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1.
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.

2.
Nat Neurosci ; 22(7): 1196, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168101

RESUMO

Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

3.
Drug Alcohol Depend ; 198: 168-175, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939374

RESUMO

BACKGROUND: Understanding differences in nicotine dependence assessments' ability to predict smoking cessation is complicated by variation in quit attempt contexts. Pregnancy reduces this variation, as each pregnant smoker receives the same strong cessation incentive. Cigarette smoking during pregnancy (SDP) provides a powerful paradigm for analyzing the interplay between nicotine dependence measures and sociodemographics in predicting cessation failure. METHODS: Data from a female twin cohort (median birth year 1980), assessed in teens and early twenties, were merged with birth records to identify those with smoking history who experienced childbirth (N = 1657 births, N = 763 mothers). Logistic regression predicting SDP, as a function of birth record sociodemographic variables, generated a sociodemographic risk-score. Further analysis incorporated the risk-score with data from research interviews on DSM-IV-Nicotine Dependence symptom count, Heaviness of Smoking Index. RESULTS: Low maternal educational level, younger age at childbirth, and being unmarried all contributed risk for SDP. In addition to sociodemographic risk-score, the best predictors of SDP included HSI-score (OR:1.51), their two-way interaction (OR:0.39; reduced impact of dependence at intermediate-high sociodemographic risk), history of ≥ two failed quit attempts (OR:1.38), and a dummy variable for prior pregnancy at time of assessment (OR:1.82). DSM-IV-Nicotine Dependence symptoms underperformed the Heaviness of Smoking Index and did not improve prediction when added to the best model. CONCLUSIONS: The 2-item Heaviness of Smoking Index measure and report of ≥ two failed quit attempts performed best for predicting SDP. The contribution of either nicotine dependence measure to SDP risk was diminished at increased levels of sociodemographic risk.

4.
Am J Med Genet B Neuropsychiatr Genet ; 180(6): 439-447, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30708398

RESUMO

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

5.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
6.
Alcohol Clin Exp Res ; 43(3): 473-482, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30589442

RESUMO

BACKGROUND: Alcohol dependence and long-term excessive alcohol use may cause liver damage, but only some patients develop cirrhosis. Similarly, high alcohol intake without evident liver disease often but not always produces abnormal enzymatic liver function tests (LFTs), particularly gamma-glutamyl transferase (GGT). We postulate that the factors predisposing to cirrhosis in alcoholics and to liver enzyme abnormality in drinkers are similar, and that biochemical LFTs could therefore be useful as markers of risk of alcoholic liver disease in excessive drinkers. METHODS: Data from participants in twin and twin-family studies on alcohol use and dependence were used to identify 1,003 people who had reported excessive alcohol intake (28 drinks or more per week). A total of 962 of these provided blood for biochemical tests at the same time. Body mass index (BMI) and biomarkers of metabolic syndrome, inflammation, and iron stores were used in logistic regression with abnormality in serum GGT, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) as outcomes. We conducted genome-wide association analyses for GGT, ALT, and AST separately in the group reporting excessive alcohol intake (N = 951) and a low-intake group reporting 14 drinks or fewer per week (N = 8,716), and compared results. RESULTS: Abnormal GGT and ALT among excessive drinkers were associated with higher BMI, triglycerides, insulin, uric acid, C-reactive protein, ferritin, and transferrin saturation; and with lower high-density-lipoprotein cholesterol. Abnormal AST was associated with triglycerides, ferritin, and transferrin saturation. ALT was significantly associated with variants at reported genetic loci for alcoholic liver disease (PNPLA3, rs738409, p = 0.0076; TM6SF2, rs10401969, p = 0.0076; HSD17B13, rs10433879, p = 0.0024). CONCLUSIONS: Known risk factors for alcoholic cirrhosis including obesity and markers of metabolic syndrome, iron overload and inflammation are associated with liver enzyme abnormality in excessive drinkers.

