Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.
Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.
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DOI：
10.1016/j.neuron.2021.12.019
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发表时间：
2022-03-16
期刊：
影响因子：
16.2
通讯作者：
Snyder MP
中科院分区：
文献类型：
--
作者：
Zhang S;Cooper-Knock J;Weimer AK;Shi M;Moll T;Marshall JNG;Harvey C;Nezhad HG;Franklin J;Souza CDS;Ning K;Wang C;Li J;Dilliott AA;Farhan S;Elhaik E;Pasniceanu I;Livesey MR;Eitan C;Hornstein E;Kenna KP;Project MinE ALS Sequencing Consortium;Veldink JH;Ferraiuolo L;Shaw PJ;Snyder MP
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汇总统计相结合，用于基因发现。通过对来自诱导多能干细胞（iPSC）的运动神经元进行转录组学和表观遗传学分析，RefMap确定了690个ALS相关基因，这代表了恢复的遗传性增加了5倍。广泛的保守性，转录组，网络和罕见的变异分析证明了候选基因在健康和患病的运动神经元和脑组织中的功能意义。常见和罕见变异之间的遗传趋同突出了KANK 1作为一个新的ALS基因。在人类神经元中再现KANK 1患者突变导致神经毒性，并证明TDP-43错误定位（ALS的标志性病理学）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。Zhang等人开发了一种新的机器学习方法，该方法将表观遗传分析与GWAS汇总统计相结合，用于基因发现。应用于ALS识别出690个风险基因，恢复遗传力增加5倍。主要候选人KANK 1在人类神经元中复制，导致TDP-43错误定位，这是ALS的标志性病理学。
Amyotrophic lateral sclerosis (ALS) is a complex disease leading to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWAS) 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 which represents 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. Zhang et al. develop a new machine learning method which integrates epigenetic profiling with GWAS summary statistics for gene discovery. Application to ALS identifies 690 risk genes with 5-fold increase in recovered heritability. Leading candidate KANK1 is reproduced in human neurons leading to TDP-43 mislocalization, a hallmark pathology of ALS.
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遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
DOI：
10.1093/brain/awu120
发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cooper-Knock J;Walsh MJ;Higginbottom A;Robin Highley J;Dickman MJ;Edbauer D;Ince PG;Wharton SB;Wilson SA;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
12.3
作者：
Chen L;Jin P;Qin ZS
通讯作者：
Qin ZS
影响因子：
14.9
作者：
Brinkman EK;Chen T;Amendola M;van Steensel B
通讯作者：
van Steensel B