[Show abstract][Hide abstract] ABSTRACT: Virtually all psychiatric traits are genetically complex. This article discusses the genetics of complex traits in psychiatry. The complexity is accounted for by numerous factors, including multiple risk alleles, epistasis, and epigenetic effects, such as methylation. Risk alleles can individually be common or rare, and can include, for example, single nucleotide polymorphisms (SNPs) and copy number variants (CNV) that are transmitted or are new mutations, and other kinds of variation. Many different kinds of variation can be important for trait risk, either together in various proportions, or as different factors in different subjects. Until recently, our approaches to complex traits were limited, and consequently only a small number of variants, usually of individually minor effect, were identified. Currently, we have a much richer armamentarium that includes the routine application of genomewide association studies (GWAS) and next-generation high throughput sequencing (NextGen); and the combination of this information with other biologically relevant information, such as expression data. We have also seen the emergence of large meta-analysis and mega-analysis consortia. These developments are extremely important for psychiatric genetics, have moved the field forward substantially, and promise formidable gains in the years to come as they are applied more widely.
[Show abstract][Hide abstract] ABSTRACT: Background
The neurofibromatosis type 1 (Nf1) gene encodes a GTPase activating protein that negatively regulates small GTPases of the Ras family.
We assessed alcohol-related behaviors including alcohol sensitivity, dependent and non-dependent drinking, and basal and alcohol-induced GABA release in the central nucleus of the amygdala (CeA) in Nf1 heterozygous null mice (Nf1+/−). We also investigated the associations of Nf1 polymorphisms with alcohol dependence risk and severity in humans.
Nf1+/− mice do not differ from wild-type (WT) mice in non-dependent drinking, such as 24-hr, 2-bottle choice (2BC), drinking in the dark binge drinking, or limited access 2BC. However, Nf1+/− mice failed to escalate alcohol drinking following chronic intermittent ethanol vapor exposure (CIE) to induce dependence. Alcohol acutely increases GABA release in the CeA and alcohol dependence is characterized by increased baseline GABA release in CeA. Interestingly, GABA release in Nf1+/− mice is greater at baseline than WT mice, is not elevated by induction of dependence by CIE, and failed to show alcohol-induced facilitation both before and after CIE. Additionally, we observed that multiple variants in the human NF1 gene are associated with a quantitative measure of alcohol dependence in both African Americans and European Americans.
In this translational investigation, we found that Nf1 activity regulates excessive drinking and basal and ethanol-stimulated GABA release in the mouse central amygdala. We also found that genetic variation in NF1 may confer an inherent susceptibility to the transition from non-dependent to dependent drinking in humans.
[Show abstract][Hide abstract] ABSTRACT: Chronic alcohol consumption may induce gene expression alterations in brain reward regions such as the prefrontal cortex (PFC), modulating the risk of alcohol use disorders (AUDs). Transcriptome profiles of 23 AUD cases and 23 matched controls (16 pairs of males and 7 pairs of females) in postmortem PFC were generated using Illumina's HumanHT-12 v4 Expression BeadChip. Probe-level differentially expressed genes and gene modules in AUD subjects were identified using multiple linear regression and weighted gene co-expression network analyses. The enrichment of differentially co-expressed genes in alcohol dependence-associated genes identified by genome-wide association studies (GWAS) was examined using gene set enrichment analysis. Biological pathways overrepresented by differentially co-expressed genes were uncovered using DAVID bioinformatics resources. Three AUD-associated gene modules in males [Module 1 (561 probes mapping to 505 genes): r = 0.42, P correlation = 0.020; Module 2 (815 probes mapping to 713 genes): r = 0.41, P correlation = 0.020; Module 3 (1,446 probes mapping to 1,305 genes): r = -0.38, P correlation = 0.030] and one AUD-associated gene module in females [Module 4 (683 probes mapping to 652 genes): r = 0.64, P correlation = 0.010] were identified. Differentially expressed genes mapped by significant expression probes (P nominal ≤ 0.05) clustered in Modules 1 and 2 were enriched in GWAS-identified alcohol dependence-associated genes [Module 1 (134 genes): P = 0.028; Module 2 (243 genes): P = 0.004]. These differentially expressed genes, including ALDH2, ALDH7A1, and ALDH9A1, are involved in cellular functions such as aldehyde detoxification, mitochondrial function, and fatty acid metabolism. Our study revealed differentially co-expressed genes in postmortem PFC of AUD subjects and demonstrated that some of these differentially co-expressed genes participate in alcohol metabolism.
