Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Methamphetamine-induced region-specific transcriptomic and epigenetic changes in the brain of male rats.

Psychostimulant methamphetamine (METH) is neurotoxic to the brain and, therefore, its misuse leads to neurological and psychiatric disorders. The gene regulatory network (GRN) response to neurotoxic METH binge remains unclear in most brain regions. Here we examined the effects of binge METH on the GRN in the nucleus accumbens, dentate gyrus, Ammon's horn, and subventricular zone in male rats. At 24 h after METH, ~16% of genes displayed altered expression and over a quarter of previously open chromatin regions - parts of the genome where genes are typically active - showed shifts in their accessibility. Intriguingly, most changes were unique to each area studied, and independent regulation between transcriptome and chromatin accessibility was observed. Unexpectedly, METH differentially impacted gene activity and chromatin accessibility within the dentate gyrus and Ammon's horn. Around 70% of the affected chromatin-accessible regions in the rat brain have conserved DNA sequences in the human genome. These regions frequently act as enhancers, ramping up the activity of nearby genes, and contain mutations linked to various neurological conditions. By sketching out the gene regulatory networks associated with binge METH in specific brain regions, our study offers fresh insights into how METH can trigger profound, region-specific molecular shifts.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

Genetic and Environmental Variation in Continuous Phenotypes in the ABCD Study®.

Twin studies yield valuable insights into the sources of variation, covariation and causation in human traits. The ABCD Study® (abcdstudy.org) was designed to take advantage of four universities known for their twin research, neuroimaging, population-based sampling, and expertise in genetic epidemiology so that representative twin studies could be performed. In this paper we use the twin data to: (i) provide initial estimates of heritability for the wide range of phenotypes assessed in the ABCD Study using a consistent direct variance estimation approach, assuring that both data and methodology are sound; and (ii) provide an online resource for researchers that can serve as a reference point for future behavior genetic studies of this publicly available dataset. Data were analyzed from 772 pairs of twins aged 9-10 years at study inception, with zygosity determined using genotypic data, recruited and assessed at four twin hub sites. The online tool provides twin correlations and both standardized and unstandardized estimates of additive genetic, and environmental variation for 14,500 continuously distributed phenotypic features, including: structural and functional neuroimaging, neurocognition, personality, psychopathology, substance use propensity, physical, and environmental trait variables. The estimates were obtained using an unconstrained variance approach, so they can be incorporated directly into meta-analyses without upwardly biasing aggregate estimates. The results indicated broad consistency with prior literature where available and provided novel estimates for phenotypes without prior twin studies or those assessed at different ages. Effects of site, self-identified race/ethnicity, age and sex were statistically controlled. Results from genetic modeling of all 53,172 continuous variables, including 38,672 functional MRI variables, will be accessible via the user-friendly open-access web interface we have established, and will be updated as new data are released from the ABCD Study. This paper provides an overview of the initial results from the twin study embedded within the ABCD Study, an introduction to the primary research domains in the ABCD study and twin methodology, and an evaluation of the initial findings with a focus on data quality and suitability for future behavior genetic studies using the ABCD dataset. The broad introductory material is provided in recognition of the multidisciplinary appeal of the ABCD Study. While this paper focuses on univariate analyses, we emphasize the opportunities for multivariate, developmental and causal analyses, as well as those evaluating heterogeneity by key moderators such as sex, demographic factors and genetic background.

Individual-, peer-, and parent-level substance use-related factors among 9- and 10-year-olds from the ABCD Study: Prevalence rates and sociodemographic differences.

