Publications by authors named "Richard Sherva"

56 Publications

Genome-wide association study of stimulant dependence.

Transl Psychiatry 2021 06 29;11(1):363. Epub 2021 Jun 29.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, 02118, USA.

Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (p = 3.6 × 10), an anxiety disorder in EAs (p = 2.1 × 10), and ADHD in both AAs (p = 3.0 × 10) and EAs (p = 6.7 × 10). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.
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http://dx.doi.org/10.1038/s41398-021-01440-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257618PMC
June 2021

Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes.

Explor Med 2021 28;2:60-73. Epub 2021 Feb 28.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted.

Methods: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts.

Results: In the discovery sample, three independent regions containing variants associated with time to dependence at < 5 x 10 were identified, one (rs61835088 = 1.03 x 10) for cocaine in the combined EA-AA meta-analysis in the gene on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, = 1.37 x 10) and 9 (rs7032521, = 3.30 x 10). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, = 3.71 x 10 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, = 2.57 x 10) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD.

Conclusions: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.
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http://dx.doi.org/10.37349/emed.2021.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192073PMC
February 2021

Identifying factors associated with opioid cessation in a biracial sample using machine learning.

Explor Med 2020 29;1(1):27-41. Epub 2020 Feb 29.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.

Aim: Racial disparities in opioid use disorder (OUD) management exist, however, and there is limited research on factors that influence opioid cessation in different population groups.

Methods: We employed multiple machine learning prediction algorithms least absolute shrinkage and selection operator, random forest, deep neural network, and support vector machine to assess factors associated with ceasing opioid use in a sample of 1,192 African Americans (AAs) and 2,557 individuals of European ancestry (EAs) who met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for OUD. Values for nearly 4,000 variables reflecting demographics, alcohol and other drug use, general health, non-drug use behaviors, and diagnoses for other psychiatric disorders, were obtained for each participant from the Semi-Structured Assessment for Drug Dependence and Alcoholism, a detailed semi-structured interview.

Results: Support vector machine models performed marginally better on average than other machine learning methods with maximum prediction accuracies of 75.4% in AAs and 79.4% in EAs. Subsequent stepwise regression considered the 83 most highly ranked variables across all methods and models and identified less recent cocaine use (AAs: odds ratio (OR) = 1.82, = 9.19 × 10; EAs: OR = 1.91, = 3.30 × 10), shorter duration of opioid use (AAs: OR = 0.55, = 5.78 × 10; EAs: OR = 0.69, = 3.01 × 10), and older age (AAs: OR = 2.44, = 1.41 × 10; EAs: OR = 2.00, = 5.74 × 10) as the strongest independent predictors of opioid cessation in both AAs and EAs. Attending self-help groups for OUD was also an independent predictor ( < 0.05) in both population groups, while less gambling severity (OR = 0.80, = 3.32 × 10) was specific to AAs and post-traumatic stress disorder recovery (OR = 1.93, = 7.88 × 10), recent antisocial behaviors (OR = 0.64, = 2.69 × 10), and atheism (OR = 1.45, = 1.34 × 10) were specific to EAs. Factors related to drug use comprised about half of the significant independent predictors in both AAs and EAs, with other predictors related to non-drug use behaviors, psychiatric disorders, overall health, and demographics.

Conclusions: These proof-of-concept findings provide avenues for hypothesis-driven analysis, and will lead to further research on strategies to improve OUD management in EAs and AAs.
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http://dx.doi.org/10.37349/emed.2020.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861053PMC
February 2020

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

Nat Commun 2020 11 3;11(1):5562. Epub 2020 Nov 3.

Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking.
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http://dx.doi.org/10.1038/s41467-020-19265-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642344PMC
November 2020

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry 2020 12 20;7(12):1032-1045. Epub 2020 Oct 20.

Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10). Cannabis use disorder and cannabis use were genetically correlated (r 0·50, p=1·50 × 10), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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http://dx.doi.org/10.1016/S2215-0366(20)30339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674631PMC
December 2020

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways.

Alzheimers Dement 2020 08 23;16(8):1134-1145. Epub 2020 Jun 23.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD.

Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes.

Results: Suggestive associations (P < 1.0 × 10 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10 ), chromosome 7 (rs60465337,P = 4.06 × 10 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10 ) and 4 (rs1304013, P = 7.73 × 10 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified.

Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.
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http://dx.doi.org/10.1002/alz.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924136PMC
August 2020

Association of OPRM1 Functional Coding Variant With Opioid Use Disorder: A Genome-Wide Association Study.

