A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

BACKGROUND: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes. METHODS: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.g., substance-use, mental health, sleep, immune, cardiovascular, metabolic) from a diverse 23andMe cohort, including European (N ≤ 2,619,939), Latin American (N ≤ 446,646) and African American (N ≤ 146,776) populations to uncover new and perhaps unexpected associations. These SNPs have been consistently implicated by both candidate gene studies and genome-wide association studies of alcohol-related behaviours but have not been investigated in detail for other relevant phenotypes in a hypothesis-free approach in such a large cohort of multiple ancestries. To provide insight into potential causal effects of alcohol consumption on the outcomes significant in the PheWAS, we performed univariable two-sample and one-sample Mendelian randomisation (MR) analyses. FINDINGS: The minor allele rs1229984-T, which is protective against alcohol behaviours, showed the highest number of PheWAS associations across the three cohorts (N = 232, European; N = 29, Latin American; N = 7, African American). rs1229984-T influenced multiple domains of health. We replicated associations with alcohol-related behaviours, mental and sleep conditions, and cardio-metabolic health. We also found associations with understudied traits related to neurological (migraines, epilepsy), immune (allergies), musculoskeletal (fibromyalgia), and reproductive health (preeclampsia). MR analyses identified evidence of causal effects of alcohol consumption on liability for 35 of these outcomes in the European cohort. INTERPRETATION: Our work demonstrates that polymorphisms in genes encoding alcohol metabolising enzymes affect multiple domains of health beyond alcohol-related behaviours. Understanding the underlying mechanisms of these effects could have implications for treatments and preventative medicine. FUNDING: MVJ, NCK, SBB, SSR and AAP were supported by T32IR5226 and 28IR-0070. SSR was also supported by NIDA DP1DA054394. NCK and RBC were also supported by R25MH081482. ASH was supported by funds from NIAAA K01AA030083. JLMO was supported by VA 1IK2CX002095. JLMO and JJMM were also supported by NIDA R21DA050160. JJMM was also supported by the Kavli Postdoctoral Award for Academic Diversity. EGA was supported by K01MH121659 from the NIMH/NIH, the Caroline Wiess Law Fund for Research in Molecular Medicine and the ARCO Foundation Young Teacher-Investigator Fund at Baylor College of Medicine. MSA was supported by the Instituto de Salud Carlos III and co-funded by the European Union Found: Fondo Social Europeo Plus (FSE+) (P19/01224, PI22/00464 and CP22/00128).

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (ncombined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.

PURPOSE: Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. METHODS: The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. RESULTS: Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. CONCLUSION: Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder.

A novel quantitative trait locus implicates Msh3 in the propensity for genome-wide short tandem repeat expansions in mice.

Short tandem repeats (STRs) are a class of rapidly mutating genetic elements typically characterized by repeated units of 1-6 bp. We leveraged whole-genome sequencing data for 152 recombinant inbred (RI) strains from the BXD family of mice to map loci that modulate genome-wide patterns of new mutations arising during parent-to-offspring transmission at STRs. We defined quantitative phenotypes describing the numbers and types of germline STR mutations in each strain and performed quantitative trait locus (QTL) analyses for each of these phenotypes. We identified a locus on Chromosome 13 at which strains inheriting the C57BL/6J (B) haplotype have a higher rate of STR expansions than those inheriting the DBA/2J (D) haplotype. The strongest candidate gene in this locus is Msh3, a known modifier of STR stability in cancer and at pathogenic repeat expansions in mice and humans, as well as a current drug target against Huntington's disease. The D haplotype at this locus harbors a cluster of variants near the 5' end of Msh3, including multiple missense variants near the DNA mismatch recognition domain. In contrast, the B haplotype contains a unique retrotransposon insertion. The rate of expansion covaries positively with Msh3 expression-with higher expression from the B haplotype. Finally, detailed analysis of mutation patterns showed that strains carrying the B allele have higher expansion rates, but slightly lower overall total mutation rates, compared with those with the D allele, particularly at tetranucleotide repeats. Our results suggest an important role for inherited variants in Msh3 in modulating genome-wide patterns of germline mutations at STRs.

Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies (GWAS) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.

A natural mutator allele shapes mutation spectrum variation in mice.

Although germline mutation rates and spectra can vary within and between species, common genetic modifiers of the mutation rate have not been identified in nature1. Here we searched for loci that influence germline mutagenesis using a uniquely powerful resource: a panel of recombinant inbred mouse lines known as the BXD, descended from the laboratory strains C57BL/6J (B haplotype) and DBA/2J (D haplotype). Each BXD lineage has been maintained by brother-sister mating in the near absence of natural selection, accumulating de novo mutations for up to 50 years on a known genetic background that is a unique linear mosaic of B and D haplotypes2. We show that mice inheriting D haplotypes at a quantitative trait locus on chromosome 4 accumulate C>A germline mutations at a 50% higher rate than those inheriting B haplotypes, primarily owing to the activity of a C>A-dominated mutational signature known as SBS18. The B and D quantitative trait locus haplotypes encode different alleles of Mutyh, a DNA repair gene that underlies the heritable cancer predisposition syndrome that causes colorectal tumors with a high SBS18 mutation load3,4. Both B and D Mutyh alleles are present in wild populations of Mus musculus domesticus, providing evidence that common genetic variation modulates germline mutagenesis in a model mammalian species.

Genome-wide association study of problematic opioid prescription use in 132,113 23andMe research participants of European ancestry.

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids 'not as prescribed'. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near LRRIQ3). POU showed positive genetic correlations with the two largest available GWAS of OUD and opioid dependence (rg = 0.64, 0.80, respectively). We also identified numerous additional genetic correlations with POU, including alcohol dependence (rg = 0.74), smoking initiation (rg = 0.63), pain relief medication intake (rg = 0.49), major depressive disorder (rg = 0.44), chronic pain (rg = 0.42), insomnia (rg = 0.39), and loneliness (rg = 0.28). Although POU was positively genetically correlated with risk-taking (rg = 0.38), conditioning POU on risk-taking did not substantially alter the magnitude or direction of these genetic correlations, suggesting that POU does not simply reflect a genetic tendency towards risky behavior. Lastly, we performed phenome- and lab-wide association analyses, which uncovered additional phenotypes that were associated with POU, including respiratory failure, insomnia, ischemic heart disease, and metabolic and blood-related biomarkers. We conclude that opioid misuse can be measured in population-based cohorts and provides a cost-effective complementary strategy for understanding the genetic basis of OUD.

Genes identified in rodent studies of alcohol intake are enriched for heritability of human substance use.

BACKGROUND: Rodent paradigms and human genome-wide association studies (GWAS) on drug use have the potential to provide biological insight into the pathophysiology of addiction. METHODS: Using GeneWeaver, we created rodent alcohol and nicotine gene-sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP heritability of these gene-sets using four large human GWAS: (1) alcoholic drinks per week, (2) problematic alcohol use, (3) cigarettes per day, and (4) smoking cessation. We benchmarked our findings with curated human alcohol and nicotine addiction gene-sets and performed specificity analyses using other rodent gene-sets (e.g., locomotor behavior) and other human GWAS (e.g., height). RESULTS: The rodent alcohol gene-set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene-set was not significantly associated with any of these traits. Both rodent gene-sets showed enrichment for several non-substance-use GWAS, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene-sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene-sets showed greater enrichment for substance use traits. CONCLUSION: Our results suggest that rodent gene expression studies can help to identify genes that contribute to the heritability of some substance use traits in humans, yet there was less specificity than expected. We outline various limitations, interpretations, and considerations for future research.

Genome-Wide Association Studies of Impulsive Personality Traits (BIS-11 and UPPS-P) and Drug Experimentation in up to 22,861 Adult Research Participants Identify Loci in the CACNA1I and CADM2 genes.

