The panorama of ALS genomics
published: July 21, 2017, recorded: May 2017, views: 864
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ALS is a complex disorder, with no single genetic or environmental cause and no known cure. While heritability estimates show us that genetic risk factors clearly play an important role in the disease, epidemiological studies indicate that multiple separate accumulated risks over the lifetime of a patient also participate in triggering the disease process. However, identifying and understanding the nature of and interaction between these various genetic and (probable) environmental factors has been a challenge, and this incomplete understanding has been the greatest obstacle to the development of effective therapies for ALS. Technological advances in the field of genomics have accelerated the discovery of genetic risk factors for ALS; such studies have often been vast in scope, scale and cost. For example, genome-wide association studies (GWAS) involving up to 36,000+ individuals have identified novel risk loci and indicated a polygenic component to ALS. Further analysis of this polygenic risk has revealed a genetic correlation between ALS and schizophrenia, indicating shared genetic risk factors and potentially overlapping biology. However, the overarching conclusion from GWAS is that ALS has a principally rare variant architecture, the elucidation of which requires more fine-grained profiling and analysis of ALS genomes. To this end, a number of recent studies have identified genes that harbour rare ALScausing mutations by sequencing the exomes (the entire protein-coding portion of the genome) of ALS patients. Ongoing work by the Project MinE Consortium is extending this approach to interrogate all rare genetic variation present across the entire genome. As discoveries continue to be made, a holistic view of ALS genomics will permit more effective patient categorisation and the identification of central disease mechanisms that reconcile the apparently multifarious genetic findings. This talk will explore the advances made in ALS genomics and discuss the successes and shortcomings of the approaches and technologies that have been adopted to date. Future avenues in ALS research will be discussed in light of a synthesis of evidence to date and the opportunities afforded by recent technological advances.
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