JAMA Psychiatry 2020 Oct;77(10):1072-1080

Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut.

Importance: With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD).

Objectives: To detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits.

Design, Setting, And Participants: A genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations.

Main Outcomes And Measures: Main outcomes were International Classification of Diseases, Ninth Revision-diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-diagnosed OUD (Million Veteran Program), and DSM-IV-defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment).

Results: A total of 114 759 individuals (101 016 men [88%]; mean [SD] age, 60.1 [12.8] years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: β = -0.066 [SE = 0.012]; P = 1.51 × 10-8). The finding was replicated in 2 independent samples. Single-nucleotide polymorphism-based heritability of OUD was 11.3% (SE = 1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis.

Conclusions And Relevance: This genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post-genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies-especially those of non-European ancestry-is a crucial next step in identifying additional significant risk loci.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.1206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270886PMC
October 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Genome-Wide Association Study of Opioid Cessation.

J Clin Med 2020 Jan 9;9(1). Epub 2020 Jan 9.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.

The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in ( = 2.24 × 10), rs36098404 in ( = 2.24 × 10), and rs592026 in ( = 6.53 × 10). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism ( = 3.79 × 10) and fibroblast growth factor (FGF) signaling ( = 2.39 × 10). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.
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http://dx.doi.org/10.3390/jcm9010180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019731PMC
January 2020

Post-GWAS analysis of six substance use traits improves the identification and functional interpretation of genetic risk loci.

Drug Alcohol Depend 2020 01 4;206:107703. Epub 2019 Nov 4.

Department of Psychiatry, Amsterdam UMC, Amsterdam Neuroscience, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; QIMR Berghofer, Translational Neurogenomics group, Brisbane, Australia.

Background: Little is known about the functional mechanisms through which genetic loci associated with substance use traits ascertain their effect. This study aims to identify and functionally annotate loci associated with substance use traits based on their role in genetic regulation of gene expression.

Methods: We evaluated expression Quantitative Trait Loci (eQTLs) from 13 brain regions and whole blood of the Genotype-Tissue Expression (GTEx) database, and from whole blood of the Depression Genes and Networks (DGN) database. The role of single eQTLs was examined for six substance use traits: alcohol consumption (N = 537,349), cigarettes per day (CPD; N = 263,954), former vs. current smoker (N = 312,821), age of smoking initiation (N = 262,990), ever smoker (N = 632,802), and cocaine dependence (N = 4,769). Subsequently, we conducted a gene level analysis of gene expression on these substance use traits using S-PrediXcan.

Results: Using an FDR-adjusted p-value <0.05 we found 2,976 novel candidate genetic loci for substance use traits, and identified genes and tissues through which these loci potentially exert their effects. Using S-PrediXcan, we identified significantly associated genes for all substance traits.

Discussion: Annotating genes based on transcriptomic regulation improves the identification and functional characterization of candidate loci and genes for substance use traits.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.107703DOI Listing
January 2020

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

Nicotine Tob Res 2020 05;22(6):900-909

MRC Integrative Epidemiology Unit (IEU) at the University of Bristol, Bristol, BS, UK.

Introduction: FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported.

Methods: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts.

Results: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND.

Conclusions: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND.

Implications: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.
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http://dx.doi.org/10.1093/ntr/ntz099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249921PMC
May 2020

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.

Nat Neurosci 2018 12 26;21(12):1656-1669. Epub 2018 Nov 26.

NIH/NIAAA, Laboratory of Neurogenetics, Bethesda, MD, USA.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10) and African ancestries (rs2066702; P = 2.2 × 10). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
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http://dx.doi.org/10.1038/s41593-018-0275-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430207PMC
December 2018

Genome-wide association meta-analysis of age at first cannabis use.

Addiction 2018 11 19;113(11):2073-2086. Epub 2018 Aug 19.

Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia.

Background And Aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants.

Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals.

Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant.

Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.
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http://dx.doi.org/10.1111/add.14368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087375PMC
November 2018

Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans.

Biol Psychiatry 2018 11 11;84(10):762-770. Epub 2018 Jan 11.

Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Massachusetts; Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, Massachusetts; VA Connecticut Healthcare Center, West Haven, Massachusetts. Electronic address:

Background: Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology.

Methods: We completed an OD genome-wide association study in 3058 opioid-exposed European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count.

Results: By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10). The association was also genome-wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 [1106 meeting DSM-IV OD criteria]; p = 3.0 × 10) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 × 10). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1.