[Show abstract][Hide abstract] ABSTRACT: Objective: A single nucleotide variation in the alcohol dehydrogenase 1B (ADH1B) gene, rs1229984, produces an ADH1B enzyme with faster acetaldehyde production. This protective variant is associated with lower alcohol consumption and lower risk for alcohol use disorders (AUDs). Based on the premise that faster ADH1B kinetics decreases alcohol consumption, we formally tested if the association between ADH1B variant rs1229984 and AUDs occurs through consumption. We also tested whether the association between rs1229984 and each of the 11 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), AUD criteria occurs through consumption. Method: A total of 1,130 lifetime drinkers from an Israeli household sample were assessed with a structured interview and genotyped for rs1229984 (protective allele frequency = 0.28). Logistic regression evaluated the association between rs1229984 and each phenotype (AUDs, 11 individual DSM-IV criteria). For phenotypes significantly related to rs1229984, the effect through consumption was tested with logistic regression and bootstrapping. Results: ADH1B rs1229984 was significantly associated with AUDs and six criteria, with odds ratios ranging from 1.32 to 1.96. The effect through consumption was significant for these relationships, explaining 23%-74% of the total ADH1B effect. Conclusions: This is the first study to show that ADH1B rs1229984 is related to 6 of the 11 DSM-IV AUD criteria and that alcohol consumption explained a significant proportion of these associations and the association of ADH1B with AUDs. Better understanding of the relationship between ADH1B and the DSM-IV AUD criteria, including effects through consumption, will enhance our understanding of the etiologic model through which AUDs can occur. (J. Stud. Alcohol Drugs, 75, 635-642, 2014).
Journal of studies on alcohol and drugs. 07/2014; 75(4):635-42.
[Show abstract][Hide abstract] ABSTRACT: Topiramate, which interacts with multiple neurotransmitter and enzyme systems, is approved by the Food and Drug Administration to treat seizure disorder, prevent migraine, and (in combination with phentermine) reduce weight. Topiramate has also been shown in multiple studies to reduce heavy drinking. The authors found that topiramate 200 mg/day significantly reduced heavy drinking in heavy drinkers with a treatment goal of reduced drinking (Kranzler et al., 2014). Further, in the European American (EA) subsample (n = 122), a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes the GluK1 subunit of the kainate receptor, moderated the effect on heavy drinking days. Here the authors examined the effects of topiramate on body mass index (BMI) and the moderating effect of rs2832407 in the EA subsample from Kranzler et al. (2014). Across the 12 weeks of treatment, BMI was reduced by 1.2 kg/m2 (p < .001) in the topiramate group but was unchanged in the placebo group. There was no evidence of moderation by rs2832407 of topiramate's effects on BMI. Controlling for changes in drinking and other potential confounders did not alter the findings. These results suggest that the effect of topiramate on drinking behavior, in which the GluK1-containing kainate receptor appears to play a key role, can be dissociated from its effect on weight, the specific mechanism of which remains to be determined. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
Experimental and clinical psychopharmacology. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Interaction of DNA methylation and sequence variants that are methylation quantitative trait loci (mQTLs) may influence susceptibility to diseases such as alcohol dependence (AD). We used genome-wide genotype data from 268 African Americans (AAs: 129 AD cases and 139 controls) and 143 European Americans (EAs: 129 AD cases and 14 controls) to identify mQTLs that were associated with promoter CpGs in 82 AD risk genes. 282 significant mQTL–CpG pairs (9.9 × 10−100 ≤ P
nominal ≤ 7.7 × 10−8) in AAs and 313 significant mQTL–CpG pairs (2.7 × 10−53 ≤ P
nominal ≤ 9.9 × 10−8) in EAs were identified [i.e., mQTL–CpG associations survived multiple-testing correction, q values (false discovery rate) ≤ 0.05]. The most significant mQTL was rs1800759, which was strongly associated with CpG cg12011299 in both AAs (P
nominal = 9.9 × 10−100; q = 6.7 × 10−91) and EAs (P
nominal = 2.7 × 10−53; q = 1.4 × 10−44). Rs1800759 (previously known to be associated to AD) and CpG cg12011299 (distance: 37 bp) are both located in alcohol dehydrogenase (ADH) 4 gene (ADH4) promoter region. In general, the strength of association between mQTLs and CpGs was inversely correlated with the distance between them. Association was also influenced by race and AD. Additionally, 48.3 % of the mQTLs identified in AAs and 65.6 % of the mQTLs identified in EAs were predicted to be expression QTLs. Three mQTLs (rs2173201, rs4147542, and rs4147541 in ADH1B-AHD1C gene cluster region) found in AAs were previously identified by our genome-wide association studies as being significantly associated with AD in AAs. Thus, DNA methylation, which can be influenced by sequence variants and is implicated in gene expression regulation, appears to at least partially underlie the association of genetic variation with AD.
