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Review
. 2021 Oct 1;34(5):756-764.
doi: 10.1097/WCO.0000000000000986.

Advances in the genetic classification of amyotrophic lateral sclerosis

Johnathan Cooper-Knock  1 , Calum Harvey  1 , Sai Zhang  2   3 , Tobias Moll  1 , Ilia Sarah Timpanaro  4 , Kevin P Kenna  4 , Alfredo Iacoangeli  5   6   7 , Jan H Veldink  4
Affiliations
Review

Advances in the genetic classification of amyotrophic lateral sclerosis

Johnathan Cooper-Knock et al. Curr Opin Neurol. .

Abstract

Purpose of review: Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease wherein disease risk and severity are, for the majority of patients, the product of interaction between multiple genetic and environmental factors. We are in a period of unprecedented discovery with new large-scale genome-wide association study (GWAS) and accelerating discovery of risk genes. However, much of the observed heritability of ALS is undiscovered and we are not yet approaching elucidation of the total genetic architecture, which will be necessary for comprehensive disease subclassification.

Recent findings: We summarize recent developments and discuss the future. New machine learning models will help to address nonlinear genetic interactions. Statistical power for genetic discovery may be boosted by reducing the search-space using cell-specific epigenetic profiles and expanding our scope to include genetically correlated phenotypes. Structural variation, somatic heterogeneity and consideration of environmental modifiers represent significant challenges which will require integration of multiple technologies and a multidisciplinary approach, including clinicians, geneticists and pathologists.

Summary: The move away from fully penetrant Mendelian risk genes necessitates new experimental designs and new standards for validation. The challenges are significant, but the potential reward for successful disease subclassification is large-scale and effective personalized medicine.

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Conflict of interest statement

Conflicts of interest: None

Figures

Figure 1
Figure 1. Manhattan plot for new ALS genome-wide association study (GWAS) including cross-ancestry meta-analysis.
Red line represents the p-value threshold for genome-wide significance based on Bonferroni multiple testing correction (p=5e-08). Genes linked to loci by prioritization analysis are labelled.
Figure 2
Figure 2. Existing ALS risk genes converge within biological pathways including mRNA processing, autophagy and axonal function.
Figure indicates example risk genes and relevant subcellular localisation.
See this image and copyright information in PMC

References

    1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011 Mar 12;377(9769):942–55. - PubMed
    1. Shepheard SR, Parker MD, Cooper-Knock J, Verber NS, Tuddenham L, Heath P, et al. Value of systematic genetic screening of patients with amyotrophic lateral sclerosis. JNNP. 2021;92:510–518. *This study describes screening for ALS associated mutations in a prospectively selected clinic population. - PMC - PubMed
    1. van Rheenen W, van der Spek RAA, Bakker MK, van Vugt JJFA, Hop PJ, Zwamborn RAJ, et al. Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. bioRxiv medRxiv. 2021 [Internet]. Available from: http://medrxiv.org/lookup/doi/10.1101/2021.03.12.21253159** This study is the new ALS GWAS which represents a step change in our understanding of the genetic architecture of ALS. - DOI - PMC - PubMed
    1. Tazelaar GHP, Boeynaems S, De Decker M, van Vugt JJFA, Kool L, Goedee HS, et al. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain Commun. 2020 May 19;2(2):fcaa064. - PMC - PubMed
    1. Cooper-Knock J, Zhang S, Kenna KP, Moll T, Franklin J, Allen S, et al. Rare Variant Burden Analysis within Enhancers Identifies CAV1 as a New ALS Risk Gene. Cell Rep. 2020 Dec 1;33(9):108456. * This study describes identification of the first non-coding genetic risk factor for ALS which is relevant to a significant number of patients. - PMC - PubMed

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