Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 359
Filtrar
1.
Am J Psychiatry ; : appiajp201919030256, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31906708

RESUMO

OBJECTIVE: Anxiety disorders are common and often disabling. The goal of this study was to examine the genetic architecture of anxiety disorders and anxiety symptoms, which are also frequently comorbid with other mental disorders, such as major depressive disorder. METHODS: Using one of the world's largest biobanks including genetic, environmental, and medical information, the Million Veteran Program, the authors performed a genome-wide association study (GWAS) of a continuous trait for anxiety (based on score on the Generalized Anxiety Disorder 2-item scale [GAD-2], N=199,611) as the primary analysis and self-report of physician diagnosis of anxiety disorder (N=224,330) as a secondary analysis. RESULTS: The authors identified five genome-wide significant signals for European Americans and one for African Americans on GAD-2 score. The strongest were on chromosome 3 (rs4603973) near SATB1, a global regulator of gene expression, and on chromosome 6 (rs6557168) near ESR1, which encodes an estrogen receptor. The locus identified on chromosome 7 (rs56226325, MAF=0.17) near MAD1L1 was previously identified in GWASs of bipolar disorder and schizophrenia. The authors replicated these findings in the summary statistics of two major published GWASs for anxiety, and also found evidence of significant genetic correlation between the GAD-2 score results and previous GWASs for anxiety (rg=0.75), depression (rg=0.81), and neuroticism (rg=0.75). CONCLUSIONS: This is the largest GWAS of anxiety traits to date. The authors identified novel genome-wide significant associations near genes involved with global regulation of gene expression (SATB1) and the estrogen receptor alpha (ESR1). Additionally, the authors identified a locus (MAD1L1) that may have implications for genetic vulnerability across several psychiatric disorders. This work provides new insights into genetic risk mechanisms underpinning anxiety and related psychiatric disorders.

2.
Drug Alcohol Depend ; : 107703, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31785998

RESUMO

BACKGROUND: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression. METHODS: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan. RESULTS: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits. DISCUSSION: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.

3.
Mol Neurobiol ; 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31786776

RESUMO

To investigate the causal relationship between blood metabolites and traits related to trauma-response, we combined genome-wide and metabolome-wide datasets generated from large-scale cohorts. Five trauma-response traits ascertained in the UK Biobank (52,816 < N < 117,900 individuals) were considered: (i) "Avoided activities/situations because of previous stressful experience" (Avoidance); (ii) "Felt distant from other people" (Distant); (iii) "Felt irritable/had angry outbursts" (Irritable); (iv) "Felt very upset when reminded of stressful experience" (Upset); (v) "Repeated disturbing thoughts of stressful experience". These were investigated with respect to 52 blood metabolites tested in a previous genome-wide-association study (N = 24,925 European-ancestry individuals). Linkage disequilibrium score regression, polygenic risk scoring (PRS), and Mendelian randomization were applied to the datasets. We observed that 14 metabolites were genetically correlated with trauma-response traits (p < 0.05). High-resolution PRS of 4 metabolites (citrate; glycoprotein acetyls; concentration of large very-low-density lipoproteins (VLDL) particles (LVLDLP); total cholesterol in medium particles of VLDL (MVLDLC)) were associated with trauma-response traits (false discovery rate Q < 10%). These genetic associations were partially due to causal relationships (Citrate→Upset ß = - 0.058, p = 9.1 × 10-4; Glycoproteins→Avoidance ß = 0.008, p = 0.003; LVLDLP→Distant ß = 0.008, p = 0.022; MVLDLC→Avoidance ß = 0.019, p = 3 × 10-4). No reverse associations were observed. In conclusion, our study supports causal relationships between certain blood metabolites and emotional and behavioral responses to traumatic experiences.

