1] Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA [2] VA CT Healthcare Center, Department of Psychiatry, West Haven, CT, USA [3] Department of Genetics, Yale University School of Medicine, New Haven, CT, USA [4] Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
Mol Psychiatry. 2014 Jun;19(6):717-23. doi: 10.1038/mp.2013.99. Epub 2013 Aug 20.
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 (8 90 000 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 × 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 × 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 × 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.
我们报告了一项针对可卡因依赖（CD）的全基因组关联研究（GWAS），该研究在三组非洲裔和欧洲裔美国人受试者（分别为 AA 和 EA）中进行，以确定与 CD 风险相关的途径、基因和等位基因。发现 GWAS 数据集（n=5697 名受试者）使用 Illumina OmniQuad 微阵列（分析了 890000 个单核苷酸多态性（SNP））进行基因分型。根据 1000 基因组参考面板进行了额外的基因型推断。通过整合来自 4063 名受试者的公开可用 GWAS 数据的信息，评估排名最高的发现。然后，在 2549 名独立受试者中对最显著的 GWAS SNP 进行了基因分型。我们观察到一个全基因组显著（GWS）结果：rs2629540 在 FAM53B（“家族与序列相似性 53，成员 B”）基因座。这在 AA 和 EA 中均得到支持；P 值（所有样本的荟萃分析）=4.28×10(-8)。该基因与我们之前连锁研究中观察到的最大峰所在的染色体区域相同。NCOR2（核受体共抑制因子 2）SNP rs150954431 在 EA 发现样本中与 P=1.19×10(-9)相关。SNP rs2456778，映射到 CDK1（“细胞周期蛋白依赖性激酶 1”），仅在发现样本中与可卡因引起的妄想相关（P=4.68×10(-8)）。这是第一项使用 GWAS 鉴定 CD 风险变异的研究。我们的研究结果暗示了新的风险位点，并为潜在的治疗和预防策略提供了见解。