Conclusions: This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.
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http://dx.doi.org/10.1016/j.biopsych.2017.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041180PMC
November 2018

Single Nucleotide Polymorphism Facilitated Down-Regulation of the Cohesin Stromal Antigen-1: Implications for Colorectal Cancer Racial Disparities.

Neoplasia 2018 03 19;20(3):289-294. Epub 2018 Feb 19.

Department of Medicine, Section of Gastroenterology, Boston University Medical Center, Boston, MA 02118, USA. Electronic address:

The biological underpinnings for racial disparities in colorectal cancer (CRC) incidence remain to be elucidated. We have previously reported that the cohesin SA-1 down-regulation is an early event in colon carcinogenesis which is dramatically accentuated in African-Americans. In order to investigate the mechanism, we evaluated single nucleotide polymorphisms (SNPs) for association with SA-1-related outcomes followed by gene editing of candidate SNP. We observed that rs34149860 SNP was significantly associated with a lower colonic mucosal SA-1 expression and evaluation of public databases showed striking racial discordance. Given that the predicted SNP would alter miR-29b binding site, we used CRISPR knock-in in CRC cells and demonstrated that the SNP but not wild-type had profound alterations in SA-1 expression with miR-29b inhibitor. This is the first demonstration of high-order chromatin regulators as a modulator of racial differences, risk alteration with SNPs and finally specific modulation by microRNAs.
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http://dx.doi.org/10.1016/j.neo.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883624PMC
March 2018

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

Alzheimers Dement 2018 05 20;14(5):623-633. Epub 2017 Dec 20.

Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, USA; Neurogenetics and Integrated Genomics, Andover Innovative Medicines (AiM) Institute, Eisai Inc, Andover, MA, USA. Electronic address:

Introduction: Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.

Methods: We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study.

Results: In CN subjects, study-wide significant (P < 8.3 × 10) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls.

Discussion: Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.
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http://dx.doi.org/10.1016/j.jalz.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938137PMC
May 2018

Genetic Risk Variants Associated With Comorbid Alcohol Dependence and Major Depression.

JAMA Psychiatry 2017 12;74(12):1234-1241

Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

Importance: Alcohol dependence (AD) and major depression (MD) are leading causes of disability that often co-occur. Genetic epidemiologic data have shown that AD and MD share a common possible genetic cause. The molecular nature of this shared genetic basis is poorly understood.

Objectives: To detect genetic risk variants for comorbid AD and MD and to determine whether polygenic risk alleles are shared with neuropsychiatric traits or subcortical brain volumes.

Design, Setting, And Participants: This genome-wide association study analyzed criterion counts of comorbid AD and MD in African American and European American data sets collected as part of the Yale-Penn study of the genetics of drug and alcohol dependence from February 14, 1999, to January 13, 2015. After excluding participants never exposed to alcohol or with missing information for any diagnostic criterion, genome-wide association studies were performed on 2 samples (the Yale-Penn 1 and Yale-Penn 2 samples) totaling 4653 African American participants and 3169 European American participants (analyzed separately). Tests were performed to determine whether polygenic risk scores derived from potentially related traits in European American participants could be used to estimate comorbid AD and MD.

Main Outcomes And Measures: Comorbid criterion counts (ranging from 0 to 14) for AD (7 criteria) and MD (9 criteria, scaled to 7) as defined by the DSM-IV.

Results: Of the 7822 participants (3342 women and 4480 men; mean [SD] age, 40.1 [10.7] years), the median comorbid criterion count was 6.2 (interquartile range, 2.3-10.9). Under the linear regression model, rs139438618 at the semaphorin 3A (SEMA3A [OMIM 603961]) locus was significantly associated with AD and MD comorbidity in African American participants in the Yale-Penn 1 sample (β = 0.89; 95% CI, 0.57-1.20; P = 2.76 × 10-8). In the independent Yale-Penn 2 sample, the association was also significant (β = 0.83; 95% CI, 0.39-1.28; P = 2.06 × 10-4). Meta-analysis of the 2 samples yielded a more robust association (β = 0.87; 95% CI, 0.61-1.12; P = 2.41 × 10-11). There was no significant association identified in European American participants. Analyses of polygenic risk scores showed that individuals with a higher risk of neuroticism (β = 1.01; 95% CI, 0.50-1.52) or depressive symptoms (β = 0.87; 95% CI, 0.32-1.42) and a lower level of subjective well-being (β = -0.94; 95% CI, -1.46 to -0.42) and educational attainment (β = -1.00, 95% CI, -1.57 to -0.44) had a higher level of AD and MD comorbidity, while larger intracranial (β = 1.07; 95% CI, 0.50 to 1.64) and smaller putamen volumes (β = -1.16; 95% CI, -1.86 to -0.46) were associated with higher risks of AD and MD comorbidity.

