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

Project MinE ALS Sequencing Consortium

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)992-1008.e11
Issue number6
StatePublished - 16 Mar 2022


FundersFunder number
Doddie Foundation
KU Leuven Opening the Future Fund
NIHR Sheffield Biomedical Research Centre for Translational Neuroscience
Stanford Genetics Bioinformatics Service Center1S10OD023452-01
National Institutes of Health1R01HL101388, S10OD025212, UM1HG009442, 1R01-HL122939, 1P50HL083800, CEGS 5P50HG00773504
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK116074
National Institute of Neurological Disorders and StrokeR01NS073873
National Institute on Handicapped ResearchNF-SI-0617-10077
Wellcome Trust216596/Z/19/Z
Motor Neurone Disease Association
European Research Council
Agentschap voor Innovatie door Wetenschap en Technologie140935
Horizon 2020772376


    • ALS
    • TDP-43 mislocalization
    • axonal dysfunction
    • epigenetics
    • gene discovery
    • genetics
    • iPSC
    • machine learning
    • motor neurons
    • multiomics


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