Background: Although a relatively large body of research has identified multiple factors associated with adolescent substance use, less is known about earlier substance-related factors during preadolescence, including curiosity to use substances. The present study examined individual-, peer-, and parent-level domains pertaining to substance use and how these domains vary by sociodemographic subgroups and substance type. Methods: Participants were 11,864 9- and 10-year-olds from the baseline sample of the Adolescent Brain Cognitive Development (ABCD) Study. Youth-reported measures were curiosity to use substances and perceived peer substance use. Parent-reported measures were availability of and rules about substances. Generalized logistic mixed models (GLMM) were used to compare these measures across alcohol, nicotine, and marijuana and across sociodemographic subgroupings (sex, race/ethnicity, household income, and family history of alcohol problems). GLMM was then used to examine predictors of curiosity to use by substance type. Results: The most striking descriptive differences were found between race/ethnicity and income categories (e.g., positive associations between greater income and greater availability of alcohol). In multivariable analyses, greater curiosity to use alcohol was associated with being male, higher household income, perceived peer alcohol use, and easy alcohol availability; greater curiosity to use nicotine was associated with being male, perceived peer cigarette use, easy availability of cigarettes, and no parental rules about cigarette use. Conclusions: This study identified substance use-related individual-, peer-, and parent-level factors among a diverse, national sample. Findings highlight the importance of considering sociodemographic and substance-specific variability and may help identify risk and protective factors preceding adolescent substance use.

Substance use patterns in 9 to 13-year-olds: Longitudinal findings from the Adolescent Brain Cognitive Development (ABCD) study.

Background: Though largely substance-naïve at enrollment, a proportion of the youth in the Adolescent Brain Cognitive Development (ABCD) Study are expected to initiate substance use (SU) as they transition into later adolescence. With annual data from youth 9-13 years-old, this study aims to describe their SU patterns over time. Here, prevalence rates of use are reported, along with predicted odds of use while analyzing common risk-factors associated with youth SU. Methods: The ABCD Study® enrolled 11,876 participants at Baseline (ages 9-10) and has followed them annually. Data through half of the third follow-up visit are available (ages 12-13; n = 6,251). SU descriptives for al psychoactive substances over time are outlined. General estimating equations (GEEs) assessed whether sociodemographic factors, internalizing and externalizing symptoms, and parental SU problems were associated with SU between Baseline and Y2 follow-up. Results: Across time, alcohol and nicotine remain the most used substances. Yearly rates of any SU increased (past year use: 13.9% in Y1; 14% Y2, 18.4% Y3). Cumulatively, by Y3, 39.7% of the cohort reported experimenting (e.g., sipping alcohol) with SU within their lifetime, while 7.4% reported a "full use" (a full alcohol drink, nicotine use, cannabis use, or any other SU) in their lifetime (past-year: 1.9% alcohol, 2.1% nicotine, 1.1% cannabis, 1.2% other substances). GEEs revealed ongoing longitudinal associations between sociodemographic factors, greater externalizing symptoms, and parental drug problems with increased odds of initiating SU. Conclusions: As ABCD participants transition into their teenage years, the cohort is initiating SU at increasing (though still low) rates.

AIAP: A Quality Control and Integrative Analysis Package to Improve ATAC-seq Data Analysis.

Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a technique widely used to investigate genome-wide chromatin accessibility. The recently published Omni-ATAC-seq protocol substantially improves the signal/noise ratio and reduces the input cell number. High-quality data are critical to ensure accurate analysis. Several tools have been developed for assessing sequencing quality and insertion size distribution for ATAC-seq data; however, key quality control (QC) metrics have not yet been established to accurately determine the quality of ATAC-seq data. Here, we optimized the analysis strategy for ATAC-seq and defined a series of QC metrics for ATAC-seq data, including reads under peak ratio (RUPr), background (BG), promoter enrichment (ProEn), subsampling enrichment (SubEn), and other measurements. We incorporated these QC tests into our recently developed ATAC-seq Integrative Analysis Package (AIAP) to provide a complete ATAC-seq analysis system, including quality assurance, improved peak calling, and downstream differential analysis. We demonstrated a significant improvement of sensitivity (20%-60%) in both peak calling and differential analysis by processing paired-end ATAC-seq datasets using AIAP. AIAP is compiled into Docker/Singularity, and it can be executed by one command line to generate a comprehensive QC report. We used ENCODE ATAC-seq data to benchmark and generate QC recommendations, and developed qATACViewer for the user-friendly interaction with the QC report. The software, source code, and documentation of AIAP are freely available at https://github.com/Zhang-lab/ATAC-seq_QC_analysis.

