Joel Gelernter

Yale University, New Haven, Connecticut, United States

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Publications (291)1646.89 Total impact

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    ABSTRACT: Previous studies indicate that topiramate reduces alcohol use among problem drinkers, with one study showing that the effect was moderated by a polymorphism (rs2832407) in GRIK1, the gene encoding the GluK1 kainate subunit. We examined whether the interactive effect of medication and genotype (1) altered the association between daily self-efficacy and later-day drinking; and (2) had an indirect effect on drinking via self-efficacy. In a 12-week, placebo-controlled trial of topiramate, we used daily interactive voice response technology to measure self-efficacy (i.e. confidence in avoiding heavy drinking later in the day) and drinking behavior in 122 European-American heavy drinkers. Topiramate's effects on both self-efficacy and drinking level were moderated by rs2832407. C-allele homozygotes treated with topiramate showed higher levels of self-efficacy and lower levels of nighttime drinking across the 12-week trial. Further, the interactive effect of topiramate and genotype on mean nighttime drinking levels was mediated by mean levels of self-efficacy. By modeling topiramate's effects on nighttime drinking across multiple levels of analysis, we found that self-efficacy, a key psychologic construct, mediated the effect of topiramate, which was moderated by rs2832407 genotype. Thus, it may be possible to use an individualized assessment (i.e. genotype) to select treatment to optimize the reduction in heavy drinking and thereby provide a personalized treatment approach.
    Addiction Biology 01/2015; DOI:10.1111/adb.12207 · 5.93 Impact Factor
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    ABSTRACT: Using retrospective reports obtained during treatment visits in 138 heavy drinkers, we found that topiramate's reduction of heavy drinking was moderated by a polymorphism (rs2832407) in GRIK1, which encodes the GluK1 kainate subunit (Kranzler et al., 2014a). A subsequent analysis of that 12-week topiramate treatment trial showed similar effects of medication and genotype on daily drinking reports obtained via interactive voice response technology (IVR; Kranzler et al., 2014b). Specifically, rs2832407*C-allele homozygotes treated with topiramate reported lower levels of drinking than those receiving placebo. This group also had the largest decreases in the expected positive effects of drinking (i.e., expectancies) and desire to drink. To extend that analysis, which focused on how mean levels of desire and expectancies changed over time with treatment, we used a within-person approach to examine whether daily variation in expectancies and desire to drink interact with topiramate treatment and genotype to predict nighttime drinking levels. In contrast to the previous analysis (Kranzler et al., 2014b), here we focus on whether alcohol expectancies and desire to drink moderate the effects of topiramate on drinking. Results showed a 3-way interaction of daily expectancies with genotype and medication, such that the protective effect of topiramate on nighttime drinking among rs2832407*C-allele homozygotes was decreased on days characterized by relatively high levels of anticipated positive effects of alcohol. There was no moderating effect of desire to drink or negative alcohol expectancies. Thus, there is specific moderation of the effects of topiramate by both genotype and cognitive process. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Experimental and Clinical Psychopharmacology 12/2014; 22(6):494-501. DOI:10.1037/a0038350 · 2.55 Impact Factor
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    ABSTRACT: There is a large body of pre-clinical and some clinical data to link the neuropeptide galanin to a range of physiological and pathological functions that include metabolism, depression, and addiction. An enhancer region upstream of the human GAL transcriptional start site has previously been characterised. In-vitro transfection studies in rat hypothalamic neurons demonstrated that the CA allele was 40% less active than the GG allele in driving galanin expression. Our hypothesis was to investigate the effect of this galanin enhancer genotype on a range of variables that relate to the known functions of the galaninergic system in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort of young adults (N = 169–6,078). Initial findings showed a positive relationship of cannabis usage (OR = 2.070, P = 0.007, N = 406 (individuals who had used cannabis at least once within the last 12 months, total sample size 2731) with the GG haplotype, consistent with the previous published data linking galanin with an increased release of dopamine. As our sample size was relatively small we replicated the analysis in a larger cohort of 2,224 African Americans and 1,840 European Americans, but no discernible trend across genotypes was observed for the relationship with cannabis usage. Further, we found no association of the galanin enhancer genotype with any of the other pathophysiological parameters measured. These findings emphasise that preclinical data does not always predict clinical outcomes in cohort studies, noting that association studies are subject to multiple confounders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2014; 165(8). DOI:10.1002/ajmg.b.32270 · 3.27 Impact Factor