[Show abstract][Hide abstract] ABSTRACT: Background
Disulfiram and naltrexone were evaluated in treatment of individuals with co-occurring alcohol dependence and other Axis I disorders (e.g., Major Depression). We explored pharmacogenetic interactions in genotyped subjects.Methods
Alcohol dependent (AD) subjects received naltrexone alone, placebo alone, disulfiram with placebo or disulfiram with naltrexone. They were genotyped for OPRM1 rs1799971 (Asn40Asp), and DBH rs1611115 (C-1021T). N = 107 male European-American subjects were included.ResultsThere were no significant interactions with OPRM1. DBH interacted with naltrexone on the primary outcome of abstinence from heavy drinking (χ2(1) = 5.23, p = .02). “T” allele carriers on naltrexone had more abstinence compared to “CC” subjects on naltrexone (FET, p = .01). “T” allele carriers on naltrexone had the highest overall rates of abstinence from heavy drinking (>90%). Also, DBH genotype interacted with disulfram (F(1,17) = 7.52, p = .01) on drinks per drinking day with less drinking for subjects with the “CC” genotype than for T allele carriers on disulfiram.ConclusionsDBH*rs1611115*T associated with better response to naltrexone, while for those on disulfiram that drank, “CC” subjects drank less than T carriers. For rs1799971*G, we did not replicate findings from previous studies showing a more favorable response to NTX, possibly due to the small available sample.Scientific SignificanceGenotyping rs1611115 may be useful in understanding inter-individual differences in AD treatment response.Future DirectionsFurther study of rs1611115 pharmacogenetics is warranted. (Am J Addict 2014;23:288–293)
American Journal on Addictions 05/2014; 23(3). · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Cocaine users typically try alcohol or marijuana before cocaine, but this ordering of substance use initiation is not universal. Characterizing cocaine-dependent users who deviate from the typical sequence may be informative for understanding the multiple pathways to cocaine dependence. Method: Data were drawn from cocaine-dependent participants (N = 6,333; 41% female) in a multisite study of the genetics of substance dependence who completed in-person structured psychiatric interviews. Participants were categorized with respect to alcohol or marijuana use as (a) never used, (b) used cocaine first, or (c) first used at the same age as or after first cocaine use. The association of a range of demographic, psychiatric, and childhood risk factors with sequences of initiation and the association of those sequences with indicators of dependence course (e.g., severity) were investigated in a series of regression analyses. Results: Women and non-European Americans were overrepresented in the atypical sequence groups. The atypical sequence groups also differed from the typical sequence groups with respect to rates of other substance use disorders. Sequences of substance use initiation were largely unrelated to other psychiatric disorders or childhood risk factors. Individuals who never used marijuana had a lower severity of dependence. Conclusions: Although only a minority of dependent cocaine users deviate from the typical sequence of substance use initiation, several characteristics distinguish them from those who follow the typical sequence. Findings underscore the diversity in pathways to cocaine dependence. (J. Stud. Alcohol Drugs, 75, 423-427, 2014).
