Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

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...

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Published inNeuron (Cambridge, Mass.) Vol. 110; no. 6; pp. 992 - 1008.e11
Main Authors Zhang, Sai, Cooper-Knock, Johnathan, Weimer, Annika K., Shi, Minyi, Moll, Tobias, Marshall, Jack N.G., Harvey, Calum, Nezhad, Helia Ghahremani, Franklin, John, Souza, Cleide dos Santos, Ning, Ke, Wang, Cheng, Li, Jingjing, Dilliott, Allison A., Farhan, Sali, Elhaik, Eran, Pasniceanu, Iris, Livesey, Matthew R., Eitan, Chen, Hornstein, Eran, Kenna, Kevin P., Blair, Ian, Wray, Naomi R., Kiernan, Matthew, Mitne Neto, Miguel, Chio, Adriano, Cauchi, Ruben, Robberecht, Wim, van Damme, Philip, Corcia, Philippe, Couratier, Philippe, Hardiman, Orla, McLaughin, Russell, Gotkine, Marc, Drory, Vivian, Ticozzi, Nicola, Silani, Vincenzo, Veldink, Jan H., van den Berg, Leonard H., de Carvalho, Mamede, Mora Pardina, Jesus S., Povedano, Monica, Andersen, Peter, Weber, Markus, Başak, Nazli A., Al-Chalabi, Ammar, Shaw, Chris, Shaw, Pamela J., Morrison, Karen E., Landers, John E., Glass, Jonathan D., Ferraiuolo, Laura, Snyder, Michael P.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 16.03.2022
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ISSN0896-6273
1097-4199
1097-4199
DOI10.1016/j.neuron.2021.12.019

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Summary: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. •Machine learning method identifies risk genes by integrating GWASs and epigenetic data•Discovered ALS risk genes lead to a 5-fold increase in recovered heritability•Genetic and experimental support for initiation of ALS pathogenesis in the distal axon•Convergent genetic and experimental data establish KANK1 as a new ALS gene Zhang et al. develop a new machine learning method that 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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AUTHOR CONTRIBUTIONS
S.Z., J.C.-K. and M.P.S. conceived and designed the study. S.Z. designed and implemented RefMap. S.Z., J.C.-K., A.K.W., M.S., T.M., J.N.G.M., I.P., M.R.L., C.H., H.G.N., J.F., C.S.S., K.N., S.F., A.A.D., J.V., L.F., P.J.S. and M.P.S. were responsible for data acquisition. S.Z., J.C.-K., A.K.W., M.S., T.M., J.N.G.M., C.H., H.G.N., J.F., C.S.S., K.N., C.W., J.L., S.F., A.A.D., E.E., I.P., M.R.L., C.E., E.H., J.V., L.F., P.J.S. and M.P.S. were responsible for analysis of data. S.Z., J.C.-K., A.K.W., T.M., J.N.G.M., C.H., H.G.N., J.F., C.S.S., K.N., C.W., J.L., S.F., A.A.D., E.E., I.P., M.R.L., C.E., E.H., K.P.K., J.V., L.F., P.J.S. and M.P.S. were responsible for interpretation of data. The Project MinE ALS Sequencing Consortium was involved in data acquisition and analysis. S.Z., J.C.-K. and M.P.S. prepared the manuscript with assistance from all authors. All authors meet the four ICMJE authorship criteria, and were responsible for revising the manuscript, approving the final version for publication, and for accuracy and integrity of the work.
ISSN:0896-6273
1097-4199
1097-4199
DOI:10.1016/j.neuron.2021.12.019