Psychiatric Genetics Group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Galicia, Spain; Universidade de Santiago de Compostela (USC), Galicia, Spain.
Psychiatric Genetics Group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Galicia, Spain; Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Galicia, Spain.
Drug Alcohol Depend. 2021 Mar 1;220:108517. doi: 10.1016/j.drugalcdep.2021.108517. Epub 2021 Jan 10.
Epidemiological data suggest that smoking may be a risk factor for schizophrenia (SCZ), but more evidence is needed. Two regions coding nicotinic acetylcholine receptor (nAchR) subunits, atCHRNA2 and the CHRNA5/A3/B4 cluster, were associated with SCZ in genome-wide association studies (GWAS). Additionally, a signal at CHRNA4 is near significance. CHRNA2 was also associated with cannabis use disorder (CUD). These regions were also associated with smoking behaviors. If tobacco is a risk factor, the GWAS signals at smoking behaviors and SCZ have to be due to the same causal variants, i.e. they have to colocalize, although colocalization does not necessarily imply causality. Here, we present colocalization analysis at these loci between SCZ and smoking behaviors.
The Bayesian approach implemented in coloc was used to check for posterior probability of colocalization versus independent signals at the three loci with some evidence of association with SCZ and smoking behaviors, using GWAS summary statistics. Colocalization was also assessed for positive control traits and CUD. Three different sensibility analyses were used to confirm the results. A visualization tool, LocusCompare, was used to facilitate interpretation of the coloc results.
Evidence for colocalization of GWAS signals between SCZ and smoking behaviors was found for CHRNA2. Evidence for independent causal variants was found for the other two loci. CUD GWAS signal at CHRNA2 colocalizes with SCZ and smoking behaviors.
Overall, the results indicate that the association between some nAchR subunit genes and SCZ cannot be solely explained by their effect on smoking behaviors.
流行病学数据表明，吸烟可能是精神分裂症（SCZ）的一个风险因素，但还需要更多的证据。两个编码烟碱型乙酰胆碱受体（nAchR）亚基的区域，atCHRNA2 和 CHRNA5/A3/B4 簇，在全基因组关联研究（GWAS）中与 SCZ 相关。此外，CHRNA4 上的信号接近显著。CHRNA2 也与大麻使用障碍（CUD）相关。这些区域也与吸烟行为有关。如果烟草是一个风险因素，那么在吸烟行为和 SCZ 中的 GWAS 信号必须归因于相同的因果变异，即它们必须共定位，尽管共定位并不一定意味着因果关系。在这里，我们在这些基因座上展示了 SCZ 和吸烟行为之间的共定位分析。
使用 coloc 中实现的贝叶斯方法，使用 GWAS 汇总统计数据，检查在三个与 SCZ 和吸烟行为有一定关联证据的基因座上，共定位与独立信号的后验概率。还对阳性对照特征和 CUD 进行了共定位评估。使用三种不同的敏感性分析来确认结果。使用可视化工具 LocusCompare 来促进 coloc 结果的解释。
在 CHRNA2 上发现了 SCZ 和吸烟行为之间的 GWAS 信号共定位的证据。在其他两个基因座上发现了独立的因果变异的证据。CHRNA2 上的 CUD GWAS 信号与 SCZ 和吸烟行为共定位。
总的来说，这些结果表明，一些 nAchR 亚基基因与 SCZ 之间的关联不能仅仅用它们对吸烟行为的影响来解释。
