Publication
Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis.
Journal Paper/Review - Jan 18, 2022
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 Kaida, Wang Cheng, Li Jingjing, Dilliott Allison A, Farhan Sali, Elhaik Eran, Pasniceanu Iris, Livesey Matthew R, Eitan Chen, Hornstein Eran, Kenna Kevin P, PROJECT MINE ALS SEQUENCING CONSORTIUM, Veldink Jan H, Ferraiuolo Laura, Openshaw Peter J M, Snyder Michael P
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Brief description/objective
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.