7.
Nat Neurosci ; 21(9): 1161-1170, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150663

RESUMO

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

8.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

9.
Psychol Med ; : 1-10, 2018 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-29729685

RESUMO

BACKGROUND: Prior research has documented shared heritable contributions to non-suicidal self-injury (NSSI) and suicidal ideation (SI) as well as NSSI and suicide attempt (SA). In addition, trauma exposure has been implicated in risk for NSSI and suicide. Genetically informative studies are needed to determine common sources of liability to all three self-injurious thoughts and behaviors, and to clarify the nature of their associations with traumatic experiences. METHODS: Multivariate biometric modeling was conducted using data from 9526 twins [59% female, mean age = 31.7 years (range 24-42)] from two cohorts of the Australian Twin Registry, some of whom also participated in the Childhood Trauma Study and the Nicotine Addiction Genetics Project. RESULTS: The prevalences of high-risk trauma exposure (HRT), NSSI, SI, and SA were 24.4, 5.6, 27.1, and 4.6%, respectively. All phenotypes were moderately to highly correlated. Genetic influences on self-injurious thoughts and behaviors and HRT were significant and highly correlated among men [rG = 0.59, 95% confidence interval (CI) (0.37-0.81)] and women [rG = 0.56 (0.49-0.63)]. Unique environmental influences were modestly correlated in women [rE = 0.23 (0.01-0.45)], suggesting that high-risk trauma may confer some direct risk for self-injurious thoughts and behaviors among females. CONCLUSIONS: Individuals engaging in NSSI are at increased risk for suicide, and common heritable factors contribute to these associations. Preventing trauma exposure may help to mitigate risk for self-harm and suicide, either directly or indirectly via reductions in liability to psychopathology more broadly. In addition, targeting pre-existing vulnerability factors could significantly reduce risk for life-threatening behaviors among those who have experienced trauma.

10.
Dev Cogn Neurosci ; 32: 97-106, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29606560

RESUMO

Biospecimen collection in the Adolescent Brain Cognitive Development (ABCD) study - of hair samples, shed deciduous (baby) teeth, and body fluids - will serve dual functions of screening for study eligibility, and providing measures of biological processes thought to predict or correlate with key study outcomes on brain and cognitive development. Biosamples are being collected annually to screen for recency of drug use prior to the neuroimaging or cognitive testing visit, and to store for the following future studies: (1) on the effects of exposure to illicit and recreational drugs (including alcohol and nicotine); (2) of pubertal hormones on brain and cognitive developmental trajectories; (3) on the contribution of genomics and epigenomics to child and adolescent development and behavioral outcomes; and (4) with pre- and post-natal exposure to environmental neurotoxicants and drugs of abuse measured from novel tooth analyses. The present manuscript describes the rationales for inclusion and selection of the specific biospecimens, methodological considerations for each measure, future plans for assessment of biospecimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Encéfalo/crescimento & desenvolvimento , Cognição/fisiologia , Neuroimagem/métodos , Manejo de Espécimes/métodos , Adolescente , Criança , Feminino , Humanos
11.
Addict Biol ; 2018 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-29532581

RESUMO

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we detected genome-wide significant association on 16p12 with smoking quantity (P = 8.5 × 10-9 ), near CLEC19A. The lead-SNP stands 22 kb from a binding site for NF-κB transcription factors, which play a role in the neurotrophin signaling pathway. However, the signal was not replicated in an independent Finnish population-based sample, FINRISK (n = 6763). Second, nicotine withdrawal showed association on 2q21 in an intron of TMEM163 (P = 2.1 × 10-9 ), and on 11p15 (P = 6.6 × 10-8 ) in an intron of AP2A2, and P = 4.2 × 10-7 for a missense variant in MUC6, both involved in the neurotrophin signaling pathway). Third, association was detected on 3p22.3 for maximum number of cigarettes smoked per day (P = 3.1 × 10-8 ) near STAC. Associating CLEC19A and TMEM163 SNPs were annotated to influence gene expression or methylation. The neurotrophin signaling pathway has previously been associated with smoking behavior. Our findings further support the role in nicotine addiction.

