Joel Gelernter

Yale University, New Haven, Connecticut, United States

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Publications (306)1749.64 Total impact

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    Tae-Hwi Schwantes-An · Juan Zhang · Li-Shiun Chen · Sarah M Hartz · Robert C Culverhouse · Xiangning Chen · Hilary Coon · Josef Frank · Helen M Kamens · Bettina Konte · [...] · Marcella Rietschel · Alec Roy · Dan Rujescu · Sirkku T Saarikoski · Gary E Swan · Alexandre A Todorov · Michael M Vanyukov · Robert B Weiss · Laura J Bierut · Nancy L Saccone
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    ABSTRACT: The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95 % C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.
    Behavior Genetics 09/2015; DOI:10.1007/s10519-015-9737-3 · 3.21 Impact Factor
  • Qian Wang · Can Yang · Joel Gelernter · Hongyu Zhao
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    ABSTRACT: Although some existing epidemiological observations and molecular experiments suggested that brain disorders in the realm of psychiatry may be influenced by immune dysregulation, the degree of genetic overlap between psychiatric disorders and immune disorders has not been well established. We investigated this issue by integrative analysis of genome-wide association studies of 18 complex human traits/diseases (five psychiatric disorders, seven immune disorders, and others) and multiple genome-wide annotation resources (central nervous system genes, immune-related expression-quantitative trait loci (eQTL) and DNase I hypertensive sites from 98 cell lines). We detected pleiotropy in 24 of the 35 psychiatric-immune disorder pairs. The strongest pleiotropy was observed for schizophrenia-rheumatoid arthritis with MHC region included in the analysis ([Formula: see text]), and schizophrenia-Crohn's disease with MHC region excluded ([Formula: see text]). Significant enrichment (>1.4 fold) of immune-related eQTL was observed in four psychiatric disorders. Genomic regions responsible for pleiotropy between psychiatric disorders and immune disorders were detected. The MHC region on chromosome 6 appears to be the most important with other regions, such as cytoband 1p13.2, also playing significant roles in pleiotropy. We also found that most alleles shared between schizophrenia and Crohn's disease have the same effect direction, with similar trend found for other disorder pairs, such as bipolar-Crohn's disease. Our results offer a novel bird's-eye view of the genetic relationship and demonstrate strong evidence for pervasive pleiotropy between psychiatric disorders and immune disorders. Our findings might open new routes for prevention and treatment strategies for these disorders based on a new appreciation of the importance of immunological mechanisms in mediating risk of many psychiatric diseases.
    Human Genetics 09/2015; DOI:10.1007/s00439-015-1596-8 · 4.82 Impact Factor
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    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2015; DOI:10.1002/ajmg.b.32357 · 3.42 Impact Factor
  • Renato Polimanti · Can Yang · Hongyu Zhao · Joel Gelernter
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    ABSTRACT: To understand the role of ancestral genomic background in substance dependence (SD) genome-wide association studies (GWAS), we analyzed population diversity at genetic loci associated with SD traits and evaluated its effect on GWAS outcomes. We investigated 24 genes with variants associated with SD by GWAS; and 82 loci with putative subordinate roles with respect to SD-associated genes. We observed high ancestry-related frequency differences in common functional alleles in GWAS relevant genes and their interactive partners. Common functional alleles with high frequency differences demonstrated significant effects on the GWAS outcomes. Population differences in SD GWAS outcomes seem not to be influenced by general variation across the genome, but by ancestry-related local haplotype structures at SD-associated loci.
