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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 66-74 |
| Number of pages | 9 |
| Journal | Biological Psychiatry |
| Volume | 76 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 1 2014 |
| Externally published | Yes |
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Keywords
- Calcium signaling
- complex traits
- convergence
- genome-wide association
- opioid dependence
- potassium
ASJC Scopus subject areas
- Biological Psychiatry
- Medicine(all)
Cite this
Genome-wide association study of opioid dependence : Multiple associations mapped to calcium and potassium pathways. / Gelernter, Joel; Kranzler, Henry R.; Sherva, Richard; Koesterer, Ryan; Almasy, Laura; Zhao, Hongyu; Farrer, Lindsay A.
In: Biological Psychiatry, Vol. 76, No. 1, 01.07.2014, p. 66-74.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genome-wide association study of opioid dependence
T2 - Multiple associations mapped to calcium and potassium pathways
AU - Gelernter, Joel
AU - Kranzler, Henry R.
AU - Sherva, Richard
AU - Koesterer, Ryan
AU - Almasy, Laura
AU - Zhao, Hongyu
AU - Farrer, Lindsay A.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
KW - Calcium signaling
KW - complex traits
KW - convergence
KW - genome-wide association
KW - opioid dependence
KW - potassium
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U2 - 10.1016/j.biopsych.2013.08.034
DO - 10.1016/j.biopsych.2013.08.034
M3 - Article
VL - 76
SP - 66
EP - 74
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 1
ER -