12.
Addiction ; 113(1): 158-166, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28833688

RESUMO

BACKGROUND AND AIMS: Both high alcohol intake and alcohol dependence increase mortality, and both are associated with smoking. We aimed to compare the associations of quantity of alcohol, number of alcohol-related symptoms and smoking history with all-cause mortality, and to assess symptom count and smoking history as confounders or mediators of the effects of high alcohol intake. DESIGN: Survival was analysed by Cox regression with sex, body mass index, alcohol intake (overall and by beverage), maximum drinks on any day, alcohol symptom count and smoking status as potential predictors of age at death. SETTING: Australia. PARTICIPANTS: Participants were apparently healthy volunteers consisting of 33 593 Australian adult twins and their relatives who completed questionnaires or interviews between 1979 and 2005. MEASUREMENTS: Data on alcohol use, smoking and occurrence of symptoms related to alcohol use disorders and death records from the Australian National Death Index. FINDINGS: A total of 3764 participants were matched with deaths occurring within Australia up to July 2014. Individually, alcohol intake [hazard ratio (HR) = 1.0082, 95% confidence interval (CI) = 1.0063-1.0102, per drink per week], beer intake (HR = 1.0159, 95% CI = 1.0123-1.0195, per drink per week), life-time maximum number of drinks in 1 day (HR = 1.0176, 95% CI = 1.0130-1.0221, per drink), symptom count (HR = 1.0867, 95% CI = 1.0633-1.1106, per symptom) and smoking status (HR = 2.82, 95% CI = 2.52-3.16 for smokers of 10+ cigarettes/day versus never-smokers) were each significant predictors of all-cause mortality. After adjustment for the independently significant predictors alcohol symptom count and smoking status, alcohol intake was no longer significant (adjusted HR = 1.0012 per drink per week, 95% CI = 0.9979-1.0145). CONCLUSIONS: Number of symptoms related to high alcohol intake and tobacco smoking appear to account for the positive association between alcohol consumption and premature mortality.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Alcoolismo/epidemiologia , Fumar Cigarros/epidemiologia , Mortalidade Prematura , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Cerveja , Causas de Morte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Fumar/epidemiologia , Análise de Sobrevida , Fumar Tabaco
13.
Alcohol Clin Exp Res ; 42(1): 120-127, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29063613

RESUMO

BACKGROUND: Few studies examine risk to offspring who experience both parental alcohol problems and parental separation and still fewer consider gender of the affected parent. We examined interactive effects of maternal versus paternal alcohol problems and parental separation on timing of first alcoholic drink in daughters. METHODS: Data were drawn from a sample of 3,539 European (or other) ancestry (EA) and 611 African ancestry (AA) female twins born between 1975 and 1985, median age 15 at first assessment. Cox proportional hazards regression models were estimated predicting age at first full drink from parental history of alcohol problems (mother only, father only, or both parents), parental separation during childhood, and the interaction of parental alcohol problems and parental separation. Cox models were estimated without and with adjustment for correlated risk factors, separately for EA and AA twins. RESULTS: For both EA and AA twins, a significant interaction between parental separation and mother-only alcohol problems was observed, suggesting reduced risk of drinking associated with mother-only alcohol problems in separated versus intact families. CONCLUSIONS: Findings highlight parental separation as an important moderator of risk to children of mothers who have a history of problem drinking, with interactive effects observed consistently across racial group. To identify underlying processes, additional research is needed with more detailed characterization of separated families where mother only has a history of alcohol problems.

14.
Prev Sci ; 19(6): 795-804, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28875252

RESUMO

The current investigation assessed for moderating effects of childhood trauma on genetic and environmental contributions to timing of alcohol use initiation and alcohol use disorder in African American (AA) and European American (EA) women. Data were drawn from diagnostic telephone interviews conducted with 3786 participants (14.6% AA) in a longitudinal female twin study. Childhood trauma was defined alternately as child maltreatment and more broadly to include other events (e.g., witnessing violence). Phenotypic associations between childhood trauma and alcohol outcomes were estimated using logistic regression analyses. Twin modeling was conducted to test for moderating effects of childhood trauma on the contributions of genetic and environmental factors to timing of initiation and alcohol use disorder. Under both definitions, childhood trauma was associated with early initiation (relative risk ratios: 1.90, 1.72) and alcohol use disorder (odds ratios: 1.92, 1.76). Yet gene by environment effects were observed only for child maltreatment and timing of initiation in EA women, with heritable influences less prominent in those who had experienced child maltreatment (0.35, 95% CI: 0.05-0.66 vs. 0.52, 95% CI: 0.30-0.73). We found more similarities than differences in the association of childhood trauma with alcohol outcomes across racial/ethnic groups, trauma type, and stages of alcohol use. However, findings suggest that the relative contribution of genetic factors to alcohol outcomes differs by childhood maltreatment history in EA women specifically in the earliest stage of alcohol use.

