Song Weichen, Lin Guan Ning, Yu Shunying, Zhao Min
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China.
Psychiatry Res. 2022 Apr;310:114453. doi: 10.1016/j.psychres.2022.114453. Epub 2022 Feb 17.
Confirming the existence and composition of the shared genetic basis of Schizophrenia and cannabis and cigarette smoking has critical values for the clinical prevention and intervention of psychosis.
To achieve this goal, we leveraged Genome-Wide summary statistics of Schizophrenia (n = 99,934), cigarette smoking (n = 518,633) and cannabis usage (n = 162,082). We applied Causal Analysis Using Summary Effect Estimates (CAUSE) and genomic structural equation modeling (GenomicSEM) to quantify the contribution of a common genetic factor of cannabis and cigarette smoking and schizophrenia (referred to as SCZ_SMO), then identified genome-wide loci that made up SCZ_SMO.
We estimated that SCZ_SMO explained 8.6% of Schizophrenia heritability (Z score <-2.5 in CAUSE, p<10 in Genomic SEM). There were 20 independent loci showing association with SCZ_SMO at the genome-wide threshold of p<5 × 10. At the top locus on chromosome 11, fine-mapping identified rs7945073 (posterior inclusion probability =0.12, p = 2.24 × 10) as the top risk variants. Gene-level association and fine-mapping highlighted NCAM1, PHC2, and SEMA6D as risk genes of SCZ_SMO. Other risk genes were enriched in cortex, neuron, and dendritic spines (adjusted p<0.05). SCZ_SMO showed significant positive correlation (p<10) with the genetic risk of attention deficit hyperactivity disorder (r = 0.50), lifestyle problems (r = 0.83), social deprivation (r = 0.58) and all-cause pregnant loss (r = 0.60).
Our result provided new evidence on the shared genetic basis model for the association between Schizophrenia and smoking and provided genetic and biological insights into their shared mechanism.
证实精神分裂症与大麻及吸烟之间共享遗传基础的存在及其构成，对于精神病的临床预防和干预具有关键价值。
为实现这一目标，我们利用了精神分裂症（n = 99,934）、吸烟（n = 518,633）和大麻使用（n = 162,082）的全基因组汇总统计数据。我们应用基于汇总效应估计的因果分析（CAUSE）和基因组结构方程模型（GenomicSEM）来量化大麻、吸烟和精神分裂症共同遗传因素（称为SCZ_SMO）的贡献，然后识别构成SCZ_SMO的全基因组位点。
我们估计SCZ_SMO解释了精神分裂症遗传度的8.6%（在CAUSE中Z分数<-2.5，在基因组结构方程模型中p<10）。在全基因组阈值p<5×10时，有20个独立位点显示与SCZ_SMO相关。在11号染色体的顶级位点上，精细定位确定rs7945073（后验包含概率=0.12，p = 2.24×10）为顶级风险变异。基因水平的关联和精细定位突出显示NCAM1、PHC2和SEMAZD为SCZ_SMO的风险基因。其他风险基因在皮质、神经元和树突棘中富集（校正p<0.05）。SCZ_SMO与注意力缺陷多动障碍的遗传风险（r = 0.50）、生活方式问题（r = 0.83）、社会剥夺（r = 0.58）和全因妊娠丢失（r = 0.60）呈显著正相关（p<10）。
我们的结果为精神分裂症与吸烟之间关联的共享遗传基础模型提供了新证据，并为它们的共享机制提供了遗传和生物学见解。