    Pharmacogenomics 08/2015; 16(13):1-12. DOI:10.2217/pgs.15.91 · 3.22 Impact Factor
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    ABSTRACT: Chronic alcohol consumption may result in sustained gene expression alterations in the brain, leading to alcohol abuse or dependence. Because of ethical concerns of using live human brain cells in research, this hypothesis cannot be tested directly in live human brains. In the present study, we used human embryonic stem cell (hESC)-derived cortical neurons as in vitro cellular models to investigate alcohol-induced expression changes of genes involved in alcohol metabolism (ALDH2), anti-apoptosis (BCL2 and CCND2), neurotransmission (NMDA receptor subunit genes: GRIN1, GRIN2A, GRIN2B, and GRIN2D), calcium channel activity (ITPR2), or transcriptional repression (JARID2). hESCs were differentiated into cortical neurons, which were characterized by immunostaining using antibodies against cortical neuron-specific biomarkers. Ethanol-induced gene expression changes were determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). After a 7-day ethanol (50 mM) exposure followed by a 24-hour ethanol withdrawal treatment, five of the above nine genes (including all four NMDA receptor subunit genes) were highly upregulated (GRIN1: 1.93-fold, P = 0.003; GRIN2A: 1.40-fold, P = 0.003; GRIN2B: 1.75-fold, P = 0.002; GRIN2D: 1.86-fold, P = 0.048; BCL2: 1.34-fold, P = 0.031), and the results of GRIN1, GRIN2A, and GRIN2B survived multiple comparison correction. Our findings suggest that alcohol responsive genes, particularly NMDA receptor genes, play an important role in regulating neuronal function and mediating chronic alcohol consumption-induced neuroadaptations.
    PLoS ONE 08/2015; 10(8):e0134907. DOI:10.1371/journal.pone.0134907 · 3.23 Impact Factor
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    ABSTRACT: The Research Domain Criteria (RDoC) project was initiated to develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures. This article reviews the rationale behind the RDoC program, its goals, and central tenets; discusses application of an RDoC framework to research with maltreated children; and highlights some clinical implications of this work. Published RDoC papers were reviewed, together with relevant preclinical and clinical studies that guide our work on risk and resilience in maltreated children. The ultimate long-term goal of the RDoC initiative is precision medicine in psychiatry. In the interim, the RDoC initiative provides a framework to organize research to help develop the database required to derive a new psychiatric nomenclature that can appropriately match treatments to patients. The primary focus of RDoC is on neural circuitry, with levels of analyses that span from molecules to behavior. There has been some concern that the RDoC framework is reductionist, with an overemphasis on neural circuits and genetics; however, the briefly reviewed, burgeoning literature on neuroplasticity and epigenetics highlights that this concern is unwarranted, as one cannot study neural circuits and genetics without considering experience. The study of maltreated children has a number of advantages for the RDoC project, including the following: study of a subset of patients who are often not responsive to standard interventions; examination of a relatively homogenous sample with onset of psychopathology proposed to be associated with stress-related mechanisms; and well-established, relevant animal models to facilitate translational research. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
    Journal of the American Academy of Child & Adolescent Psychiatry 06/2015; 54(8). DOI:10.1016/j.jaac.2015.06.001 · 7.26 Impact Factor
  • Cécile M Denis · Joel Gelernter · Amy B Hart · Henry R Kranzler
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    ABSTRACT: Although studies have examined the impact of changes made in DSM-5 on the estimated prevalence of substance use disorder (SUD) diagnoses, there is limited evidence concerning the reliability of DSM-5 SUDs. We evaluated the inter-observer reliability of four DSM-5 SUDs in a sample in which we had previously evaluated the reliability of DSM-IV diagnoses, allowing us to compare the two systems. Two different interviewers each assessed 173 subjects over a 2-week period using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Using the percent agreement and kappa (κ) coefficient, we examined the reliability of DSM-5 lifetime alcohol, opioid, cocaine, and cannabis use disorders, which we compared to that of SSADDA-derived DSM-IV SUD diagnoses. We also assessed the effect of additional lifetime SUD and lifetime mood or anxiety disorder diagnoses on the reliability of the DSM-5 SUD diagnoses. Reliability was good to excellent for the four disorders, with κ values ranging from 0.65 to 0.94. Agreement was consistently lower for SUDs of mild severity than for moderate or severe disorders. DSM-5 SUD diagnoses showed greater reliability than DSM-IV diagnoses of abuse or dependence or dependence only. Co-occurring SUD and lifetime mood or anxiety disorders exerted a modest effect on the reliability of the DSM-5 SUD diagnoses. For alcohol, opioid, cocaine and cannabis use disorders, DSM-5 criteria and diagnoses are at least as reliable as those of DSM-IV. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 05/2015; 153. DOI:10.1016/j.drugalcdep.2015.05.019 · 3.42 Impact Factor
