Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene.
paper
Primary
Public
- Authors
- Gelernter, J; Sherva, R; Koesterer, R; Almasy, L; Zhao, H; Kranzler, H R; Farrer, L
- Year
- 2014
- Journal
- Molecular psychiatry
- PMID
- 23958962
- DOI
- 10.1038/mp.2013.99
- PMCID
- PMC3865158
We report a genome-wide association study (GWAS) for cocaine dependence (CD) in three sets of African- and European-American subjects (AAs and EAs, respectively) to identify pathways, genes and alleles important in CD risk. The discovery GWAS data set (n=5697 subjects) was genotyped using the Illumina OmniQuad microarray (8β90β000 analyzed single-nucleotide polymorphisms (SNPs)). Additional genotypes were imputed based on the 1000 Genomes reference panel. Top-ranked findings were evaluated by incorporating information from publicly available GWAS data from 4063 subjects. Then, the most significant GWAS SNPs were genotyped in 2549 independent subjects. We observed one genome-wide-significant (GWS) result: rs2629540 at the FAM53B ('family with sequence similarity 53, member B') locus. This was supported in both AAs and EAs; P-value (meta-analysis of all samples)=4.28 Γ 10(-8). The gene maps to the same chromosomal region as the maximum peak we observed in a previous linkage study. NCOR2 (nuclear receptor corepressor 2) SNP rs150954431 was associated with P=1.19 Γ 10(-9) in the EA discovery sample. SNP rs2456778, which maps to CDK1 ('cyclin-dependent kinase 1'), was associated with cocaine-induced paranoia in AAs in the discovery sample only (P=4.68 Γ 10(-8)). This is the first study to identify risk variants for CD using GWAS. Our results implicate novel risk loci and provide insights into potential therapeutic and prevention strategies.
Regional Manhattan plot for FAM53B, showing the meta-analysis P-value from EAs and AAs in the discovery and SAGE, as well as a single point for the phase 1β3 meta-analysis result (the highest purple dot on the graph). Since the result is driven primarily by AAs, the LD heat map is based on AAs also. Imputed SNPs are shown as circles, and genotyped SNPs as squares.
Manhattan plot, CD case/control analysis, EA population (discovery sample)
Q/Q plot for same. Other Q/Q plots similarly showed negligible inflation.
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| Name | Type |
|---|---|
| 1000 Genomes Project | cohort |
| AA | cohort |
| AA case-control local | cohort |
| AA discovery sample local | cohort |
| AA Sympcountadj local | cohort |
| African American | cohort |
| African American Hispanic local | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alzheimer's disease | phenotype |
| ATP2B2 local | gene |
| ATP2C2 | gene |
| Ca2+ | drug |
| Calm1 | gene |
| cannabis dependence | phenotype |
| cannabis use | phenotype |
| Case-control local | phenotype |
| Case-control results local | phenotype |
| CD | phenotype |
| CDK1 local | gene |
| CD symptom count local | phenotype |
| CEU | cohort |
| CHB | cohort |
| CIP | phenotype |
| CIP trait local | phenotype |
| cocaine | phenotype |
| cocaine-induced paranoia | phenotype |
| Cocaine-related effects local | phenotype |
| COGEND | cohort |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| combined cohort | cohort |
| complex traits | phenotype |
| conduct disorder | phenotype |
| Discovery+SAGE meta-analysis local | cohort |
| discovery sample | cohort |
| EA-AA meta-analysis local | cohort |
| EA discovery sample local | cohort |
| EAs | cohort |
| EA Sympcountadj local | cohort |
| European American Hispanic local | cohort |
| European ancestry | cohort |
| European population | cohort |
| Exposed controls local | cohort |
| FAM53B | gene |
| Family study of cocaine dependence | cohort |
| GWAS | cohort |
| HapMap 3 reference local | cohort |
| illicit drug dependence | phenotype |
| Illumina GoldenGate Genotyping Universal-32 local | drug |
| Illumina Human1M array | drug |
| Illumina HumanOmni1-Quad v1.0 microarray | drug |
| Impute2 | drug |
| Ingenuity Pathway Analysis local | drug |
| KCNN2 local | gene |
| KCNQ4 local | gene |
| KCNT2 | gene |
| Locus_1 local | variant |
| methamphetamine response local | phenotype |
| NCOR1 local | gene |
| NCOR2 local | gene |
| NCS1 | gene |
| nicotine dependence | phenotype |
| OD | phenotype |
| olfaction | phenotype |
| opioid | drug |
| opioid dependence | phenotype |
| opioid sensitivity | phenotype |
| OR3A1 local | gene |
| OR3A2 local | gene |
| Phase 1 | cohort |
| Phase 1 dataset local | cohort |
| Phase 1 discovery sample local | cohort |
| Phase 2 | cohort |
| Phase 2 dataset local | cohort |
| Phase 3 dataset local | cohort |
| Phase 3 EA sample local | cohort |
| Phase 3 replication sample local | cohort |
| population | cohort |
| population group local | cohort |
| Public domain GWASed samples local | cohort |
| RANP6 local | gene |
| replication sample | cohort |
| rs11944332 local | variant |
| rs150954431 local | variant |
| rs1757939 local | variant |
| rs2005290 local | variant |
| rs2456778 local | variant |
| rs2629540 local | variant |
| rs4129566 local | variant |
| rs6677435 local | variant |
| rs72840936 local | variant |
| SAGE | cohort |
| SAGE dataset | cohort |
| SAGE project local | cohort |
| SAGE samples local | cohort |
| SCLT1 local | gene |
| SD | phenotype |
| small nuclear families (SNFs) local | cohort |
| Snap25 | gene |
| SNP | cohort |
| SSADDA-assessed GWAS sample local | cohort |
| SSADDA-assessed replication sample local | cohort |
| stimulant dependence | phenotype |
| Study of Addiction: Genetics and Environment | cohort |
| substance use | phenotype |
| Sympcountadj local | phenotype |
| symptom count | phenotype |
| TaqMan method local | drug |
| unrelated individuals | cohort |
| YRI | cohort |
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