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Advances in the genetic classification of amyotrophic lateral sclerosis

Authors :
Ilia Sarah Timpanaro
Johnathan Cooper-Knock
Sai Zhang
Alfredo Iacoangeli
Jan H. Veldink
Kevin P. Kenna
Calum Harvey
Tobias Moll
Source :
Current opinion in neurology
Publication Year :
2021

Abstract

Purpose of review \ud \ud 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.\ud \ud \ud \ud Recent findings \ud \ud 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.\ud \ud \ud \ud Summary \ud \ud 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.

Details

ISSN :
14736551 and 13507540
Volume :
34
Issue :
5
Database :
OpenAIRE
Journal :
Current opinion in neurology
Accession number :
edsair.doi.dedup.....67468bfbfedd6c4dcc8f9d26af97257a