Temporal trends in smoking and nicotine dependence in relation to co-occurring substance use in the United States, 2005-2016.

BACKGROUND: Despite an overall decline in tobacco use in the United States, secular trends of smoking and nicotine dependence with co-occurring substance use are not well characterized. METHODS: We examined self-reported tobacco and other substance use in 22,245 participants age 21-59 in the United States from six waves of the National Health and Nutrition Examination Survey (NHANES). Using Joinpoint regression, we assessed secular trends of smoking and nicotine dependence as a function of co-occurring use of alcohol, prescription opioids, marijuana/hashish, cocaine/heroin/methamphetamine, or other injection drug use. Multivariable logistic regressions were fitted to identify the potential risk factors. RESULTS: During 2005-2016, the prevalence of current smoking decreased (without co-occurring substance use: 17.0 %-12.7 %; with co-occurring use of one substance: 35.3 % to 24.6 %; with co-occurring use of two or more substances: 53.8 %-42.2 %), and moderate-to-severe nicotine dependence decreased as well (8.0 %-4.2 %, 16.0 %-8.8 %, and 23.9 %-15.7 %, respectively). Smoking and nicotine dependence were more likely in those with co-occurring use of one substance (current smoking: odds ratio [OR] = 2.22, 95 % confidence interval [CI] = 2.01-2.45); nicotine dependence: OR = 1.88, 95 % CI = 1.63-2.17) and in those with co-occurring use of two or more substances (current smoking: OR = 5.25, 95 % CI = 4.63-5.95; nicotine dependence: OR = 3.24, 95 % CI = 2.72-3.87). CONCLUSIONS: Co-occurring substance use was associated with smaller reductions in tobacco use, over time, and with increased odds of nicotine dependence. This suggests that co-occurring substance users should be regarded as a tobacco-related disparity group and prioritized for tobacco control interventions.

Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent.

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3'hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained ~38% of NMR variation, a substantial increase from the ~20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3'hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.

Marital status, partner acknowledgment of paternity, and neighborhood influences on smoking during first pregnancy: findings across race/ethnicity in linked administrative and census data.

BACKGROUND: Improving prediction of cigarette smoking during pregnancy (SDP), including differences by race/ethnicity and geography, is necessary for interventions to achieve greater and more equitable SDP reductions. METHODS: Using individual-level data on singleton first births, 2010-2017 (N = 182,894), in a US state with high SDP rates, we predicted SDP risk as a function of reproductive partner relationship (marital status, paternity acknowledgement), maternal and residential census tract sociodemographics, and census tract five-year SDP rate. RESULTS: SDP prevalence was 12.7% (white non-Hispanics, WNH), 6.8% (Black/African Americans, AA), 19.5% (Native American, NA), 4.7% (Hispanic, H), and 2.8% (Asian, AS). In WNH and AA, with similar trends in other groups, after adjustment for non-linear effects of maternal age and education and for census tract risk-factors, there was a consistent risk-ordering of SDP rates by reproductive partner relationship: married/with paternity acknowledged < unmarried/acknowledged < unmarried/unacknowledged < married/unacknowledged. Associations with census tract SDP rate, adjusted for maternal and census tract sociodemographics, were stronger for AA and H (OR 2.65-2.67) than for NA (OR = 1.91), WNH (OR = 1.75), or AS (NS). AA SDP was increased in tracts having a higher proportion of WNH residents and was reduced in comparison with WNH at every combination of age, education and partner relationship. CONCLUSIONS: Inattention to differences by race/ethnicity may obscure SDP risk factors. Despite marked race/ethnic differences in unmarried-partner cohabitation rates, failure to acknowledge paternity emerged as an important and consistent risk-predictor. Census-tract five-year SDP rates have heterogeneous origins, but the association of AA SDP risk with increased racial heterogeneity suggests an important influence of neighbor risk behaviors.