15.
Biol Psychiatry ; 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-29129318

RESUMO

BACKGROUND: The heterogeneity of genetic effects on major depressive disorder (MDD) may be partly attributable to moderation of genetic effects by environment, such as exposure to childhood trauma (CT). Indeed, previous findings in two independent cohorts showed evidence for interaction between polygenic risk scores (PRSs) and CT, albeit in opposing directions. This study aims to meta-analyze MDD-PRS × CT interaction results across these two and other cohorts, while applying more accurate PRSs based on a larger discovery sample. METHODS: Data were combined from 3024 MDD cases and 2741 control subjects from nine cohorts contributing to the MDD Working Group of the Psychiatric Genomics Consortium. MDD-PRS were based on a discovery sample of ∼110,000 independent individuals. CT was assessed as exposure to sexual or physical abuse during childhood. In a subset of 1957 cases and 2002 control subjects, a more detailed five-domain measure additionally included emotional abuse, physical neglect, and emotional neglect. RESULTS: MDD was associated with the MDD-PRS (odds ratio [OR] = 1.24, p = 3.6 × 10-5, R2 = 1.18%) and with CT (OR = 2.63, p = 3.5 × 10-18 and OR = 2.62, p = 1.4 ×10-5 for the two- and five-domain measures, respectively). No interaction was found between MDD-PRS and the two-domain and five-domain CT measure (OR = 1.00, p = .89 and OR = 1.05, p = .66). CONCLUSIONS: No meta-analytic evidence for interaction between MDD-PRS and CT was found. This suggests that the previously reported interaction effects, although both statistically significant, can best be interpreted as chance findings. Further research is required, but this study suggests that the genetic heterogeneity of MDD is not attributable to genome-wide moderation of genetic effects by CT.

16.
JAMA Psychiatry ; 74(12): 1242-1250, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28979981

RESUMO

Importance: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic variants have, however, not been identified. Objectives: To estimate the single-nucleotide polymorphism-based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. Design, Setting, and Participants: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). Main Outcome and Measures: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. Results: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = -0.52, P = .005) was detected. Conclusions and Relevance: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.


Assuntos
Transtorno da Personalidade Antissocial , Transtorno da Conduta , Adolescente , Adulto , Transtorno da Personalidade Antissocial/epidemiologia , Transtorno da Personalidade Antissocial/genética , Transtorno da Personalidade Antissocial/psicologia , Criança , Transtorno da Conduta/epidemiologia , Transtorno da Conduta/genética , Transtorno da Conduta/psicologia , Meio Ambiente , Feminino , Finlândia/epidemiologia , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fatores Sexuais
17.
J Stud Alcohol Drugs ; 78(5): 745-753, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28930062

RESUMO

OBJECTIVE: Few studies linking single motherhood and maternal smoking during pregnancy consider correlated risk from problem substance use beyond history of smoking and concurrent use of alcohol. In the present study, we used propensity score methods to examine whether the risk of smoking during pregnancy associated with single motherhood is the result of potential confounders, including alcohol dependence. METHOD: Data were drawn from mothers participating in a birth cohort study of their female like-sex twin offspring (n = 257 African ancestry; n = 1,711 European or other ancestry). We conducted standard logistic regression models predicting smoking during pregnancy from single motherhood at twins' birth, followed by propensity score analyses comparing single-mother and two-parent families stratified by predicted probability of single motherhood. RESULTS: In standard models, single motherhood predicted increased risk of smoking during pregnancy in European ancestry but not African ancestry families. In propensity score analyses, rates of smoking during pregnancy were elevated in single-mother relative to two-parent European ancestry families across much of the spectrum a priori risk of single motherhood. Among African ancestry families, within-strata comparisons of smoking during pregnancy by single-mother status were nonsignificant. CONCLUSIONS: These findings highlight single motherhood as a unique risk factor for smoking during pregnancy in European ancestry mothers, over and above alcohol dependence. Additional research is needed to identify risks, beyond single motherhood, associated with smoking during pregnancy in African ancestry mothers.