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    ABSTRACT: Background We examined whether the effects of topiramate and a single nucleotide polymorphism (rs2832407) in GRIK1, which encodes a kainate receptor subunit, persisted following a 12-week, placebo-controlled trial in 138 heavy drinkers with a treatment goal of reduced drinking. During treatment, topiramate 200 mg/d significantly reduced heavy drinking days and increased the frequency of abstinent days (Am J Psychiatry, 2014, 171:445). In the European-American (EA) subsample (n = 122), rs2832407 moderated the treatment effect on heavy drinking.Methods Patients were re-interviewed 3 and 6 months after the end of treatment. During treatment, we obtained 92.4% of drinking data, with 89.1 and 85.5% complete data at the 3- and 6-month follow-up visits, respectively. We examined 4 outcomes over time in the overall sample and the EA subsample: percent heavy drinking days (PHDD), percent days abstinent (PDA), serum γ-glutamyl transpeptidase (GGTP) concentration, and a measure of alcohol-related problems.ResultsIn the full sample, the lower PHDD and higher PDA seen with topiramate treatment were no longer significant during follow-up. Nonetheless, the topiramate-treated patients had lower alcohol-related problem scores during treatment and both follow-up periods. Further, in the EA subsample, the greater reduction in PHDD seen with topiramate treatment in rs2832407*C-allele homozygotes persisted throughout follow-up, with no significant effects in A-allele carriers. A reduction in GGTP concentration was consistent with the reduction in heavy drinking, but did not reach statistical significance.Conclusions There are persistent therapeutic effects of topiramate in heavy drinkers, principally in rs2832407*C-allele homozygotes.
    Alcoholism Clinical and Experimental Research 12/2014; 38(12). DOI:10.1111/acer.12578 · 3.31 Impact Factor
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    ABSTRACT: Background The ADH1B gene has consistently been implicated in problem drinking, but rarely incorporated into gene by environment investigations of alcohol phenotypes. This study examined the joint effects of variation in ADH1B and childhood adversity—a well-documented risk factor for alcohol problems and moderator of genetic liability to psychiatric outcomes—on maximum drinks consumed in a 24-hour period (maxdrinks) and alcohol use disorder (AUD) symptoms.Methods Data were drawn from 2,617 African-American (AA) and 1,436 European-American (EA) participants (42% female) in a multisite genetic study of substance dependence. We tested the most significant ADH1B single nucleotide polymorphisms for alcohol dependence from a genomewide association study with this sample, ADH1B-rs1229984 (Arg48His) and ADH1B-rs2066702 (Arg370Cys), in EA and AA subsamples, respectively.ResultsOrdinal regression analyses conducted separately by sex and population revealed significant main effects for childhood adversity for both alcohol phenotypes in AA women and men and for maxdrinks in EA women. A significant rs1229984 by childhood adversity interaction was observed for AUD symptoms in EA men. Unexposed His-allele carriers reported a mean of 3.6 AUD criteria, but adversity-exposed His-allele carriers endorsed approximately the same number (6.3) as those without the protective allele (6.3 and 7.0 for adversity-exposed and -unexposed groups, respectively).Conclusions Results suggest that under conditions of childhood adversity, the His allele does not exert its protective effects in EA men (OR = 0.57, CI: 0.32 to 1.01; p = 0.056). Findings highlight the robust risk effect conferred by childhood adversity and the importance of considering population and sex in genetically informative investigations of its association with alcohol outcomes.
    Alcoholism Clinical and Experimental Research 11/2014; 38(12). DOI:10.1111/acer.12572 · 3.31 Impact Factor
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    ABSTRACT: Evidence now implicates inflammatory proteins in the neurobiology of internalizing disorders. Genetic factors may influence individual responses to maltreatment; however, little work has examined inflammatory genetic variants in adults and none in children. The present study examined the role of an interleukin 1B gene (IL1B) variant in preschoolers exposed to maltreatment and other forms of adversity in internalizing symptom development. One hundred ninety-eight families were enrolled, with one child (age 3-5 years) from each family. Adversity measures included child protective service documentation of moderate-severe maltreatment in the last 6 months and interview-assessed contextual stressors. Internalizing symptoms were measured using the Child Behavior Checklist and the Diagnostic Infant and Preschool Assessment. Maltreated children had higher major depressive disorder (MDD) and posttraumatic stress disorder symptoms and marginally higher internalizing symptoms on the Child Behavior Checklist. Controlling for age, sex, and race, IL1B genotype was associated with MDD symptoms (p = .002). Contextual stressors were significantly associated with MDD and posttraumatic stress disorder and marginally with internalizing symptoms. The IL1B genotype interacted with contextual stress such that children homozygous for the minor allele had more MDD symptoms (p = .045). These results suggest that genetic variants of IL1B may modulate the development of internalizing symptoms in the face of childhood adversity.
    61st Meeting of American Academy of Child and Adolescent Psychiatry; 11/2014