Journal of studies on alcohol and drugs 05/2014; 75(3):423-7. · 1.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We (Kranzler et al., 2014) reported that topiramate 200 mg/day reduced heavy drinking days and increased abstinent days in 138 heavy drinkers whose treatment goal was to reduce drinking to safe levels. In that 12-week, placebo-controlled study, we measured drinking using the Timeline Follow-back method at each treatment visit. In addition to the intent-to-treat effects of topiramate, we found that a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the GluK1 subunit of the kainate receptor, moderated the treatment effect in European Americans (EAs; n = 122). Topiramate reduced heavy drinking only in rs2832407*C allele homozygotes. Here, we augment those analyses by using patients' daily reports obtained using interactive voice response technology; (a) to validate the interactive effects of GRIK1 and topiramate as predictors of drinking level; and, (b) to examine changes in expected positive effects of drinking (i.e. positive outcome expectancies) and desire to drink. We found that rs2832407*C allele homozygotes treated with topiramate drank less overall during treatment than those receiving placebo, validating our earlier findings for heavy drinking days (Kranzler et al., 2014). There was also a study day × medication group × genotype group interaction that predicted both positive alcohol expectancies and desire to drink, with rs2832407*C-allele homozygotes treated with topiramate showing the largest decreases in these outcomes during the study period. Changes in positive alcohol expectancies or desire to drink did not mediate the effects on drinking. These findings validate and extend our previous pharmacogenetic findings with topiramate.
The International Journal of Neuropsychopharmacology 04/2014; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children.
A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible.
Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p < 5.0 × 10(-7), all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5).
This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed.
Journal of the American Academy of Child and Adolescent Psychiatry 04/2014; 53(4):417-424.e5. · 6.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. METHOD A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. RESULTS The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramate's effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes. CONCLUSIONS These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate's effects on heavy drinking.
American Journal of Psychiatry 02/2014; · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To explore clinical features of methamphetamine-induced paranoia (MIP) and associations between MIP and a genetic polymorphism in dopamine β-hydroxylase (DBH -1021C→T).
Retrospective analysis of clinical presentation and genetic association by chi-square test and logistic regression analysis.
A Thai substance abuse treatment center PARTICIPANTS: 727 Methamphetamine-dependent (MD) individuals MEASURES: Clinical: Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) and the Methamphetamine Experience Questionnaire (MEQ). Genetic: DBH -1021C→T.
Forty percent of individuals (289 of 727) with MD had MIP. Within-binge latency to MIP onset occurred more rapidly in the most recent compared with initial MIP episode (p=0.02), despite unchanging intake (p=0.89). Individuals with MIP were significantly less likely to carry lower (TT/CT) compared with higher (CC) activity genotypes (34% vs 43%; χ(2) 1 =5, p=0.03). DBH effects were confirmed (OR=0.7, p=0.04) after controlling for associated clinical variables (MD severity, OR=3.4, p<0.001; antisocial personality disorder, OR=2.2, p<0.001; alcohol dependence, OR=1.4, p=0.05; and nicotine dependence, OR=1.4, p=0.06). TT/CT carriers were more likely to initiate cigarette smoking (OR=3.9, p=0.003) and probably less likely to be dependent on alcohol (OR=0.6, p=0.05).
Among methamphetamine-dependent individuals, paranoia appears to occur increasingly rapidly in the course of a session of methamphetamine use. Severity of methamphetamine dependence and antisocial personality disorder predicts methamphetamine-induced paranoia. The genetic polymorphism in dopamine β-hydroxylase is associated with methamphetamine-induced paranoia and influences smoking initiation.
