A transcriptome-wide association study elucidates the genetic role of KLC1 in modulating mitophagy involved in non-syndromic cleft lip with or without palate

This study investigated pathogenic genes associated with non-syndromic cleft lip with or without cleft palate (NSCL/P) through transcriptome-wide association studies (TWAS). By integrating expression quantitative trait loci (eQTL) data with genome-wide association study (GWAS) data, we identified key susceptibility genes, including KLC1. Notably, the variant rs12884809 G>A was linked to an increased risk of NSCL/P by enhancing the binding of the transcription factor ELK1 to the KLC1 promoter, thereby upregulating its expression. This alteration in KLC1 expression subsequently impacted mitophagy, leading to significant changes in cellular behavior and zebrafish morphology. Our findings illuminate the genetic mechanisms underlying NSCL/P and provide valuable insights for future prevention strategies and a deeper understanding of this condition.

本研究通过全转录组关联研究（transcriptome-wide association studies, TWAS），探究了与非综合征性唇裂伴或不伴腭裂（non-syndromic cleft lip with or without cleft palate, NSCL/P）相关的致病基因。本研究将表达数量性状基因座（expression quantitative trait loci, eQTL）数据与全基因组关联研究（genome-wide association study, GWAS）数据进行整合，成功鉴定出包括KLC1在内的关键易感基因。值得注意的是，变异位点rs12884809 G>A可通过增强转录因子ELK1与KLC1启动子的结合，上调KLC1的表达，进而增加NSCL/P的发病风险。KLC1表达的该种改变后续会影响线粒体自噬（mitophagy）过程，导致细胞行为与斑马鱼（zebrafish）形态出现显著变化。本研究阐明了NSCL/P的潜在遗传机制，可为该疾病的未来预防策略提供宝贵见解，同时为深入理解该病症奠定了基础。