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    ABSTRACT: Genomewide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a paradigm that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28%[EA] and 6%[AA]) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the associate of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.Neuropsychopharmacology accepted article preview online, 07 May 2015. doi:10.1038/npp.2015.131.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2015; DOI:10.1038/npp.2015.131 · 7.05 Impact Factor
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    ABSTRACT: Alcohol dependence is frequently co-morbid with cognitive impairment. The relationship between these traits is complex as cognitive dysfunction may arise as a consequence of heavy drinking or exist prior to the onset of dependence. In the present study, we tested the genetic overlap between cognitive abilities and alcohol dependence using polygenic risk scores (PGRS). We created two independent PGRS derived from two recent genome-wide association studies (GWAS) of alcohol dependence (SAGE GWAS: n = 2750; Yale-Penn GWAS: n = 2377) in a population-based cohort, Generation Scotland: Scottish Family Health Study (GS:SFHS) (n = 9863). Data on alcohol consumption and four tests of cognitive function [Mill Hill Vocabulary (MHV), digit symbol coding, phonemic verbal fluency (VF) and logical memory] were available. PGRS for alcohol dependence were negatively associated with two measures of cognitive function: MHV (SAGE: P = 0.009, β = -0.027; Yale-Penn: P = 0.001, β = -0.034) and VF (SAGE: P = 0.0008, β = -0.036; Yale-Penn: P = 0.00005, β = -0.044). VF remained robustly associated after adjustment for education and social deprivation; however, the association with MHV was substantially attenuated. Shared genetic variants may account for some of the phenotypic association between cognitive ability and alcohol dependence. A significant negative association between PGRS and social deprivation was found (SAGE: P = 5.2 × 10(-7) , β = -0.054; Yale-Penn: P = 0.000012, β = -0.047). Individuals living in socially deprived regions were found to carry more alcohol dependence risk alleles which may contribute to the increased prevalence of problem drinking in regions of deprivation. Future work to identify genes which affect both cognitive impairment and alcohol dependence will help elucidate biological processes common to both disorders. © 2015 Society for the Study of Addiction.
    Addiction Biology 05/2015; DOI:10.1111/adb.12245 · 5.36 Impact Factor
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    ABSTRACT: Background We conducted a genomewide association study (GWAS) for maximum number of alcoholic drinks consumed in a 24-hour period (“MaxDrinks”), in 2 independent samples comprised of over 9,500 subjects, following up on our GWAS for alcohol dependence (AD) in European Americans (EAs) and African Americans (AAs).Methods The samples included our GWAS samples (Yale-UPenn) recruited for studies of the genetics of drug or AD, and a publicly available sample: the Study of Addiction: Genetics and Environment (SAGE). Genomewide association analysis was performed for ~890,000 single nucleotide polymorphisms (SNPs) using linear association random effects models. EAs and AAs were separately analyzed.ResultsThe results confirmed significant associations of the well-known functional loci at ADH1B with MaxDrinks in EAs (rs1229984 Arg48His p = 5.96 × 10−15) and AAs (rs2066702 Arg370Cys, p = 2.50 × 10−10). The region of significant association on chromosome 4 was extended to LOC100507053 in AAs but not EAs. We also identified potentially novel significant common SNPs for MaxDrinks in EAs in the Yale-UPenn sample: rs1799876 at SERPINC1 on chromosome 1 (4.00 × 10−8) and rs2309169 close to ANKRD36 on chromosome 2 (p = 5.58 × 10−9). After adjusting for the peak SNP rs1229984 on ADH1B, rs1799876 was nearly significant (p = 1.99 × 10−7) and rs2309169 remained highly significant (2.12 × 10−9).Conclusions The results provide further support that ADH1B modulates alcohol consumption. Future replications of potential novel loci are warranted. This is the largest MaxDrinks GWAS to date, the first in AAs.
