title: Genome-wide association study of copy number variations (CNVs) with opioid dependence.
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 5152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genome-wide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genome-wide (eg, 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, whereas 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.
authors.affiliation: 1] Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA [2] Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT, USA [3] Department of Computer Science, University of Vermont, Burlington, VT, USA [4] Neuroscience, Behavior, and Health Initiative, University of Vermont, Burlington, VT, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.affiliation: 1] Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA [2] Department of Genetics, School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine and VISN 4 MIRECC, Philadelphia VAMC, Philadelphia, PA, USA.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA.
authors.forename: Ming D
authors.initials: MD
authors.lastname: Li
authors.affiliation: Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Jensen
authors.affiliation: Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Zayats
authors.affiliation: Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Genetics and Genomics, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: 1] Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA [2] Department of Genetics, School of Medicine, Yale University, New Haven, CT, USA [3] VA Connecticut Healthcare Center, Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D017493:Leukocyte Common Antigens / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D009293:Opioid-Related Disorders / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D051178:alpha Catenin / Q000235:genetics*
chemical_list: C441963:CTNNA3 protein, human; D051178:alpha Catenin; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2