Comparison of differential accessibility analysis strategies for ATAC-seq data.

ATAC-seq is widely used to measure chromatin accessibility and identify open chromatin regions (OCRs). OCRs usually indicate active regulatory elements in the genome and are directly associated with the gene regulatory network. The identification of differential accessibility regions (DARs) between different biological conditions is critical in determining the differential activity of regulatory elements. Differential analysis of ATAC-seq shares many similarities with differential expression analysis of RNA-seq data. However, the distribution of ATAC-seq signal intensity is different from that of RNA-seq data, and higher sensitivity is required for DARs identification. Many different tools can be used to perform differential analysis of ATAC-seq data, but a comprehensive comparison and benchmarking of these methods is still lacking. Here, we used simulated datasets to systematically measure the sensitivity and specificity of six different methods. We further discussed the statistical and signal density cut-offs in the differential analysis of ATAC-seq by applying them to real data. Batch effects are very common in high-throughput sequencing experiments. We illustrated that batch-effect correction can dramatically improve sensitivity in the differential analysis of ATAC-seq data. Finally, we developed a user-friendly package, BeCorrect, to perform batch effect correction and visualization of corrected ATAC-seq signals in a genome browser.

Genetic aetiology of self-harm ideation and behaviour.

Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability (hsnp2) estimates were ~10%, and both traits were highly genetically correlated (LDSC rg > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant.

Eating disorders in a community-based sample of women with alcohol use disorder and nicotine dependence.

BACKGROUND: Studies consistently report a higher prevalence of substance use disorders (SUDs) among women with eating disorders than control women. However, limited research exists on the prevalence of eating disorder symptoms and diagnoses in women with SUDs, especially in community-based populations. We examined the prevalence of eating disorder symptoms and diagnosis by the presence or absence of lifetime alcohol use disorder (AUD) and/or nicotine dependence (ND) in a community-based sample of women. METHODS: 3756 women (median age = 22 years) from the Missouri Adolescent Female Twin Study completed a modified semi-structured interview assessing lifetime DSM-IV psychiatric disorders and SUDs. Logistic regression models adjusted for demographic characteristics and other psychopathology, and robust standard errors accounted for the non-independence of twin data. RESULTS: In general, women with comorbid AUD and ND had a higher prevalence of eating disorder symptoms and diagnoses than women with AUD or ND Only, who in turn had a higher prevalence than those without either SUD. After adjustment for covariates, women with AUD and ND had significantly greater risk of broad anorexia nervosa (RRR = 3.17; 99 % CI = 1.35, 7.44), purging disorder (2.59; 1.24, 5.43), and numerous eating disorder symptoms than women with neither disorder. Significant differences emerged between individuals with both AUD and ND versus women with AUD Only or ND Only for some eating disorder symptoms. CONCLUSIONS: Women with lifetime AUD or ND diagnoses are at high risk for eating disorder symptoms and diagnoses, underscoring the importance of assessing eating disorder symptoms among women with these disorders.

Genomic prediction of alcohol-related morbidity and mortality.

While polygenic risk scores (PRS) have been shown to predict many diseases and risk factors, the potential of genomic prediction in harm caused by alcohol use has not yet been extensively studied. Here, we built a novel polygenic risk score of 1.1 million variants for alcohol consumption and studied its predictive capacity in 96,499 participants from the FinnGen study and 39,695 participants from prospective cohorts with detailed baseline data and up to 25 years of follow-up time. A 1 SD increase in the PRS was associated with 11.2 g (=0.93 drinks) higher weekly alcohol consumption (CI = 9.85-12.58 g, p = 2.3 × 10-58). The PRS was associated with alcohol-related morbidity (4785 incident events) and the risk estimate between the highest and lowest quintiles of the PRS was 1.83 (95% CI = 1.66-2.01, p = 1.6 × 10-36). When adjusted for self-reported alcohol consumption, education, marital status, and gamma-glutamyl transferase blood levels in 28,639 participants with comprehensive baseline data from prospective cohorts, the risk estimate between the highest and lowest quintiles of the PRS was 1.58 (CI = 1.26-1.99, p = 8.2 × 10-5). The PRS was also associated with all-cause mortality with a risk estimate of 1.33 between the highest and lowest quintiles (CI = 1.20-1.47, p = 4.5 × 10-8) in the adjusted model. In conclusion, the PRS for alcohol consumption independently associates for both alcohol-related morbidity and all-cause mortality. Together, these findings underline the importance of heritable factors in alcohol-related health burden while highlighting how measured genetic risk for an important behavioral risk factor can be used to predict related health outcomes.

