title: Genome-wide association study of opioid dependence: multiple associations mapped to calcium and potassium pathways.
abstract: BACKGROUND
  We report a genome-wide association study (GWAS) of two populations, African-American and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify pathways, genes, and alleles important in OD risk.
  
  
  METHODS
  The design employed three phases (on the basis of separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed with opioid and/or other substance dependence and control subjects. Subjects were genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available Study of Addiction: Genetics and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32% AA). Analyses were performed with case-control and ordinal trait designs.
  
  
  RESULTS
  Most significant results emerged from the AA subgroup. Genome-wide-significant associations (p < 5.0 × 10(-8)) were observed with SNPs from multiple loci-KCNG2*rs62103177 was most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1 and KCNG2). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation.
  
  
  CONCLUSIONS
  This is the first study to identify risk variants for OD with GWAS. Our results strongly implicate risk pathways and provide insights into novel therapeutic and prevention strategies and might biologically bridge OD and other non-substance dependence psychiatric traits where similar pathways have been implicated.
authors.affiliation: Department of Psychiatry, Division of Human Genetics, Departments of Genetics and Neurobiology, Yale University School of Medicine, VA Connecticut Healthcare Center, West Haven. Electronic address: joel.gelernter@yale.edu.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Philadelphia VA Medical Center, Philadelphia, Pennsylvania.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Sherva
authors.affiliation: University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Ryan
authors.initials: R
authors.lastname: Koesterer
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: Departments Biostatistics and Genetics, Yale School of Public Health, Yale University, New Haven, CT.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts; Departments of Neurology, Ophthalmology, Genetics and Genomics, Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D015220:Calcium Channels / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics*; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics; D009293:Opioid-Related Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D015220:Calcium Channels; D024642:Potassium Channels, Voltage-Gated; D011188:Potassium
keywords: Calcium signaling; complex traits; convergence; genome-wide association; opioid dependence; potassium