Genetic variants in the transcription regulatory region of MEGF10 are associated with autism in Chinese Han population.

Multiple epidermal growth factor-like-domains 10 (MEGF10), a critical member of the apoptotic engulfment pathway, mediates axon pruning and synapse elimination during brain development. Previous studies indicated that synaptic pruning deficit was associated with autism-related phenotypes. However, the relationship between MEGF10 and autism remains poorly understood. Disease-associated variants are significantly enriched in the transcription regulatory regions. These include the transcription start site (TSS) and its cis-regulatory elements. To investigate the role of MEGF10 variants with putative transcription regulatory function in the etiology of autism, we performed a family-based association study in 410 Chinese Han trios. Our results indicate that three single nucleotide polymorphisms (SNPs), rs4836316, rs2194079 and rs4836317 near the TSS are significantly associated with autism following Bonferroni correction (p = 0.0011, p = 0.0088, and p = 0.0023, respectively). Haplotype T-A-G (rs4836316-rs2194079-rs4836317) was preferentially transmitted from parents to affected offspring (p permutation = 0.0055). Consistently, functional exploration further verified that the risk allele and haplotype might influence its binding with transcription factors, resulting in decreased transcriptional activity of MEGF10. Our findings indicated that the risk alleles and haplotype near the MEGF10 TSS might modulate transcriptional activity and increase the susceptibility to autism.

多表皮生长因子样结构域10（MEGF10）是细胞凋亡吞噬通路的关键成员，在大脑发育过程中调节轴突修剪和突触消除。先前的研究表明，突触修剪缺陷与自闭症相关表型有关。然而，MEGF10与自闭症之间的关系仍知之甚少。疾病相关变异在转录调控区域显著富集，包括转录起始位点（TSS）及其顺式调控元件。为了研究具有潜在转录调控功能的MEGF10变异在自闭症病因中的作用，我们在410个中国汉族三联体家庭中进行了一项基于家庭的关联研究。我们的结果表明，转录起始位点附近的三个单核苷酸多态性（SNP），即rs4836316、rs2194079和rs4836317，在经过邦费罗尼校正后与自闭症显著相关（分别为p = 0.0011、p = 0.0088和p = 0.0023）。单倍型T - A - G（rs4836316 - rs2194079 - rs4836317）优先从父母传递给患病后代（p置换 = 0.0055）。一致地，功能探索进一步证实，风险等位基因和单倍型可能影响其与转录因子的结合，导致MEGF10转录活性降低。我们的研究结果表明，MEGF10转录起始位点附近的风险等位基因和单倍型可能调节转录活性，并增加自闭症的易感性。