Conclusions And Relevance: SEMA3A variation is significantly and replicably associated with comorbid AD and MD in African American participants. Analyses of polygenic risk scores identified pleiotropy with neuropsychiatric traits and brain volumes. Further studies are warranted to understand the biological and genetic mechanisms of this comorbidity, which could facilitate development of medications and other treatments for comorbid AD and MD.
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http://dx.doi.org/10.1001/jamapsychiatry.2017.3275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331050PMC
December 2017

Oxytocin receptor gene polymorphisms, attachment, and PTSD: Results from the National Health and Resilience in Veterans Study.

J Psychiatr Res 2017 11 8;94:139-147. Epub 2017 Jul 8.

U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

The human oxytocin system is implicated in social behavior and stress recovery. Polymorphisms in the oxytocin receptor gene (OXTR) may interact with attachment style to predict stress-related psychopathology like posttraumatic stress disorder (PTSD). The objective of this study was to examine independent and interactive effects of the OXTR single nucleotide polymorphism (SNP) rs53576, which has been associated with stress reactivity, support-seeking, and PTSD in prior studies, and attachment style on risk for PTSD in a nationally representative sample of 2163 European-American (EA) U.S. military veterans who participated in two independent waves of the National Health and Resilience in Veterans Study (NHRVS). Results revealed that insecure attachment style [adjusted odds ratio (OR) = 4.29; p < 0.001] and the interaction of rs53576 and attachment style (OR = 2.58, p = 0.02) were associated with probable lifetime PTSD. Among individuals with the minor A allele, the prevalence of probable PTSD was significantly higher among those with an insecure attachment style (23.9%) than those with a secure attachment style (2.0%), equivalent to an adjusted OR of 10.7. We attempted to replicate these findings by utilizing dense marker data from a genome-wide association study of 2215 high-risk civilians; one OXTR variant, though not rs53576, was associated with PTSD. Exploratory analyses in the veteran sample revealed that the interaction between this variant and attachment style predicting probable PTSD approached statistical significance. Results indicate that polymorphisms in the OXTR gene and attachment style may contribute to vulnerability to PTSD in U.S. military veterans.
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http://dx.doi.org/10.1016/j.jpsychires.2017.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605420PMC
November 2017

identified in a genome-wide gene × cannabis dependence interaction analysis of risky sexual behaviours.

J Psychiatry Neurosci 2017 06;42(4):252-261

From the Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, Conn., USA (Polimanti, Pearlson, Gelernter); Olin Research Center, Institute of Living/Hartford Hospital, Hartford, Conn., USA (Meda, Pearlson); the Department of Neuroscience, Yale University School of Medicine, New Haven, Conn., USA (Pearlson, Gelernter); the Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Mass., USA (Sherva, Farrer); the Department of Biostatistics, Yale University School of Public Health, New Haven, Conn., USA (Zhao); the Department of Genetics, Yale University School of Medicine, New Haven, Conn., USA (Zhao, Gelernter); the Departments of Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Mass., USA (Farrer); and the Department of Psychiatry, University of Pennsylvania School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, Pa., USA (Kranzler).

Background: We conducted a genome-wide gene × environment interaction analysis to identify genetic variants that interact with cannabis dependence (CaD) in influencing risky sexual behaviours (RSB).

Methods: Our sample included cannabis-exposed and sexually experienced African-American and European-American participants. A DSM-IV CaD diagnosis and RSB were evaluated using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We analyzed RSBs as a score that takes into account experiences of unprotected sex and multiple sexual partners.

Results: A total of 3350 people participated in our study; 43% had a CaD diagnosis, 56% were African-American and 33% were women. We identified a genome-wide significant locus in African-American participants ( rs72993629, = 2.73 × 10) and a potential transpopulation signal in women ( rs12944716, = 5.27 × 10). A resting-state fMRI follow-up analysis of rs72993629 conducted in an independent cohort showed 2 significant associations: reduced power of the left paracentral lobule in amplitude of low frequency fluctuations (ALFF) analysis ( = 7.8 × 10) and reduced power of the right pallidum in fractional ALFF analysis ( = 4.6 × 10). The activity of these brain regions is known to be involved in sexual functions and behaviours. The result functionally recapitulated our finding observed in our previous genome-wide association study of CaD. The probability of identifying 2 genes in 2 independent genome-wide investigations by chance is approximately 1 in 1.1 million.