[Show abstract][Hide abstract] ABSTRACT: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) replaced the fourth edition's (DSM-IV) diagnosis of Pathological Gambling (PG) with Gambling Disorder (GD). GD differs from PG in that it requires 4 rather than 5 criteria for diagnosis and excludes the "Illegal Acts" criterion. We examined the prevalence of GD and its characteristics and validity in a substance-use disorder (SUD) sample. Participants (N = 6,613) in genetic studies of substance dependence underwent a semistructured psychiatric interview. Individuals who reported ever having gambled $10 at least monthly (n = 1,507) were the focus of the analyses. Approximately one third of acknowledged gamblers (n = 563; 8.5% of the total sample) received PG (DSM-IV) and GD (DSM-5) diagnoses and 678 (10.3% of the total) received only a DSM-5 diagnosis, representing an increase of 20.4% relative to DSM-IV. Although the 3 groups were comparable demographically, the DSM-5-Only group was intermediate between the other 2 groups on the prevalence of comorbid SUDs, the distribution of DSM-IV PG criteria endorsed, and the types of gambling reported. Multinomial logistic regression analysis showed that the DSM-5-Only group was more likely than the No-Diagnosis group and less likely than the Both-Diagnoses group to acknowledge a gambling problem. In conclusion, there was a high prevalence of PG in this SUD sample. Analysis of non-DSM variables suggested that the increased sensitivity of the DSM-5 GD diagnosis successfully identifies a broader set of individuals with clinically significant gambling-related problems. Prospective studies of individuals with GD are needed to validate this finding. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
Experimental and Clinical Psychopharmacology 02/2014; 22(1):50-6. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) suggests that a complex disease is
typically affected by many genetic variants with small or moderate effects.
Identification of these risk variants remains to be a very challenging problem.
Traditional approaches focusing on a single GWAS dataset alone ignore relevant
information that could potentially improve our ability to detect these
variants. We proposed a novel statistical approach, named GPA, to performing
integrative analysis of multiple GWAS datasets and functional annotations.
Hypothesis testing procedures were developed to facilitate statistical
inference of pleiotropy and enrichment of functional annotation. We applied our
approach to perform systematic analysis of five psychiatric disorders. Not only
did GPA identify many weak signals missed by the original single phenotype
analysis, but also revealed interesting genetic architectures of these
disorders. We also applied GPA to the bladder cancer GWAS data with the ENCODE
DNase-seq data from 125 cell lines and showed that GPA can detect cell lines
that are more biologically relevant to the phenotype of interest.
[Show abstract][Hide abstract] ABSTRACT: 5HTTLPR, which is the trivial name for a variable number of tandem repeats (VNTR) polymorphism mapped to the 5' region of the SLC6A4 (serotonin transporter protein) gene, is one of the most studied variants with respect to psychiatric traits. It is also widely studied in the context of intermediate phenotypes such as neuroimaging measures, and gene-by-environment interaction, the latter generally in the context of affective and anxiety phenotypes. In this article, the author discusses the importance of the variant in the context of a population genetics article published in Human Genetics sixteen years ago.
[Show abstract][Hide abstract] ABSTRACT: Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). α4β2 nAChRs are the most abundant in mammalian brain, and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine. A number of rare variants in the CHRNA4 gene that encodes the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers. We compared three of these variants (α4R336C, α4P451L and α4R487Q) to the common variant to determine their effects on α4β2 nAChR pharmacology. We examined [3H]-epibatidine binding, interacting proteins and phosphorylation of the α4 nAChR subunit with LC-MS/MS in HEK 293 cells, and voltage-clamp electrophysiology in Xenopus oocytes. We observed significant effects of the α4 variants on nAChR expression, subcellular distribution, and sensitivity to nicotine-induced receptor upregulation. Proteomic analysis of immunopurified α4β2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions. Electrophysiological characterization in Xenopus oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants, as well as shifts in receptor function following incubation with nicotine. Taken together, these experiments suggest that genetic variation at CHRNA4 alters the assembly and expression of α4β2 nAChRs resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant. The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants.
Journal of Pharmacology and Experimental Therapeutics 01/2014; · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
We report a GWAS of nicotine dependence (ND) defined on the basis of scores on the Fagerström Test for Nicotine Dependence (FTND) in European-American (EA) and African-American (AA) populations.
Our sample, from that used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime: 2,114 EA and 2,602 AA subjects, and an additional 927 AA and 2,003 EA subjects from the SAGE project (via dbGAP). GWAS analysis considered FTND score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a SNP subset.
In EAs, one chromosome 7 intergenic region was genomewide-significant (GWS): rs13225753, p=3.48x10-8 (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 basepairs (minimal p=4.74x10-10). Two chromosome 8 regions were associated: p=4.45x10-8 at DLC1 SNP rs289519 (unadjusted), and p=1.10x10-9 at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with ND and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p=1.46x10-7) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase (eNOS) and AMP activated protein kinase (AMPK) pathways in EAs.
The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.