Al-Soufi Laila, Costas Javier
Psychiatric Genetics group, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Galicia, Spain.
Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Spain.
Psychol Med. 2023 Oct;53(14):6806-6816. doi: 10.1017/S0033291723000326. Epub 2023 Mar 6.
Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking.
Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings.
Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as , , and .
Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health.
精神分裂症（SCZ）患者中吸烟的患病率高于普通人群。基因研究提供了一些吸烟对SCZ有因果效应的证据。我们旨在描述受吸烟遗传易感性影响的SCZ遗传易感性特征。
基于多性状的条件和联合分析应用于最大规模的欧洲SCZ全基因组关联研究（GWAS），以去除由吸烟驱动的对SCZ的遗传效应，该效应通过基于广义汇总数据的孟德尔随机化进行估计。进行富集分析以比较原始的条件GWAS。评估条件设定后SCZ与相关性状之间遗传相关性的变化。进行共定位分析以确定证实一般发现的特定基因座。
条件分析确定了19个新的SCZ风险基因座和42个缺失基因座，其与SCZ的关联可能部分由吸烟驱动。共定位分析加强了这些结果。富集分析表明，条件设定后产前脑阶段差异表达基因的关联性更高。条件设定后，SCZ与物质使用和依赖、注意力缺陷多动障碍以及一些外化性状的遗传相关性发生了显著变化。在一些缺失基因座中确定了SCZ与这些性状之间关联信号的共定位，如 、 和 。
我们的方法导致鉴定出潜在的新SCZ基因座、通过吸烟与SCZ部分相关的基因座，以及SCZ与与外化表型相关的吸烟行为之间共享的遗传易感性。将这种方法应用于其他精神疾病和物质可能有助于更好地理解物质对心理健康的作用。