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    ABSTRACT: Single nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the "missing heritability" might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5,152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genomewide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genomewide (e.g., P=2 × 10(-8) and OR (95% CI)=0.64 (0.54-0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, while others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication.Neuropsychopharmacology accepted article preview online, 27 October 2014. doi:10.1038/npp.2014.290.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2014; 40(4). DOI:10.1038/npp.2014.290 · 8.68 Impact Factor
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    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. Methods 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. Results 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. Conclusions The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.
    Biological Psychiatry 09/2014; DOI:10.1016/j.biopsych.2014.08.025 · 9.47 Impact Factor
  • Joel Gelernter
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    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.
    Biological Psychiatry 08/2014; 77(1). DOI:10.1016/j.biopsych.2014.08.005 · 9.47 Impact Factor
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    ABSTRACT: Background The neurofibromatosis type 1 (Nf1) gene encodes a GTPase activating protein that negatively regulates small GTPases of the Ras family. Methods 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. Results 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. Conclusions 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.
    Biological Psychiatry 08/2014; DOI:10.1016/j.biopsych.2014.07.031 · 9.47 Impact Factor
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    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.
    Human Genetics 07/2014; 133(11). DOI:10.1007/s00439-014-1473-x · 4.52 Impact Factor
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    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).
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    ABSTRACT: Growing evidence suggests that some individuals may exhibit symptoms of dependence to ultraviolet light, a known carcinogen, in the context of tanning. Genetic associations with tanning dependence (TD) have not yet been explored. We conducted an exome-wide association study in 79 individuals who exhibited symptoms of TD and 213 individuals with volitional exposure to ultraviolet light, but who were not TD based on three TD scales. 300,000 mostly exomic single nucleotide polymorphisms primarily in coding regions were assessed using an Affymetrix Axiom Array. We performed a gene burden test with Bonferroni correction for the number of genes examined (p<0.05/14,904 = 3.36 x 10-6). One gene, Patched Domain Containing 2 (PTCHD2), yielded a statistically significant p-value of 2.5 x 10-6 (OR = 0.27) with fewer individuals classified as TD having a minor allele at this locus. These results require replication, but are the first to support a specific genetic association with TD.This article is protected by copyright. All rights reserved.
    Experimental Dermatology 07/2014; 23(10). DOI:10.1111/exd.12503 · 4.12 Impact Factor
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    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; DOI:10.1037/a0037309 · 2.55 Impact Factor
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    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.
    Human Genetics 06/2014; DOI:10.1007/s00439-014-1452-2 · 4.52 Impact Factor
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    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). DOI:10.1111/j.1521-0391.2014.12102.x · 1.74 Impact Factor
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    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
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    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; DOI:10.1017/S1461145714000510 · 5.64 Impact Factor
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    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. DOI:10.1016/j.jaac.2013.12.025 · 6.97 Impact Factor
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    ABSTRACT: Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h(2) = 0.32 ± 0.05; P = 4.61 × 10(-14) ) with a strong genetic correlation with AUD (ρg = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10(-6) ) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10(-3) ), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10(-4) ), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2014; 165(4). DOI:10.1002/ajmg.b.32231 · 3.27 Impact Factor

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10k Citations
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Institutions

  • 1998–2015
    • Yale University
      • Department of Psychiatry
      New Haven, Connecticut, United States
  • 1991–2014
    • Yale-New Haven Hospital
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
  • 2009–2010
    • Medical University of South Carolina
      • Department of Psychiatry and Behavioral Sciences
      Charleston, SC, United States
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Boston University
      Boston, Massachusetts, United States
  • 2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006
    • University of Texas at Austin
      • Waggoner Center for Alcohol and Addiction Research
      Austin, Texas, United States
  • 2004
    • University of California, San Diego
      • Department of Psychiatry
      San Diego, CA, United States
  • 1996
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1995
    • National Institutes of Health
      Maryland, United States