Publication

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

Journal Paper/Review - Jan 18, 2022

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Citation
Zhang S, Cooper-Knock J, Weimer A, Shi M, Moll T, Marshall J, Harvey C, Nezhad H, Franklin J, Souza C, Ning K, Wang C, Li J, Dilliott A, Farhan S, Elhaik E, Pasniceanu I, Livesey M, Eitan C, Hornstein E, Kenna K, PROJECT MINE ALS SEQUENCING CONSORTIUM, Veldink J, Ferraiuolo L, Openshaw P, Snyder M. Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis. Neuron 2022; 110:992-1008.e11.
Type
Journal Paper/Review (English)
Journal
Neuron 2022; 110
Publication Date
Jan 18, 2022
Issn Electronic
1097-4199
Pages
992-1008.e11
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.