Impulsive personality traits are complex heritable traits that are governed by frontal-subcortical circuits and are associated with numerous neuropsychiatric disorders, particularly drug abuse and attention-deficit/hyperactivity disorder (ADHD). In collaboration with the genetics company 23andMe, we performed 10 genome-wide association studies on measures of impulsive personality traits [the short version of the UPPS-P Impulsive Behavior Scale, and the Barratt Impulsiveness Scale (BIS-11)] and drug experimentation (the number of drug classes an individual had tried in their lifetime) in up to 22,861 male and female adult human research participants of European ancestry. Impulsive personality traits and drug experimentation showed single nucleotide polymorphism heritabilities that ranged from 5 to 11%. Genetic variants in the CADM2 locus were significantly associated with UPPS-P Sensation Seeking (p = 8.3 × 10-9, rs139528938) and showed a suggestive association with Drug Experimentation (p = 3.0 × 10-7, rs2163971; r2 = 0.68 with rs139528938). Furthermore, genetic variants in the CACNA1I locus were significantly associated with UPPS-P Negative Urgency (p = 3.8 × 10-8; rs199694726). The role of these genes was supported by single variant, gene- and transcriptome-based analyses. Multiple subscales from both UPPS-P and BIS showed strong genetic correlations (>0.5) with Drug Experimentation and other substance use traits measured in independent cohorts, including smoking initiation, and lifetime cannabis use. Several UPPS-P and BIS subscales were genetically correlated with ADHD (rg = 0.30-0.51), supporting their validity as endophenotypes. Our findings demonstrate a role for common genetic contributions to individual differences in impulsivity. Furthermore, our study is the first to provide a genetic dissection of the relationship between different types of impulsive personality traits and various psychiatric disorders.SIGNIFICANCE STATEMENT Impulsive personality traits (IPTs) are heritable traits that are governed by frontal-subcortical circuits and are associated with neuropsychiatric disorders, particularly substance use disorders. We have performed genome-wide association studies of IPTs to identify regions and genes that account for this heritable variation. IPTs and drug experimentation were modestly heritable (5-11%). We identified an association between single nucleotide polymorphisms in CADM2 and both sensation seeking and drug experimentation; and between variants in CACNA1I and negative urgency. The role of these genes was supported by single variant, gene- and transcriptome-based analyses. This study provides evidence that impulsivity can be genetically separated into distinct components. We showed that IPT are genetically associated with substance use and ADHD, suggesting impulsivity is an endophenotype contributing to these psychiatric conditions.

Genome-wide association study of alcohol use disorder identification test (AUDIT) scores in 20 328 research participants of European ancestry.

Genetic factors contribute to the risk for developing alcohol use disorder (AUD). In collaboration with the genetics company 23andMe, Inc., we performed a genome-wide association study of the alcohol use disorder identification test (AUDIT), an instrument designed to screen for alcohol misuse over the past year. Our final sample consisted of 20 328 research participants of European ancestry (55.3% females; mean age = 53.8, SD = 16.1) who reported ever using alcohol. Our results showed that the 'chip-heritability' of AUDIT score, when treated as a continuous phenotype, was 12%. No loci reached genome-wide significance. The gene ADH1C, which has been previously implicated in AUD, was among our most significant associations (4.4 × 10-7 ; rs141973904). We also detected a suggestive association on chromosome 1 (2.1 × 10-7 ; rs182344113) near the gene KCNJ9, which has been implicated in mouse models of high ethanol drinking. Using linkage disequilibrium score regression, we identified positive genetic correlations between AUDIT score, high alcohol consumption and cigarette smoking. We also observed an unexpected positive genetic correlation between AUDIT and educational attainment and additional unexpected negative correlations with body mass index/obesity and attention-deficit/hyperactivity disorder. We conclude that conducting a genetic study using responses to an online questionnaire in a population not ascertained for AUD may represent a cost-effective strategy for elucidating aspects of the etiology of AUD.

Social and anxiety-like behaviors contribute to nicotine self-administration in adolescent outbred rats.

