. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015 Mar 27;347(6229):1436-41. Epub 2015 Feb 19 PubMed.


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  1. This paper tells us there are probably no unidentified common genes for ALS, because the frequency of mutations found in this study are generally less that 1 percent. However, this does not exclude the possibility there is a common gene with a mutation like the C9orf72 expansion, because a variant such as this would not be picked up by this type of analysis.

    I think this paper also tells us that to get the most out of exome sequencing we have to really analyze large numbers of exomes.  We are at a similar stage to where we were with genome-wide association studies 10 years ago.  It's only when large numbers of cases were analyzed that the real genes came through.

    There are many reports in the literature of putative ALS genes.  I think this study is very useful in helping to work out what is and what is not a true ALS gene.


  2. This is a very important and comprehensive study in which exome sequencing of 2,874 ALS patients and 6,405 controls has been used to identify genes contributing to ALS predisposition using a population of predominantly sporadic ALS cases. In particular, the major gene revealed from this study, but not evident in any earlier studies using exome sequencing or GWAS, was TBK1, a protein involved in autophagy and directly responsible for the phosphorylation of optineurin and p62/sequestosome, already identified as familial ALS (FALS) genes.

    The size of the multicenter cohort and the analytical procedure used (gene-based collapsing analysis), where DNA variants satisfying defined criteria qualified for inclusion in a gene-based analysis, significantly contributed to the success of the study. After the initial discovery phase, 51 genes were selected for a replication study in a further 1,318 cases and 2,371 controls using the same analytical approach, and when both studies were combined they yielded a high level of significance for the association of DNA variants with disease and an overall prevalence of DNA variants in TBK1 of 1.1 percent in cases and 0.2  in controls.

    It was also of great interest to see that using the same methodology to study the association between clinical features and DNA variants in known genes, including TBK1, only one gene reached statistical significance and that was D-amino acid oxidase (DAO), an enzyme that degrades D-serine, an obligate co-agonist at the N-methyl-D-aspartate subtype of glutamate receptor. This is highly relevant in the light of accumulating data that expression of DAO mutations in motor neuron cell lines or primary motor neuron cultures leads to ubiquitinated protein aggregate formation, increased autophagy, and apoptotic cell death, key processes occurring universally in ALS pathogenesis.

    Overall, this study has clearly demonstrated the value of exome sequencing for defining genes that underlie predisposition to ALS, most importantly relevant to sporadic cases of ALS, but with strong implications for familial cases as well. This opens up the field to a greater understanding of ALS predisposition and pathogenesis.

    Please note that exome sequencing data has been contributed to this study from our Imperial College FALS cohort, through the FALS sequencing Consortium.

  3. I think this is a really exciting paper. A few people from our group were involved (Jan Veldink and Leonard van den Berg), so I was already aware of the findings. In ALS there is a discussion about where the missing heritability is and it has been suggested that it could be in rare variants. Therefore, it has been proposed that large whole-exome or whole-genome sequencing studies could be the way forward. This paper seems to confirm that view. It is reassuring that they find SOD1 and TARDBP as major hits (positive controls).

    The statistics for the TBK1 gene are convincing and it is even more intriguing that it points toward previously implicated pathways and genes. The fact that most aggregates that are found in the motor neurons of ALS patients stain positive for OPTN and SQSTM1 suggests that these genes (or their pathways) are highly relevant to ALS, despite the fact that mutations in these genes are rare. Similarly, the frequency of mutations in TBK1 is low, but the fact that the gene again implicates autophagy and inflammation is exciting. This suggests that these are pathways on which we should be focusing. Larger and collaborative next generation sequencing are underway and hopefully these will reveal more pieces of the ALS puzzle.

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