Limitations: We were not able to identify any African-American cohort with appropriate sample size, and phenotypic assessment is available to replicate our findings.

Conclusion: The and genes, which are located on different chromosomes, encode specialized calcium-binding proteins. These data support a role for calcium homeostasis in individuals with CaD and its induced behaviours.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487272PMC
http://dx.doi.org/10.1503/jpn.160189DOI Listing
June 2017

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.

Alcohol Clin Exp Res 2017 May 30;41(5):911-928. Epub 2017 Mar 30.

Privatklinik Meiringen, Meiringen, Switzerland.

Background: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified.

Methods: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue.

Results: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc).

Conclusions: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.
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http://dx.doi.org/10.1111/acer.13362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404949PMC
May 2017

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Alzheimers Dement 2017 Jul 7;13(7):727-738. Epub 2017 Feb 7.

Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA; Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA; National Center for PTSD, Behavioral Science Division, Boston VA Healthcare System, Boston, MA, USA.

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.

Results: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10).

Discussion: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.
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http://dx.doi.org/10.1016/j.jalz.2016.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496797PMC
July 2017

Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity.

Am J Addict 2017 Jan 16;26(1):42-49. Epub 2016 Dec 16.

Department of Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts.

Background And Objectives: There is significant variability in severity of neonatal abstinence syndrome (NAS) due to in utero opioid exposure. Our previous study identified single nucleotide polymorphisms (SNPs) in the prepronociceptin (PNOC) and catechol-O-methyltransferase (COMT) genes that were associated with differences in NAS outcomes. This study looks at the same SNPs in PNOC and COMT in an independent cohort in an attempt to replicate previous findings.

Methods: For the replication cohort, full-term opioid-exposed newborns and their mothers (n = 113 pairs) were studied. A DNA sample was obtained and genotyped for five SNPs in the PNOC and COMT genes. The association of each SNP with NAS outcomes (length of hospitalization, need for pharmacologic treatment, and total opioid days) was evaluated, with an experiment-wise significance level set at α < .003 and point-wise level of α < .05. SNP associations in a combined cohort of n = 199 pairs (replication cohort plus 86 pairs previously reported), were also examined.

Results: In the replication cohort, mothers with the COMT rs4680 G allele had infants with a reduced risk for treatment with two medications for NAS (adjusted OR = .5, p = .04), meeting point-wise significance. In the combined cohort, infants with the PNOC rs4732636 A allele had a reduced need for medication treatment (adjusted OR 2.0, p = .04); mothers with the PNOC rs351776 A allele had infants who were treated more often with two medications (adjusted OR 2.3, p = .004) with longer hospitalization by 3.3 days (p = .01). Mothers with the COMT rs740603 A allele had infants who were less often treated with any medication (adjusted OR .5, p = .02). Though all SNP associations all met point wise and clinical significance, they did not meet the experiment-wise significance threshold.

Conclusions And Scientific Significance: We found differences in NAS outcomes depending on PNOC and COMT SNP genotype. This has important implications for identifying infants at risk for severe NAS who could benefit from tailored treatment regimens. Further testing in a larger sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants with NAS. (Am J Addict 2017;26:42-49).
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http://dx.doi.org/10.1111/ajad.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206487PMC
January 2017

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

Alzheimers Dement 2017 02 20;13(2):119-129. Epub 2016 Oct 20.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Introduction: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power.

Methods: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs.

Results: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10), upstream of COBL, and rs16961023 (P = 4.6 × 10), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability.

Discussion: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.
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http://dx.doi.org/10.1016/j.jalz.2016.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318231PMC
February 2017

The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable.

Neurobiol Aging 2016 May 21;41:115-121. Epub 2016 Feb 21.

Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address:

Late-onset Alzheimer's disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%-7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843522PMC
May 2016

Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks.

JAMA Psychiatry 2016 May;73(5):472-80

VA Cooperative Studies Program Coordinating Center, West Haven, Connecticut8Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut13Department of Psychiatry, VA Connecticut Healthcare Center, Yale University School of Medicine, West Hav.

Importance: Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated.

Objective: To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics.

Design, Setting, And Participants: This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015.