4.
Sci Rep ; 9(1): 18070, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792237

RESUMO

Sex differences in opioid dependence (OD) are genetically influenced. We conducted genomewide gene-by-sex interaction scans for the DSM-IV diagnosis of OD in 8,387 African-American (AA) or European-American subjects (43.6% women; 4,715 OD subjects). Among AAs, 9 SNPs were genome-wide significant at ADGRV1 (adhesion G-protein-coupled receptor V1, lead-SNP rs2366929*(C/T), p = 1.5 × 10-9) for sex-different risk of OD, with the rs2366929*C-allele increasing OD risk only for men. The top co-expressions in brain were between ADGRV1 and GRIK2 in substantia nigra and medullary inferior olivary nucleus, and between ADGRV1 and EFHC2 in frontal cortex and putamen. Significant sex-differential ADGRV1 expression from GTEx was detected in breast (Bonferroni-corrected-p < 0.002) and in heart (p < 0.0125), with nominal significance identified in brain, thyroid, lung, and stomach (p < 0.05). ADGRV1 co-expression and disease-enrichment analysis identifying the top 10 diseases showed strikingly sexually dimorphic risks. The enrichment and transcriptome analyses provided convergent support that ADGRV1 exerts a sex-different effect on OD risk. This is the first study to identify genetic variants contributing to sex differences in OD. It shows that ADGRV1 contributes to OD risk only in AA men, a finding that warrants further study.

5.
Sci Rep ; 9(1): 18774, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31801960

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31886626

RESUMO

Anxiety disorders (ANX), namely generalized anxiety, panic disorder, and phobias, are common, etiologically complex syndromes that show increasing prevalence and comorbidity throughout adolescence and beyond. Few genome-wide association studies (GWAS) examining ANX risk have been published and almost exclusively in individuals of European ancestry. In this study, we phenotyped participants from the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) to approximate DSM-based ANX diagnoses. We factor-analyzed those to create a single dimensional anxiety score for each subject. GWAS were conducted using that score within each of three ancestral groups (EUR, AFR, LAT) and then meta-analyzed across ancestries (NTotal = 16,510). We sought to (a) replicate prior ANX GWAS findings in ANGST; (b) determine whether results extended to other ancestry groups; and (c) meta-analyze with ANGST for increased power to identify novel susceptibility loci. No reliable genome-wide significant SNP associations were detected in STARRS. However, SNPs within the CAMKMT gene located in region 2p21 associated with shared ANX risk in ANGST were replicated in EUR soldiers but not other ancestry groups. Combining EUR STARRS and ANGST (N = 28,950) yielded a more robust 2p21 association signal (p = 9.08x10-11 ). Gene-based analyses supported three genes within 2p21 and LBX1 on chromosome 10. More powerful ANX genetic studies will be required to identify further loci.

7.
Transl Psychiatry ; 9(1): 309, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31740666

RESUMO

Cannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10-10), rs74722579 (P = 2.81 × 10-9), and rs1938228 (P = 1.57 × 10-8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs' association signals were increased (meta-P-values 1.32 × 10-10 and 2.60 × 10-9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.

8.
J Clin Med ; 8(12)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766499

RESUMO

Computerized device use (CDU) is societally ubiquitous but its effects on mental health are unknown. We performed genetic correlation, Mendelian randomization, and latent causal variable analyses to identify shared genetic mechanisms between psychiatric disorders (Psychiatric Genomics Consortium; 14,477 < N < 150,064) and CDU (UK Biobank; N = 361,194 individuals). Using linkage disequilibrium score regression, we detected strong genetic correlations between "weekly usage of mobile phone in last 3 months" (PhoneUse) vs. attention deficit hyperactivity disorder (ADHD; rg = 0.425, p = 4.59 × 10-29) and "plays computer games" (CompGaming) vs. schizophrenia (SCZ; rg = -0.271, p = 7.16 × 10-26). Focusing on these correlations, we used two sample MRs to detect the causal relationships between trait pairs by treating single nucleotide polymorphisms as non-modifiable risk factors underlying both phenotypes. Significant bidirectional associations were detected (PhoneUse→ADHD ß = 0.132, p = 1.89 × 10-4 and ADHD→PhoneUse ß = 0.084, p = 2.86 × 10-10; CompGaming→SCZ ß = -0.02, p = 6.46 × 10-25 and CompGaming→SCZ ß = -0.194, p = 0.005) and the latent causal variable analyses did not support a causal relationship independent of the genetic correlations between these traits. This suggests that molecular pathways contribute to the genetic overlap between these traits. Dopamine transport enrichment (Gene Ontology:0015872, pSCZvsCompGaming = 2.74 × 10-10) and DRD2 association (pSCZ = 7.94 × 10-8; pCompGaming = 3.98 × 10-25) were detected in SCZ and CompGaming and support their negative correlative relationship. FOXP2 was significantly associated with ADHD (p = 9.32 × 10-7) and PhoneUse (p = 9.00 × 10-11) with effect directions concordant with their positive genetic correlation. Our study demonstrates that epidemiological associations between psychiatric disorders and CDUs are due, in part, to the molecular mechanisms shared between them rather than a causal relationship. Our findings imply that biological mechanisms underlying CDU contribute to the psychiatric phenotype manifestation.

