Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, 02118, USA.
Departments of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Transl Psychiatry. 2021 Jun 29;11(1):363. doi: 10.1038/s41398-021-01440-5.
Stimulant dependence is heritable, but specific genetic factors underlying the trait have not been identified. A genome-wide association study for stimulant dependence was performed in a discovery cohort of African- (AA) and European-ancestry (EA) subjects ascertained for genetic studies of alcohol, opioid, and cocaine use disorders. The sample comprised individuals with DSM-IV stimulant dependence (393 EA cases, 5288 EA controls; 155 AA cases, 5603 AA controls). An independent cohort from the family-based Collaborative Study on the Genetics of Alcoholism (532 EA cases, 7635 EA controls; 53 AA cases, AA 3352 controls) was used for replication. One variant in SLC25A16 (rs2394476, p = 3.42 × 10, odds ratio [OR] = 3.70) was GWS in AAs. Four other loci showed suggestive evidence, including KCNA4 in AAs (rs11500237, p = 2.99 × 10, OR = 2.31) which encodes one of the potassium voltage-gated channel protein that has been linked to several other substance use disorders, and CPVL in the combined population groups (rs1176440, p = 3.05 × 10, OR = 1.35), whose expression was previously shown to be upregulated in the prefrontal cortex from users of cocaine, cannabis, and phencyclidine. Analysis of the top GWAS signals revealed a significant enrichment with nicotinic acetylcholine receptor genes (adjusted p = 0.04) and significant pleiotropy between stimulant dependence and alcohol dependence in EAs (p = 3.6 × 10), an anxiety disorder in EAs (p = 2.1 × 10), and ADHD in both AAs (p = 3.0 × 10) and EAs (p = 6.7 × 10). Our results implicate novel genes and pathways as having roles in the etiology of stimulant dependence.
兴奋剂依赖具有遗传性，但尚未确定导致该特征的特定遗传因素。对一组通过基因研究确定的酒精、阿片类药物和可卡因使用障碍的非洲裔（AA）和欧洲裔（EA）受试者进行了兴奋剂依赖的全基因组关联研究。该样本包括符合 DSM-IV 兴奋剂依赖标准的个体（393 例 EA 病例，5288 例 EA 对照；155 例 AA 病例，5603 例 AA 对照）。使用来自基于家族的酒精遗传合作研究（532 例 EA 病例，7635 例 EA 对照；53 例 AA 病例，AA 对照组 3352 例）的独立队列进行复制。在 AA 中，SLC25A16 中的一个变体（rs2394476，p=3.42×10，优势比[OR] = 3.70）为 GWS。另外四个位点显示出提示性证据，包括 AA 中的 KCNA4（rs11500237，p=2.99×10，OR=2.31），该基因编码一种钾电压门控通道蛋白，与其他几种物质使用障碍有关，以及在合并人群中的 CPVL（rs1176440，p=3.05×10，OR=1.35），先前的研究表明可卡因、大麻和苯环利定使用者的前额叶皮层中 CPVL 的表达上调。对全基因组关联研究的最高信号进行分析表明，尼古丁乙酰胆碱受体基因显著富集（调整后 p=0.04），并且 EA 中的兴奋剂依赖与酒精依赖之间存在显著的多效性（p=3.6×10），EA 中的焦虑障碍（p=2.1×10），以及 AA（p=3.0×10）和 EA（p=6.7×10）中的 ADHD。我们的结果表明，新的基因和途径可能在兴奋剂依赖的发病机制中起作用。