Main Outcomes And Measures: Criterion count for DSM-IV CAD.

Results: Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54, P = 4.32 × 10-10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54, P = 1.33 × 10-9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (β = 0.29, P = 2.13 × 10-8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development.

Conclusions And Relevance: These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974817PMC
May 2016

The genetics of alcohol dependence: Twin and SNP-based heritability, and genome-wide association study based on AUDIT scores.

Am J Med Genet B Neuropsychiatr Genet 2015 Dec 14;168(8):739-48. Epub 2015 Sep 14.

Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.

Alcohol dependence (AD) is among the most common and costly public health problems contributing to morbidity and mortality throughout the world. In this study, we investigate the genetic basis of AD in a Dutch population using data from the Netherlands Twin Register (NTR) and the Netherlands Study of Depression and Anxiety (NESDA). The presence of AD was ascertained via the Alcohol Use Disorders Identification Test (AUDIT) applying cut-offs with good specificity and sensitivity in identifying those at risk for AD. Twin-based heritability of AD-AUDIT was estimated using structural equation modeling of data in 7,694 MZ and DZ twin pairs. Variance in AD-AUDIT explained by all SNPs was estimated with genome-wide complex trait analysis (GCTA). A genome-wide association study (GWAS) was performed in 7,842 subjects. GWAS SNP effect concordance analysis was performed between our GWAS and a recent AD GWAS using DSM-IV diagnosis. The twin-based heritability of AD-AUDIT was estimated at 60% (55-69%). GCTA showed that common SNPs jointly capture 33% (SE = 0.12, P = 0.002) of this heritability. In the GWAS, the top hits were positioned within four regions (4q31.1, 2p16.1, 6q25.1, 7p14.1) with the strongest association detected for rs55768019 (P = 7.58 × 10(-7) ). This first GWAS of AD using the AUDIT measure found results consistent with previous genetic studies using DSM diagnosis: concordance in heritability estimates and direction of SNPs effect and overlap with top hits from previous GWAS. Thus, the use of appropriate questionnaires may represent cost-effective strategies to phenotype samples in large-scale biobanks or other population-based datasets.
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http://dx.doi.org/10.1002/ajmg.b.32379DOI Listing
December 2015

Variations in opioid receptor genes in neonatal abstinence syndrome.

Drug Alcohol Depend 2015 Oct 8;155:253-9. Epub 2015 Jul 8.

Psychology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States. Electronic address:

Background: There is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability.

Methods: Full-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated.

Results: SNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=-6.9 days, p=0.02) and COMT rs740603 A allele (β=-5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level.

Conclusions: These findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581974PMC
October 2015

Genomewide Association Study for Maximum Number of Alcoholic Drinks in European Americans and African Americans.

Alcohol Clin Exp Res 2015 Jul 3;39(7):1137-47. Epub 2015 Jun 3.

Department of Psychiatry, Yale School of Medicine, and VA CT Healthcare Center, West Haven, Connecticut.

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.

Results: The 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.
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http://dx.doi.org/10.1111/acer.12751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706077PMC
July 2015

Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.

Biol Psychiatry 2015 Mar 16;77(5):493-503. Epub 2014 Sep 16.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts; Departments of Neurology, Ophthalmology, Genetics and Genomics, and Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts.

Background: We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerström Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations.

Methods: Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered Fagerström Test for Nicotine Dependence 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 single nucleotide polymorphism (SNP) subset.

Results: In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 × 10(-8) (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 × 10(-10)). Two chromosome 8 regions were associated: p = 4.45 × 10(-8) at DLC1 SNP rs289519 (unadjusted) and p = 1.10 × 10(-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 nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 × 10(-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 and adenosine monophosphate-activated protein kinase pathways in EAs.

Conclusions: The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.
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http://dx.doi.org/10.1016/j.biopsych.2014.08.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386684PMC
March 2015

Nf1 regulates alcohol dependence-associated excessive drinking and gamma-aminobutyric acid release in the central amygdala in mice and is associated with alcohol dependence in humans.

Biol Psychiatry 2015 May 19;77(10):870-879. Epub 2014 Aug 19.

Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.

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 nondependent drinking, and basal and alcohol-induced gamma-aminobutyric acid (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 mice in nondependent drinking, such as 24-hour, 2-bottle choice drinking in the dark binge drinking or limited access 2-bottle choice. 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 wild-type 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 nondependent to dependent drinking in humans.
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http://dx.doi.org/10.1016/j.biopsych.2014.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428692PMC
May 2015
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