Alcohol Dependence and Reproductive Onset in Women, Updated: Analyses of Research and State-Level Administrative Data.

OBJECTIVE: The present study updates prior research, incorporating state-level administrative data to examine associations between self-reported history of alcohol dependence and birth record-derived reproductive onset, the latter assessed through peak childbearing years. METHOD: Participants included 542 African ancestry (AA) and 2,928 European or other ancestry (EA) female twins ascertained through Missouri birth records and recruited as part of a birth cohort study of like-sex female pairs born between 1975 and 1985. Analyses were limited to twins for whom residence in Missouri when of reproductive age could be documented, including twins who left Missouri but later returned. Cox proportional hazards regression models were estimated predicting age at first childbirth from history of alcohol dependence, separately for AA and EA twins, without and with adjustment for sociodemographic characteristics, comorbid psychopathology and other substance involvement, overweight/obesity status, and family-of-origin and childhood risk factors. RESULTS: Among EA twins, alcohol dependence predicted both early and delayed childbearing; in adjusted models, alcohol dependence was associated with overall delayed childbearing. Associations between alcohol dependence and reproductive onset were nonsignificant among AA twins. CONCLUSIONS: Findings for EA twins are consistent with the broader literature indicating increased risk of teen motherhood associated with early-onset and problem drinking, but suggest that this may be explained by other correlated risk factors. The more robust finding, confirming relatively recent research, is of delayed childbearing associated with alcohol dependence.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.

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.

Associations between polygenic risk for tobacco and alcohol use and liability to tobacco and alcohol use, and psychiatric disorders in an independent sample of 13,999 Australian adults.

BACKGROUND: Substance use, substance use disorders (SUDs), and psychiatric disorders commonly co-occur. Genetic risk common to these complex traits is an important explanation; however, little is known about how polygenic risk for tobacco or alcohol use overlaps the genetic risk for the comorbid SUDs and psychiatric disorders. METHODS: We constructed polygenic risk scores (PRSs) using GWAS meta-analysis summary statistics from a large discovery sample, GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN), for smoking initiation (SI; N = 631,564), age of initiating regular smoking (AI; N = 258,251), cigarettes per day (CPD; N = 258,999), smoking cessation (SC; N = 312,273), and drinks per week (DPW; N = 527,402). We then estimated the fixed effect of these PRSs on the liability to 15 phenotypes related to tobacco and alcohol use, substance use disorders, and psychiatric disorders in an independent target sample of Australian adults. RESULTS: After adjusting for multiple testing, 10 of 75 combinations of discovery and target phenotypes remained significant. PRS-SI (R2 range: 1.98%-5.09 %) was positively associated with SI, DPW, and with DSM-IV and FTND nicotine dependence, and conduct disorder. PRS-AI (R2: 3.91 %) negatively associated with DPW. PRS-CPD (R2: 1.56 %-1.77 %) positively associated with DSM-IV nicotine dependence and conduct disorder. PRS-DPW (R2: 3.39 %-6.26 %) positively associated with only DPW. The variation of DPW was significantly influenced by sex*PRS-SI, sex*PRS-AI and sex*PRS-DPW. Such interaction effect was not detected in the other 14 phenotypes. CONCLUSIONS: Polygenic risks associated with tobacco use are also associated with liability to alcohol consumption, nicotine dependence, and conduct disorder.

Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability.

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.