9.
Genetics ; 213(4): 1225-1236, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31591132

RESUMO

Longitudinal phenotypes have been increasingly available in genome-wide association studies (GWAS) and electronic health record-based studies for identification of genetic variants that influence complex traits over time. For longitudinal binary data, there remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-based method for genetic association analysis of longitudinal binary outcomes. We also develop RGMMAT, a retrospective, generalized linear mixed model-based association test. Both tests are retrospective score approaches in which genotypes are treated as random conditional on phenotype and covariates. They allow both static and time-varying covariates to be included in the analysis. Through simulations, we illustrated that retrospective association tests are robust to ascertainment and other types of phenotype model misspecification, and gain power over previous association methods. We applied L-BRAT and RGMMAT to a genome-wide association analysis of repeated measures of cocaine use in a longitudinal cohort. Pathway analysis implicated association with opioid signaling and axonal guidance signaling pathways. Lastly, we replicated important pathways in an independent cocaine dependence case-control GWAS. Our results illustrate that L-BRAT is able to detect important loci and pathways in a genome scan and to provide insights into genetic architecture of cocaine use.

10.
Transl Psychiatry ; 9(1): 249, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591379

RESUMO

Alcohol-related behaviors are moderately heritable and have ethnic-specific characteristics. At present, genetic studies for alcohol dependence (AD) in Chinese populations are underrepresented. We are the first to conduct a genome-wide association study (GWAS) for AD using 533 male alcoholics and 2848 controls of Han Chinese ethnicity and replicate our findings in 146 male alcoholics and 200 male controls. We then assessed genetic effects on AD characteristics (drinking volume/age onset/Michigan Alcoholism Screening Test (MAST)/Barratt Impulsiveness Scale (BIS-11)), and compared the polygenic risk of AD in Han Chinese with other populations (Thai, European American and African American). We found and validated two significant loci, one located in 4q23, with lead SNP rs2075633*ADH1B (Pdiscovery = 6.64 × 10-16) and functional SNP rs1229984*ADH1B (Pdiscovery = 3.93 × 10-13); and the other located in 12q24.12-12q24.13, with lead SNP rs11066001*BRAP (Pdiscovery = 1.63 × 10-9) and functional SNP rs671*ALDH2 (Pdiscovery = 3.44 × 10-9). ADH1B rs1229984 was associated with MAST, BIS_total score and average drinking volume. Polygenic risk scores from the Thai AD and European American AD GWAS were significantly associated with AD in Han Chinese, which were entirely due to the top two loci, however there was no significant prediction from African Americans. This is the first case-control AD GWAS in Han Chinese. Our findings demonstrate that these variants, which were highly linked with ALDH2 rs671 and ADH1B rs1229984, were significant modulators for AD in our Han Chinese cohort. A larger replication cohort is still needed to validate our findings.

