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

Project MinE ALS Sequencing Consortium

doi:10.1016/j.neuron.2021.12.019

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

Project MinE ALS Sequencing Consortium

Neurology

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

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 language	English
Pages (from-to)	992-1008.e11
Journal	Neuron
Volume	110
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2021.12.019
State	Published - 16 Mar 2022

Funding

Funders	Funder number
Doddie Foundation
KU Leuven Opening the Future Fund
Motor Neurone Disease Association
National Institutes of Health
NIHR Sheffield Biomedical Research Centre for Translational Neuroscience
European Research Council
Horizon 2020
Wellcome Trust	216596/Z/19/Z, 216596
National Institute of Neurological Disorders and Stroke	R01NS073873
Agentschap voor Innovatie door Wetenschap en Technologie	140935
Horizon 2020 Framework Programme	772376
NIH Office of the Director	S10OD025212, S10OD023452, S10OD020141
National Heart, Lung, and Blood Institute	R01HL162939, R01HL122939, P50HL083800, R01HL101388
National Human Genome Research Institute	UM1HG009442, P50HG007735
Stanford Genetics Bioinformatics Service Center	1S10OD023452-01
National Institute of Diabetes and Digestive and Kidney Diseases	P30DK116074
National Institute on Handicapped Research	NF-SI-0617-10077
Medical Research Council	MR/L501529/1

Keywords

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

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10.1016/j.neuron.2021.12.019

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@article{6293ae45721d44ff99005bf0478c27aa,

title = "Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis",

abstract = "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.",

keywords = "ALS, TDP-43 mislocalization, axonal dysfunction, epigenetics, gene discovery, genetics, iPSC, machine learning, motor neurons, multiomics",

author = "{Project MinE ALS Sequencing Consortium} and Sai Zhang and Johnathan Cooper-Knock and Weimer, {Annika K.} and Minyi Shi and Tobias Moll and Marshall, {Jack N.G.} and Calum Harvey and Nezhad, {Helia Ghahremani} and John Franklin and Souza, {Cleide dos Santos} and Ke Ning and Cheng Wang and Jingjing Li and Dilliott, {Allison A.} and Sali Farhan and Eran Elhaik and Iris Pasniceanu and Livesey, {Matthew R.} and Chen Eitan and Eran Hornstein and Kenna, {Kevin P.} and Ian Blair and Wray, {Naomi R.} and Matthew Kiernan and {Mitne Neto}, Miguel and Adriano Chio and Ruben Cauchi and Wim Robberecht and {van Damme}, Philip and Philippe Corcia and Philippe Couratier and Orla Hardiman and Russell McLaughin and Marc Gotkine and Vivian Drory and Nicola Ticozzi and Vincenzo Silani and Veldink, {Jan H.} and {van den Berg}, {Leonard H.} and {de Carvalho}, Mamede and {Mora Pardina}, {Jesus S.} and Monica Povedano and Peter Andersen and Markus Weber and Ba{\c s}ak, {Nazli A.} and Ammar Al-Chalabi and Chris Shaw and Shaw, {Pamela J.} and Morrison, {Karen E.} and Landers, {John E.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = mar,

day = "16",

doi = "10.1016/j.neuron.2021.12.019",

language = "אנגלית",

volume = "110",

pages = "992--1008.e11",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "6",

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AU - Project MinE ALS Sequencing Consortium

AU - Zhang, Sai

AU - Cooper-Knock, Johnathan

AU - Weimer, Annika K.

AU - Shi, Minyi

AU - Moll, Tobias

AU - Marshall, Jack N.G.

AU - Harvey, Calum

AU - Nezhad, Helia Ghahremani

AU - Franklin, John

AU - Souza, Cleide dos Santos

AU - Ning, Ke

AU - Wang, Cheng

AU - Li, Jingjing

AU - Dilliott, Allison A.

AU - Farhan, Sali

AU - Elhaik, Eran

AU - Pasniceanu, Iris

AU - Livesey, Matthew R.

AU - Eitan, Chen

AU - Hornstein, Eran

AU - Kenna, Kevin P.

AU - Blair, Ian

AU - Wray, Naomi R.

AU - Kiernan, Matthew

AU - Mitne Neto, Miguel

AU - Chio, Adriano

AU - Cauchi, Ruben

AU - Robberecht, Wim

AU - van Damme, Philip

AU - Corcia, Philippe

AU - Couratier, Philippe

AU - Hardiman, Orla

AU - McLaughin, Russell

AU - Gotkine, Marc

AU - Drory, Vivian

AU - Ticozzi, Nicola

AU - Silani, Vincenzo

AU - Veldink, Jan H.

AU - van den Berg, Leonard H.

AU - de Carvalho, Mamede

AU - Mora Pardina, Jesus S.

AU - Povedano, Monica

AU - Andersen, Peter

AU - Weber, Markus

AU - Başak, Nazli A.

AU - Al-Chalabi, Ammar

AU - Shaw, Chris

AU - Shaw, Pamela J.

AU - Morrison, Karen E.

AU - Landers, John E.

PY - 2022/3/16

Y1 - 2022/3/16

N2 - 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.

AB - 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.

KW - ALS

KW - TDP-43 mislocalization

KW - axonal dysfunction

KW - epigenetics

KW - gene discovery

KW - genetics

KW - iPSC

KW - machine learning

KW - motor neurons

KW - multiomics

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U2 - 10.1016/j.neuron.2021.12.019

DO - 10.1016/j.neuron.2021.12.019

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C2 - 35045337

AN - SCOPUS:85126111540

SN - 0896-6273

VL - 110

SP - 992-1008.e11

JO - Neuron

JF - Neuron

IS - 6

ER -

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

Abstract

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Keywords

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