Both emotional and social traits interact with genetic factors to influence smoking behavior. We previously established a socially acquired nicotine intravenous self-administration model where social learning of a nicotine-associated odor cue reversed conditioned flavor aversion and promoted nicotine intake. In this study, we first phenotyped ~800 adolescent heterogeneous stock rats in open field, novel object interaction, social interaction, elevated plus maze, and marble burying behaviors. These rats were then phenotyped on socially acquired nicotine self-administration. We found 243 significant correlations between different behavioral tests. Principal component regression analysis found that ~10-20% of the variance in nicotine-related measures, such as intake during the first or the last three fixed-ratio sessions, the progressive ratio session, and reinstatement behavior, can be explained by variations in behavioral traits. Factors corresponding to social behavior and anxiety were among the strongest predictors of nicotine intake and reinstatement of nicotine-seeking behavior. We also found many sex differences in behavioral measures. These data indicated that the genetic diversity of this population, in combination with social behaviour and anxiety, are significant contributors to the divergent nicotine self-administration behavior and indicated a high probability of discovering sex-specific genetic mechanisms for nicotine intake in future genome-wide association studies.

Genome wide association analysis in a mouse advanced intercross line.

The LG/J x SM/J advanced intercross line of mice (LG x SM AIL) is a multigenerational outbred population. High minor allele frequencies, a simple genetic background, and the fully sequenced LG and SM genomes make it a powerful population for genome-wide association studies. Here we use 1,063 AIL mice to identify 126 significant associations for 50 traits relevant to human health and disease. We also identify thousands of cis- and trans-eQTLs in the hippocampus, striatum, and prefrontal cortex of ~200 mice. We replicate an association between locomotor activity and Csmd1, which we identified in an earlier generation of this AIL, and show that Csmd1 mutant mice recapitulate the locomotor phenotype. Our results demonstrate the utility of the LG x SM AIL as a mapping population, identify numerous novel associations, and shed light on the genetic architecture of mammalian behavior.

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

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.

Glyoxalase 1 (GLO1) Inhibition or Genetic Overexpression Does Not Alter Ethanol's Locomotor Effects: Implications for GLO1 as a Therapeutic Target in Alcohol Use Disorders.

BACKGROUND: Glyoxalase 1 (GLO1) is an enzyme that metabolizes methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors. Inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol (EtOH) drinking. This study assessed whether inhibition of GLO1, or genetic overexpression of Glo1, would also alter the locomotor effects of EtOH, which might explain reduced EtOH consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control. METHODS: Male C57BL/6J mice were pretreated with either the GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether locomotor response to a range of EtOH doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of EtOH doses in FVB/NJ wild-type and transgenic Glo1 overexpressing mice (Experiment 3). Anxiety-like behavior (time spent in the center of the open field) was assessed in all 3 experiments. RESULTS: The EtOH dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low EtOH doses and potentiated locomotor sedation at higher EtOH doses. No drug or genotype differences were seen in anxiety-like behavior after EtOH treatment. CONCLUSIONS: The dose of pBBG used in this study is within the effective range shown previously to reduce EtOH drinking. Glo1 overexpression has been previously shown to increase EtOH drinking. However, neither manipulation altered the dose-response curve for EtOH's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of EtOH. The present data demonstrate that reduced EtOH drinking caused by GLO1 inhibition is not due to potentiation of EtOH's stimulant or depressant effects.

Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats.

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.

Impulsivity as a mechanism linking child abuse and neglect with substance use in adolescence and adulthood.

Emerging developmental perspectives suggest that adverse rearing environments promote neurocognitive adaptations that heighten impulsivity and increase vulnerability to risky behavior. Although studies document links between harsh rearing environments and impulsive behavior on substance use, the developmental hypothesis that impulsivity acts as mechanism linking adverse rearing environments to downstream substance use remains to be investigated. The present study investigated the role of impulsivity in linking child abuse and neglect with adult substance use using data from (a) a longitudinal sample of youth (Study 1, N = 9,421) and (b) a cross-sectional sample of adults (Study 2, N = 1,011). In Study 1, the links between child abuse and neglect and young adult smoking and marijuana use were mediated by increases in adolescent impulsivity. In Study 2, indirect links between child abuse and neglect and substance use were evidenced via delayed reward discounting and impulsivity traits. Among impulsivity subcomponents, robust indirect effects connecting childhood experiences to cigarette use emerged for negative urgency. Negative urgency, positive urgency, and sensation seeking mediated the effect of child abuse and neglect on cannabis and alcohol use. Results suggest that child abuse and neglect increases risk for substance use in part, due to effects on impulsivity. Individuals with adverse childhood experiences may benefit from substance use preventive intervention programs that target impulsive behaviors.

Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry.

Delay discounting (DD), the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated single-nucleotide polymorphism was rs6528024 (P = 2.40 × 10-8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition and body weight.

Interrelationships among parental family history of substance misuse, delay discounting, and personal substance use.

RATIONALE: Despite consistent evidence of the familiality of substance misuse, the mechanisms by which family history (FH) increases the risk of addiction are not well understood. One behavioral trait that may mediate the risk for substance use and addiction is delay discounting (DD), which characterizes an individual's preferences for smaller immediate rewards compared to larger future rewards. OBJECTIVES: The aim of this study is to examine the interrelationships among FH, DD, and diverse aspects of personal substance use, and to test DD as a mediator of the relationship between FH and personal substance use. METHODS: The study used crowdsourcing to recruit a community sample of adults (N = 732). Family history was assessed using a brief assessment of perceived parental substance use problems, personal substance use was assessed using the Alcohol Use Disorders Identification Test and a measure of frequency of use, and delay discounting was assessed using a latent index of discounting preferences across six reward magnitudes. RESULTS: Steeper discounting was significantly associated with personal alcohol, tobacco, and marijuana use, and level of substance experimentation. Steeper DD was also associated with a denser parental FH of alcohol, tobacco, and overall substance misuse. Parental FH density was significantly associated with several aspects of personal substance use, and these relationships were partially mediated by DD. CONCLUSIONS: The current study suggests that impulsivity, as measured by DD, is one proximal mechanism by which parental FH increases substance use later in life. The causal role of DD in this relationship will need to be established in future longitudinal studies.

Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility.

PURPOSE: Epilepsy is a complex disease characterized by a predisposition toward seizures. There are numerous barriers to the successful treatment of epilepsy. For instance, current antiepileptic drugs have adverse side effects and variable efficacies. Furthermore, the pathophysiologic basis of epilepsy remains largely elusive. Therefore, investigating novel genes and biologic processes underlying epilepsy may provide valuable insight and enable the development of new therapeutic agents. We previously identified methylglyoxal (MG) as an endogenous γ-aminobutyric acid (GABAA ) receptor agonist. Here, we investigated the role of MG and its catabolic enzyme, glyoxalase 1 (GLO1), in seizures. METHODS: We pretreated mice with MG before seizure induction with picrotoxin or pilocarpine and then assessed seizures behaviorally or by electroencephalography (EEG). We then investigated the role of GLO1 in seizures by treating mice with a pharmacologic inhibitor of GLO1 before seizure induction with pilocarpine and measured subsequent seizure phenotypes. Next, we explored the genetic relationship between Glo1 expression and seizures. We analyzed seizure phenotypes among C57BL/6J × DBA/2J (BXD) recombinant inbred (RI) mice with differential Glo1 expression. Lastly, we investigated a causal role for Glo1 in seizures by administering pilocarpine to transgenic (Tg) mice that overexpress Glo1. KEY FINDINGS: Pretreatment with MG attenuated pharmacologically-induced seizures at both the behavioral and EEG levels. GLO1 inhibition, which increases MG concentration in vivo, also attenuated seizures. Among BXD RI mice, high Glo1 expression was correlated with increased seizure susceptibility. Tg mice overexpressing Glo1 displayed reduced MG concentration in the brain and increased seizure severity. SIGNIFICANCE: These data identify MG as an endogenous regulator of seizures. Similarly, inhibition of GLO1 attenuates seizures, suggesting that this may be a novel therapeutic approach for epilepsy. Furthermore, this system may represent an endogenous negative feedback loop whereby high metabolic activity increases inhibitory tone via local accumulation of MG. Finally, Glo1 may contribute to the genetic architecture of epilepsy, as Glo1 expression regulates both MG concentration and seizure severity.