11.
Nat Commun ; 10(1): 4558, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594949

RESUMO

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

13.
J Psychiatry Neurosci ; 44(6): 180098, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31490055

RESUMO

Background: Phenotypic heterogeneity and complicated gene­environment interplay in etiology are among the primary factors that hinder the identification of genetic variants associated with cocaine use disorder. Methods: To detect novel genetic variants associated with cocaine use disorder, we derived disease traits with reduced phenotypic heterogeneity using cluster analysis of a study sample (n = 9965). We then used these traits in genome-wide association tests, performed separately for 2070 African Americans and 1570 European Americans, using a new mixed model that accounted for the moderating effects of 5 childhood environmental factors. We used an independent sample (918 African Americans, 1382 European Americans) for replication. Results: The cluster analysis yielded 5 cocaine use disorder subtypes, of which subtypes 4 (n = 3258) and 5 (n = 1916) comprised heavy cocaine users, had high heritability estimates (h2 = 0.66 and 0.64, respectively) and were used in association tests. Seven of the 13 identified genetic loci in the discovery phase were available in the replication sample. In African Americans, rs114492924 (discovery p = 1.23 × E−8), a single nucleotide polymorphism in LINC01411, was replicated in the replication sample (p = 3.63 × E−3). In a meta-analysis that combined the discovery and replication results, 3 loci in African Americans were significant genome-wide: rs10188036 in TRAK2 (p = 2.95 × E−8), del-1:15511771 in TMEM51 (p = 9.11 × E−10) and rs149843442 near LPHN2 (p = 3.50 × E−8). Limitations: Lack of data prevented us from replicating 6 of the 13 identified loci. Conclusion: Our results demonstrate the importance of considering phenotypic heterogeneity and gene­environment interplay in detecting genetic variations that contribute to cocaine use disorder, because new genetic loci have been identified using our novel analytic method.

14.
Depress Anxiety ; 36(9): 834-845, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31385647

RESUMO

BACKGROUND: Although the ε4 allele of the apolipoprotein E (APOE) gene and posttraumatic stress disorder (PTSD) have been linked to cognitive dysfunction and dementia risk, it is unknown whether they interact to predict cognitive dysfunction. METHODS: We analyzed data from European-American (EA) veterans who participated in the National Health and Resilience in Veterans Study (NHRVS): main sample (n = 1,386) and primary replication sample (n = 509). EAs from the Yale-Penn Study cohort (n = 948) served as a second replication sample. Multivariable analyses were conducted to evaluate the predictive effects of ε4 carrier status and PTSD on cognitive functioning, with a focus on whether PTSD moderates the effect of ε4 carrier status. RESULTS: APOE ε4 allele carrier status (d = 0.15 and 0.17 in the main and primary replication NHRVS samples, respectively) and PTSD (d = 0.31 and 0.17, respectively) were independently associated with lower cognitive functioning. ε4 carriers with PTSD scored lower than those without PTSD (d = 0.68 and 1.29, respectively) with the most pronounced differences in executive function (d's = 0.75-1.50) and attention/concentration (d's = 0.62-1.33). A significant interaction was also observed in the Yale-Penn sample, with ε4 carriers with PTSD making more perseverative errors on a measure of executive function than those without PTSD (24.7% vs. 17.6%; d = 0.59). CONCLUSIONS: APOE ε4 allele carriers with PTSD have substantially greater cognitive difficulties than ε4 carriers without PTSD. These results underscore the importance of assessing, monitoring, and treating PTSD in trauma-affected individuals who are at genetic risk for cognitive decline and dementia.

15.
Alcohol Clin Exp Res ; 43(10): 2111-2121, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31386212

RESUMO

BACKGROUND: Hazardous alcohol consumption has significant adverse medical consequences. These effects may be mediated, in part, by alterations in DNA methylation. Thus, DNA methylation signatures in peripheral cells may provide biomarkers of the medical impact of alcohol use and the risk for future alcohol consumption. METHOD: Using a high-density methylation array, we characterized epigenome-wide DNA methylation in saliva cells with respect to alcohol consumption in a large cohort of male European American veterans. In this study, DNA methylation of over 870,000 CpG DNA sites was profiled in 1,135 European American men. Alcohol consumption was assessed using the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). Linear regression was applied in an epigenome-wide association study (EWAS), adjusted for confounders. Gene set enrichment analysis was performed in the KEGG database with a correction for gene length. RESULTS: We found that a total of 70 CpG sites reached EWAS-corrected significance (p < 6E-08) with small effects on alcohol consumption for individual CpG sites, including 64 new CpG sites and 6 CpG sites that were previously reported as associated with alcohol use disorder, liver function, body mass index, and lipid metabolism. The most significant CpG site was located in SLC7A11 (t = -11.34, p = 2.66E-28), a gene involved specifically in cysteine and glutamate transportation. The 70 significant CpG sites were located on 44 genes, including genes involved in amino acid transport and metabolism systems. We identified 68 pathways with a false discovery rate < 0.05. CONCLUSIONS: We identified novel DNA methylation sites associated with alcohol consumption. Results may shed light on peripheral mechanisms of alcohol consumption on adverse health outcomes among heavy drinkers.