Assuntos
Alcoolismo/epidemiologia , Complicações na Gravidez/epidemiologia , Fumar/epidemiologia , Adolescente , Adulto , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Mães , Pais , Gravidez , Pontuação de Propensão , Fatores de Risco , Gêmeos , Adulto Jovem
18.
Drug Alcohol Depend ; 179: 146-152, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28779616

RESUMO

BACKGROUND: Childhood maltreatment is a known risk factor for cannabis initiation and problem use, but the extent to which this association is attributable to shared familial influences is unknown. We estimate the magnitude of associations between childhood maltreatment, timing of cannabis initiation, and cannabis-related problems, in European-American (EA) and African-American (AA) women, and parse the relative influence of additive genetic (A), shared environmental (C), and individual-specific environmental (E) factors on these constructs and their covariation. METHODS: Data were from diagnostic telephone interviews conducted with 3786 participants (14.6% AA) in a population-based study of female twins. Logistic regression analyses and twin modeling were used to test for associations, and estimate the relative contributions of genetic and environmental influences to childhood maltreatment and cannabis outcomes and their covariation. RESULTS: Maltreatment was significantly associated with increased likelihood of cannabis initiation before age 15 among EAs (OR=6.33) and AAs (OR=3.93), but with increased likelihood of later initiation among EAs only (OR=1.68). Maltreatment was associated with cannabis problems among both groups (EA OR=2.32; AA OR=2.03). Among EA women, the covariation between maltreatment and cannabis outcomes was primarily attributable to familial environment (rC=0.67-0.70); among AAs, only individual-specific environment contributed (rE=0.37-0.40). CONCLUSION: Childhood maltreatment is a major contributor to early initiation of cannabis as well as progression to cannabis problems in both AA and EA women. Distinctions by race/ethnicity are not in the relative contribution of genetic factors, but rather in the type of environmental influences that contribute to stages of cannabis involvement.


Assuntos
Cannabis/efeitos dos fármacos , Grupo com Ancestrais do Continente Europeu/genética , Gêmeos/genética , Cannabis/química , Cognição , Progressão da Doença , Meio Ambiente , Feminino , Humanos , Fenótipo , Fatores de Risco , Estados Unidos , Adulto Jovem
19.
Alcohol Clin Exp Res ; 41(5): 911-928, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28226201

RESUMO

BACKGROUND: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. METHODS: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. RESULTS: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). CONCLUSIONS: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.


Assuntos
Alcoolismo/genética , Etanol/administração & dosagem , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Modelos Animais , Adulto , Alcoolismo/diagnóstico , Alcoolismo/epidemiologia , Animais , Caenorhabditis elegans , Estudos de Casos e Controles , Drosophila , Feminino , Loci Gênicos/efeitos dos fármacos , Predisposição Genética para Doença/epidemiologia , Humanos , Irlanda/epidemiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Ratos
20.
Am J Addict ; 26(5): 437-445, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27749011

RESUMO

BACKGROUND AND OBJECTIVES: We examined the associations of religious attendance during childhood (C-RA) and adulthood (A-RA) with alcohol involvement (ever drinking, timing of first alcohol use, and alcohol use disorder [AUD]) in White and Black female twins. As genetic and environmental factors influence religious attendance and alcohol involvement, we examined the extent to which they contribute to their association. METHODS: Data on 3,234 White and 553 Black female twins (18-29 years) from the Missouri Adolescent Female twin Study. Significant correlations between C-RA or A-RA and alcohol involvement were parsed into their additive genetic, shared environmental, and individual-specific environmental sources. RESULTS: C-RA was associated with ever drinking and timing of first alcohol use in Whites. A-RA was associated with ever drinking and AUD in both Whites and Blacks. Shared environmental influences did not contribute to alcohol or religiosity phenotypes in Blacks. In Whites, the association between C-RA and alcohol was due to shared environmental influences, whereas the association between A-RA and alcohol was attributable to additive genetic, shared environmental, and individual-specific environmental sources. Individual-specific environment and genetics contributed to associations between A-RA and ever drinking and AUD, respectively, in Blacks. CONCLUSIONS: Factors other than C-RA contribute to lower rates of alcohol involvement in Blacks. Shared environment does not contribute to links between A-RA and alcohol involvement in Blacks. SCIENTIFIC SIGNIFICANCE: The protective impact of childhood religiosity on alcohol use and misuse is important in Whites and is due to familial factors shared by religiosity and alcohol involvement. (Am J Addict 2017;26:437-445).


Assuntos
Afro-Americanos/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Grupo com Ancestrais do Continente Europeu/psicologia , Religião , Gêmeos/psicologia , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Meio Ambiente , Feminino , Humanos , Adulto Jovem
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