Smokescreen: a targeted genotyping array for addiction research.
- Authors
- Baurley, James W; Edlund, Christopher K; Pardamean, Carissa I; Conti, David V; Bergen, Andrew W
- Year
- 2016
- Journal
- BMC genomics
- PMID
- 26921259
- DOI
- 10.1186/s12864-016-2495-7
- PMCID
- PMC4769529
BACKGROUND: Addictive disorders are a class of chronic, relapsing mental disorders that are responsible for increased risk of mental and medical disorders and represent the largest, potentially modifiable cause of death. Tobacco dependence is associated with increased risk of disease and premature death. While tobacco control efforts and therapeutic interventions have made good progress in reducing smoking prevalence, challenges remain in optimizing their effectiveness based on patient characteristics, including genetic variation. In order to maximize collaborative efforts to advance addiction research, we have developed a genotyping array called Smokescreen. This custom array builds upon previous work in the analyses of human genetic variation, the genetics of addiction, drug metabolism, and response to therapy, with an emphasis on smoking and nicotine addiction. RESULTS: The Smokescreen genotyping array includes 646,247 markers in 23 categories. The array design covers genome-wide common variation (65.67, 82.37, and 90.72% in African (YRI), East Asian (ASN), and European (EUR) respectively); most of the variation with a minor allele frequency ≥ 0.01 in 1014 addiction genes (85.16, 89.51, and 90.49% for YRI, ASN, and EUR respectively); and nearly all variation from the 1000 Genomes Project Phase 1, NHLBI GO Exome Sequencing Project and HapMap databases in the regions related to smoking behavior and nicotine metabolism: CHRNA5-CHRNA3-CHRNB4 and CYP2A6-CYP2B6. Of the 636 pilot DNA samples derived from blood or cell line biospecimens that were genotyped on the array, 622 (97.80%) passed quality control. In passing samples, 90.08% of markers passed quality control. The genotype reproducibility in 25 replicate pairs was 99.94%. For 137 samples that overlapped with HapMap2 release 24, the genotype concordance was 99.76%. In a genome-wide association analysis of the nicotine metabolite ratio in 315 individuals participating in nicotine metabolism laboratory studies, we identified genome-wide significant variants in the CYP2A6 region (min p = 9.10E-15). CONCLUSIONS: We developed a comprehensive genotyping array for addiction research and demonstrated its analytic validity and utility through pilot genotyping of HapMap and study samples. This array allows researchers to perform genome-wide, candidate gene, and pathway-based association analyses of addiction, tobacco-use, treatment response, comorbidities, and associated diseases in a standardized, high-throughput platform.
Smokescreen coverage estimates by increasing observed imputation r 2 thresholds: genome-wide and addiction genes. Left panel: Genome-wide coverage. Right panel: Addiction genes coverage. Solid line: MAF ≥ 0.05. Dashed line: MAF ≥ 0.01. Red: EUR. Blue: YRI. Green: ASN. Observed imputation r 2 (obsRSQ) is the correlation between imputed (continuous) genotype dosage and the measured genotype from the 1000 Genomes Project. The proportion of 1000 Genome Project Phase 1 variants with an obsRSQ above the threshold on the x-axis is represented on the y-axis. The average obsRSQ differs by race/ethnicity and by array content categories (e.g., genome-wide versus addiction genes). The coverage (fraction of variants with obsRSQ above the threshold) decreases as the obsRSQ threshold increases. A typical threshold used in evaluating array coverage is 0.80
CYP2A6 - CYP2B6 regional association with the nicotine metabolism ratio. Blue triangle: African-American. Green circle: Asian-American. Red square: European-American. Black star: Meta-analysis
| # | Section | Preview |
|---|---|---|
| 40 | Methods — Smokescreen genotyping pilot — Ethics approval and consent to participate | A total of 636 purified DNA samples (including 27 replicates) derived from blood or cell line were… |
| 41 | Methods — Smokescreen genotyping pilot — Ethics approval and consent to participate | further analysis. Remaining samples were genotyped for all probesets (stage 2 genotyping), using… |
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