Department of Genetics, Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, S10 2HQ, UK.
Neuron. 2022 Mar 16;110(6):992-1008.e11. doi: 10.1016/j.neuron.2021.12.019. Epub 2022 Jan 18.
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases.
肌萎缩侧索硬化症（ALS）是一种导致运动神经元死亡的复杂疾病。尽管遗传率估计为 52%，但全基因组关联研究（GWAS）发现的相关基因位点相对较少。我们开发了一种名为 RefMap 的机器学习方法，该方法将功能基因组学与 GWAS 汇总统计数据相结合，用于基因发现。通过对诱导多能干细胞（iPSC）衍生的运动神经元进行转录组和表观遗传分析，RefMap 鉴定出 690 个与 ALS 相关的基因，这将遗传率恢复提高了 5 倍。广泛的保守性、转录组、网络和罕见变异分析表明，候选基因在健康和患病的运动神经元和脑组织中具有功能意义。常见和罕见变异之间的遗传趋同突出了 KANK1 是一个新的 ALS 基因。在人类神经元中重现 KANK1 患者突变会导致神经毒性，并表明 TDP-43 定位错误，这是 ALS 的标志病理学，是轴突功能障碍的下游。RefMap 可以很容易地应用于其他复杂疾病。