16.
AIDS Behav ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31435887

RESUMO

We contrast three types of abstinence: quit after alcohol associated problems (Q-AP), quit for other reasons (Q-OR), and lifetime abstainer (LTA). We summarized the characteristics of people living with HIV (PLWH), and matched uninfected individuals, by levels of alcohol use and types of abstinence. We then identified factors that differentiate abstinence and determined whether the association with an alcohol biomarker or a genetic polymorphism is improved by differentiating abstinence. Among abstainers, 34% of PLWH and 38% of uninfected were Q-AP; 53% and 53% were Q-OR; and 12% and 10% were LTA. Logistic regression models found smoking, alcohol, cocaine, and hepatitis C increased odds of Q-AP, whereas smoking and marijuana decreased odds of LTA. Differentiating types of abstinence improved association. Q-APs and LTAs can be readily differentiated by an alcohol biomarker and genetic polymorphism. Differentiating type of abstinence may enhance understanding of alcohol health effects.

17.
AIDS Behav ; 23(12): 3340-3349, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31317364

RESUMO

A better understanding of predisposition to transition to high-dose, long-term opioid therapy after initial opioid receipt could facilitate efforts to prevent opioid use disorder (OUD). We extracted data on 69,268 patients in the Veterans Aging Cohort Study who received any opioid prescription between 1998 and 2015. Using latent growth mixture modelling, we identified four distinguishable dose trajectories: low (53%), moderate (29%), escalating (13%), and rapidly escalating (5%). Compared to low dose trajectory, those in the rapidly escalating dose trajectory were proportionately more European-American (59% rapidly escalating vs. 38% low); had a higher prevalence of HIV (31% vs. 29%) and hepatitis C (18% vs. 12%); and during follow-up, had a higher incidence of OUD diagnoses (13% vs. 3%); were hospitalised more often [18.1/100 person-years (PYs) vs. 12.5/100 PY]; and had higher all-cause mortality (4.7/100 PY vs. 1.8/100 PY, all p < 0.0001). These measures can potentially be used in future prevention research, including genetic discovery.

18.
Nicotine Tob Res ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294817

RESUMO

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

19.
Nat Neurosci ; 22(9): 1394-1401, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358989

RESUMO

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10-10: CAMKV; chromosome 17 closest to KANSL1, but within a large high linkage disequilibrium region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the African American cohort of the sample. Results in European Americans were replicated in the UK Biobank data. These results provide new insights into the biology of PTSD in a well-powered genome-wide association study.


Assuntos
Predisposição Genética para Doença/genética , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Estados Unidos , Veteranos , Saúde dos Veteranos
20.
Addict Biol ; : e12811, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362332

RESUMO

The United States is experiencing the worst opioid overdose (OpOD) crisis in its history. We carried out a genome-wide association study on OpOD severity among 3 477 opioid-exposed individuals, 1 019 of whom experienced OpODs, including 2 032 European Americans (EAs) (653 overdose cases), and 1 445 African Americans (AAs) (366 overdose cases). Participants were scored 1 to 4 based on their reported overdose status and the number of times that medical treatment was required. Genome-wide association study (GWAS) of EAs and AAs separately resulted in two genome-wide significant (GWS) signals in AAs but none in EAs. The first signal was represented by three closely mapped variants (rs115208233, rs116181528, and rs114077267) located near mucolipin 1 (MCOLN1) and patatin-like phospholipase domain containing 6 (PNPLA6), and the other signal was represented by rs369098800 near dead-box helicase 18 (DDX18). There were no additional GWS signals in the trans-population meta-analysis, so that post-GWAS analysis focused on these loci. In network analysis, MCOLN1 was coexpressed with PNPLA6, but only MCOLN1-associated genes were enriched in functional categories relevant to OpOD, including calcium and cation channel activities; no enrichment was observed for PNPLA6-associated genes. Drug repositioning analysis was carried out in the connectivity map (CMap) database for MCOLN1 (PNPLA6 was not available in CMap) and showed that the opioid agonist drug-induced expression profile is similar to that of MCOLN1 overexpression and yielded the highest-ranked expression profile of 83 drug classes. Thus, MCOLN1 may be a risk gene for OpOD, but replication is needed. This knowledge could be helpful in the identification of drug targets for preventing OpOD.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA