Background and Hypothesis The synaptic pruning hypothesis posits that schizophrenia (SCZ) and autism spectrum disorder (ASD) may represent opposite ends of neurodevelopmental disorders: individuals with ASD exhibit an overabundance of synapses and connections while SCZ was characterized by excessive pruning of synapses and a reduction. Given the strong genetic predisposition of both disorders, we propose a shared genetic component, with certain loci having differential regulatory impacts. Study Design Genome-Wide single nucleotide polymorphism (SNP) data of European descent from SCZ (N cases = 53 386, N controls = 77 258) and ASD (N cases = 18 381, N controls = 27 969) were analyzed. We used genetic correlation, bivariate causal mixture model, conditional false discovery rate method, colocalization, Transcriptome-Wide Association Study (TWAS), and Phenome-Wide Association Study (PheWAS) to investigate the genetic overlap and gene expression pattern. Study Results We found a positive genetic correlation between SCZ and ASD (rg = .26, SE = 0.01, P = 7.87e−14), with 11 genomic loci jointly influencing both conditions (conjFDR <0.05). Functional analysis highlights a significant enrichment of shared genes during early to mid-fetal developmental stages. A notable genetic region on chromosome 17q21.31 (lead SNP rs2696609) showed strong evidence of colocalization (PP.H4.abf = 0.85). This SNP rs2696609 is linked to many imaging-derived brain phenotypes. TWAS indicated opposing gene expression patterns (primarily pseudogenes and long noncoding RNAs [lncRNAs]) for ASD and SCZ in the 17q21.31 region and some genes (LRRC37A4P, LINC02210, and DND1P1) exhibit considerable variation in the cerebellum across the lifespan. Conclusions Our findings support a shared genetic basis for SCZ and ASD. A common genetic variant, rs2696609, located in the Chr17q21.31 locus, may exert differential risk regulation on SCZ and ASD by altering brain structure. Future studies should focus on the role of pseudogenes, lncRNAs, and cerebellum in synaptic pruning and neurodevelopmental disorders.

中文翻译：

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精神分裂症和自闭症谱系障碍的共同遗传决定因素暗示相反的风险模式：常见变异的全基因组分析

背景和假设突触修剪假说认为，精神分裂症（SCZ）和自闭症谱系障碍（ASD）可能代表神经发育障碍的相反两端：患有 ASD 的个体表现出过多的突触和连接，而 SCZ 的特点是突触的过度修剪和减少。 。鉴于这两种疾病都有很强的遗传倾向，我们提出了一个共同的遗传成分，某些基因座具有不同的调节影响。研究设计 对来自 SCZ 的欧洲血统（N 例 = 53 386，N 对照 = 77 258）和 ASD（N 例 = 18 381，N 对照 = 27 969）的全基因组单核苷酸多态性 (SNP) 数据进行了分析。我们使用遗传相关性、双变量因果混合模型、条件错误发现率法、共定位、全转录组关联研究（TWAS）和全表型关联研究（PheWAS）来研究遗传重叠和基因表达模式。研究结果 我们发现 SCZ 和 ASD 之间存在正向遗传相关性（rg = .26，SE = 0.01，P = 7.87e−14），其中 11 个基因组位点共同影响这两种情况（conjFDR <0.05）。功能分析强调了胎儿早期到中期发育阶段共享基因的显着富集。染色体 17q21.31 上的一个显着遗传区域（先导 SNP rs2696609）显示出共定位的有力证据（PP.H4.abf = 0.85）。该 SNP rs2696609 与许多成像衍生的大脑表型相关。 TWAS 表明 17q21.31 区域 ASD 和 SCZ 具有相反的基因表达模式（主要是假基因和长非编码 RNA [lncRNA]），并且一些基因（LRRC37A4P、LINC02210 和 DND1P1）在整个生命周期的小脑中表现出相当大的变化。结论 我们的研究结果支持 SCZ 和 ASD 具有共同的遗传基础。位于 Chr17q21.31 位点的常见遗传变异 rs2696609 可能通过改变大脑结构对 SCZ 和 ASD 发挥差异性风险调节作用。未来的研究应重点关注假基因、lncRNA 和小脑在突触修剪和神经发育障碍中的作用。