drogas Ilícitas , Nicotina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/patologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-34288400

RESUMO

Suicide is a major public health problem. The contribution of common genetic variants for major depressive disorder (MDD) independent of personal and parental history of MDD has not been established. Polygenic risk score (using PRS-CS) for MDD was calculated for US Army soldiers of European ancestry. Associations between polygenic risk for MDD and lifetime suicide attempt (SA) were tested in models that also included parental or personal history of MDD. Models were adjusted for age, sex, tranche (where applicable), and 10 principal components reflecting ancestry. In the first cohort, 417 (6.3%) of 6,573 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.83, 95% CI:3.09-4.75] and parental history of MDD [OR = 1.43, 95% CI:1.13-1.82 for one parent and OR = 1.64, 95% CI:1.20-2.26 for both parents), MDD PRS was significantly associated with SA (OR = 1.22 [95% CI:1.10-1.36]). In the second cohort, 204 (4.2%) of 4,900 soldiers reported a lifetime history of SA. In a multivariable model that included personal [OR = 3.82, 95% CI:2.77-5.26] and parental history of MDD [OR = 1.42, 95% CI:0.996-2.03 for one parent and OR = 2.21, 95% CI:1.33-3.69 for both parents) MDD PRS continued to be associated (at p = .0601) with SA (OR = 1.15 [95% CI:0.994-1.33]). A soldier's PRS for MDD conveys information about likelihood of a lifetime SA beyond that conveyed by two predictors readily obtainable by interview: personal or parental history of MDD. Results remain to be extended to prospective prediction of incident SA. These findings portend a role for PRS in risk stratification for suicide attempts.

11.
Transl Psychiatry ; 11(1): 363, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34226506

RESUMO

Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10-10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10-7, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10-7, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (padj = 3.6 × 10-3), an anxiety disorder in EAs (padj = 2.1 × 10-4), and ADHD in both AAs (padj = 3.0 × 10-33) and EAs (padj = 6.7 × 10-35). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.


Assuntos
Estudo de Associação Genômica Ampla , Transtornos Relacionados ao Uso de Substâncias , Afro-Americanos , Autoantígenos , Grupo com Ancestrais do Continente Europeu , Predisposição Genética para Doença , Humanos , Proteínas de Membrana Transportadoras , Polimorfismo de Nucleotídeo Único , Transtornos Relacionados ao Uso de Substâncias/genética
12.
Brain Sci ; 11(7)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202057

RESUMO

BACKGROUND: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990-1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). METHODS: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene-gene and gene-environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. CONCLUSIONS: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

13.
Explor Med ; 2: 60-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34124712

RESUMO

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted. Methods: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts. Results: In the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 x 10-8 were identified, one (rs61835088 = 1.03 x 10-8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 x 10-8) and 9 (rs7032521, P = 3.30 x 10-8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 x 10-9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 x 10-8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD. Conclusions: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.

14.
Psychol Med ; : 1-10, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34085609

RESUMO

BACKGROUND: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are commonly reported co-occurring mental health consequences of psychological trauma exposure. The disorders have high genetic overlap. Trauma is a complex phenotype but research suggests that trauma sensitivity has a heritable basis. We investigated whether sensitivity to trauma in those with MDD reflects a similar genetic component in those with PTSD. METHODS: Genetic correlations between PTSD and MDD in individuals reporting trauma and MDD in individuals not reporting trauma were estimated, as well as with recurrent MDD and single-episode MDD, using genome-wide association study (GWAS) summary statistics. Genetic correlations were replicated using PTSD data from the Psychiatric Genomics Consortium and the Million Veteran Program. Polygenic risk scores were generated in UK Biobank participants who met the criteria for lifetime MDD (N = 29 471). We investigated whether genetic loading for PTSD was associated with reporting trauma in these individuals. RESULTS: Genetic loading for PTSD was significantly associated with reporting trauma in individuals with MDD [OR 1.04 (95% CI 1.01-1.07), Empirical-p = 0.02]. PTSD was significantly more genetically correlated with recurrent MDD than with MDD in individuals not reporting trauma (rg differences = ~0.2, p < 0.008). Participants who had experienced recurrent MDD reported significantly higher rates of trauma than participants who had experienced single-episode MDD (χ2 > 166, p < 0.001). CONCLUSIONS: Our findings point towards the existence of genetic variants associated with trauma sensitivity that might be shared between PTSD and MDD, although replication with better powered GWAS is needed. Our findings corroborate previous research highlighting trauma exposure as a key risk factor for recurrent MDD.

15.
Nat Neurosci ; 24(7): 954-963, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34045744

RESUMO

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.


Assuntos
Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Veteranos
16.
Psychol Med ; : 1-9, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33947479

RESUMO

BACKGROUND: Definition of disorder subtypes may facilitate precision treatment for posttraumatic stress disorder (PTSD). We aimed to identify PTSD subtypes and evaluate their associations with genetic risk factors, types of stress exposures, comorbidity, and course of PTSD. METHODS: Data came from a prospective study of three U.S. Army Brigade Combat Teams that deployed to Afghanistan in 2012. Soldiers with probable PTSD (PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition ≥31) at three months postdeployment comprised the sample (N = 423) for latent profile analysis using Gaussian mixture modeling and PTSD symptom ratings as indicators. PTSD profiles were compared on polygenic risk scores (derived from external genomewide association study summary statistics), experiences during deployment, comorbidity at three months postdeployment, and persistence of PTSD at nine months postdeployment. RESULTS: Latent profile analysis revealed profiles characterized by prominent intrusions, avoidance, and hyperarousal (threat-reactivity profile; n = 129), anhedonia and negative affect (dysphoric profile; n = 195), and high levels of all PTSD symptoms (high-symptom profile; n = 99). The threat-reactivity profile had the most combat exposure and the least comorbidity. The dysphoric profile had the highest polygenic risk for major depression, and more personal life stress and co-occurring major depression than the threat-reactivity profile. The high-symptom profile had the highest rates of concurrent mental disorders and persistence of PTSD. CONCLUSIONS: Genetic and trauma-related factors likely contribute to PTSD heterogeneity, which can be parsed into subtypes that differ in symptom expression, comorbidity, and course. Future studies should evaluate whether PTSD typology modifies treatment response and should clarify distinctions between the dysphoric profile and depressive disorders.

17.
Drug Alcohol Depend ; 225: 108762, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34049101

RESUMO

BACKGROUND: In an initial study, we reported that topiramate reduced heavy drinking among individuals who sought to reduce their drinking and that the effect was moderated by a single nucleotide polymorphism (SNP; rs2832407) in GRIK1, which encodes the kainate GluK1 receptor subunit (Kranzler et al., 2014). In a subsequent study that prospectively randomized patients to medication group based on their rs2832407 genotype, we replicated the main effect of topiramate but not the moderating effect of the SNP (Kranzler et al., 2021). Given the similar design of the two studies, here we combined the findings to provide greater statistical power to test the pharmacogenetic effect. MATERIAL AND METHODS: This secondary analysis of two 12-week, randomized controlled trials of topiramate included a total of 292 European-ancestry individuals (67.1 % male; topiramate: 48.3 %, placebo: 51.7 %) with problematic alcohol use. Using MANOVA, we examined changes in self-reported alcohol consumption, problems resulting from alcohol use, and quality of life, and the biomarker γ-glutamyltransferase. To test the pharmacogenetic hypothesis, all patients were genotyped for rs2832407. RESULTS: There was a significant overall effect of topiramate on the alcohol-related outcomes (partial η2 = 0.134, p < 0.001), with follow-up analyses showing significant reductions in percent heavy drinking days (Cohen's d = 0.49), percent days abstinent (d = 0.23), drinks/day (d = 0.29) and alcohol-related problems (d = 0.45). Overall, the moderating effect of the SNP was non-significant (partial η² = 0.026, p = 0.37). CONCLUSIONS: Although topiramate is an efficacious medication for reducing drinking and alcohol-related problems among patients with problematic alcohol use, rs2832407 does not appear to moderate its therapeutic effects. www.clinicaltrials.gov registrations: NCT00626925 and NCT02371889.


Assuntos
Alcoolismo , Consumo de Bebidas Alcoólicas , Alcoolismo/tratamento farmacológico , Alcoolismo/genética , Feminino , Frutose/efeitos adversos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Qualidade de Vida , Topiramato/uso terapêutico
18.
Addiction ; 116(11): 3227-3234, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33950550

RESUMO

BACKGROUND AND AIMS: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking. DESIGN: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ. SETTING: Genome-wide association studies were published previously as part of international consortia. PARTICIPANTS: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry. MEASUREMENTS: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses. FINDINGS: Genetic liability to CUD was significantly associated with SCZ [ß = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (ß = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence). CONCLUSIONS: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.


Assuntos
Cannabis , Esquizofrenia , Estudo de Associação Genômica Ampla , Genômica , Humanos , Esquizofrenia/genética
19.
World J Biol Psychiatry ; 22(10): 792-799, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33821766

RESUMO

OBJECTIVES: To examine whether attachment style moderates the relationship between polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) re-experiencing (PTSDREX) symptoms and the severity of and positive screen for traumatic loss-related PTSD. METHODS: Data were analysed from 631 US veterans who endorsed 'unexpected death of a loved one' as their 'worst' traumatic event. Multivariable models evaluated the association between PRS for PTSDREX, attachment style, and their interaction in predicting severity and positive screen for PTSD. A gene enrichment analysis was conducted to identify possible molecular mechanisms underlying the association between PTSDREX PRS and PTSD. RESULTS: PTSDREX PRS (ß = 0.17; odds ratio [OR] = 1.85), attachment style (ß= -0.33; OR = 0.14), and PTSDREX PRS × attachment style interaction (ß= -0.12; OR = 0.53) were significant predictors of the severity and positive screen for PTSD. The most significant gene set detected was the gene ontology (GO) cellular component podosome set (GO:0002102, p < 3.95 × 10-5). CONCLUSIONS: Having a secure attachment style may help mitigate polygenic risk for developing traumatic loss-related PTSD in US veterans. Podosomes, which are implicated in inflammatory and neuroplasticity processes, may contribute to the genetic liability to developing loss-related PTSD. Psychological treatments targeting attachment security may help mitigate increased polygenic risk for loss-related PTSD in this population.

20.
Hum Mol Genet ; 30(14): 1360-1370, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-33831179

RESUMO

Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10-6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10-7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B-show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug-gene interactions, we identified process 'transmission across chemical synapses' (P < 2.78 × 10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.

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