    Alcoholism Clinical and Experimental Research 05/2015; 39(7). DOI:10.1111/acer.12751 · 3.21 Impact Factor
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    ABSTRACT: In archival samples of European-ancestry subjects, light-eyed individuals have been found to consume more alcohol than dark-eyed individuals. No published population-based studies have directly tested the association between alcohol dependence (AD) and eye color. We hypothesized that light-eyed individuals have a higher prevalence of AD than dark-eyed individuals. A mixture model was used to select a homogeneous sample of 1,263 European-Americans and control for population stratification. After quality control, we conducted an association study using logistic regression, adjusting for confounders (age, sex, and genetic ancestry). We found evidence of association between AD and blue eye color (P = 0.0005 and odds ratio = 1.83 (1.31–2.57)), supporting light eye color as a risk factor relative to brown eye color. Network-based analyses revealed a statistically significant (P = 0.02) number of genetic interactions between eye color genes and AD-associated genes. We found evidence of linkage disequilibrium between an AD-associated GABA receptor gene cluster,GABRB3/GABRG3, and eye color genes,OCA2/HERC2, as well as between AD-associated GRM5 and pigmentation-associated TYR. Our population-phenotype, network, and linkage disequilibrium analyses support association between blue eye color and AD. Although we controlled for stratification we cannot exclude underlying occult stratification as a contributor to this observation. Although replication is needed, our findings suggest that eye pigmentation information may be useful in research on AD. Further characterization of this association may unravel new AD etiological factors.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2015; 168(5). DOI:10.1002/ajmg.b.32316 · 3.42 Impact Factor
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    ABSTRACT: Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding. © 2015 Society for the Study of Addiction.
    Addiction Biology 04/2015; DOI:10.1111/adb.12244 · 5.36 Impact Factor
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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 · 5.36 Impact Factor
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    ABSTRACT: The genetic diversity of loci and mutations underlying hereditary hearing loss is an active area of investigation. To identify loci associated with predominantly non-syndromic sensorineural hearing loss, we performed exome sequencing of families and of single probands, as well as copy number variation (CNV) mapping in a case-control cohort. Analysis of three distinct families revealed several candidate loci in two families and a single strong candidate gene, MYH7B, for hearing loss in one family. MYH7B encodes a Type II myosin, consistent with a role for cytoskeletal proteins in hearing. High-resolution genome-wide CNV analysis of 150 cases and 157 controls revealed deletions in genes known to be involved in hearing (e.g. GJB6, OTOA, and STRC, encoding connexin 30, otoancorin, and stereocilin, respectively), supporting CNV contributions to hearing loss phenotypes. Additionally, a novel region on chromosome 16 containing part of the PDXDC1 gene was found to be frequently deleted in hearing loss patients (OR = 3.91, 95% CI: 1.62-9.40, p = 1.45 x 10-7). We conclude that many known as well as novel loci and distinct types of mutations not typically tested in clinical settings can contribute to the etiology of hearing loss. Our study also demonstrates the challenges of exome sequencing and genome-wide CNV mapping for direct clinical application, and illustrates the need for functional and clinical follow-up as well as curated open-access databases.
    BMC Genomics 12/2014; 15(1):1155. DOI:10.1186/1471-2164-15-1155 · 3.99 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 · 2.71 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 · 3.42 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 · 3.21 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 · 3.21 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 · 7.05 Impact Factor

Publication Stats

12k Citations
1,749.64 Total Impact Points


  • 1998–2015
    • Yale University
      • Department of Psychiatry
      New Haven, Connecticut, United States
  • 2000–2014
    • Yale-New Haven Hospital
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
  • 2011
    • University of New Haven
      New Haven, Connecticut, United States
  • 2010
    • Medical University of South Carolina
      • Department of Psychiatry and Behavioral Sciences
      Charleston, SC, United States
  • 2009
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2008
    • University of Connecticut
      Storrs, Connecticut, United States
  • 2007
    • National Center for PTSD
      Washington, Washington, D.C., United States
  • 2005
    • First Pavlov State Medical University Of St Petersburg
      Sankt-Peterburg, St.-Petersburg, Russia
  • 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