. Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol. 2015 Jan;77(1):100-13. Epub 2014 Nov 27 PubMed.

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  1. I am not surprised by these findings. When we initially proposed that some familial ALS cases might be oligogenic, this view was met with considerable skepticism. Since then, multiple papers have come out looking at multiple genes in a cohort of patients. In all of the studies, patients carrying variants in multiple ALS genes were identified. I am working on an overview of all these papers, but it looks like about 5 to 10 percent of patients with a family history are oligogenic.

    There are not many studies that have looked at large cohorts of sporadic cases. The Cady study is one the first to do this. Sporadic ALS is thought to be caused by multiple genetic and environmental factors. Therefore, you would expect that sporadic patients carry multiple variants. What we do not know is what type of variants these are (rare variants with minor allele frequency of less than 1 percent, lots of common variants, combinations of rare and common variants, copy number variations, repeat expansions, etc.). There is an influential paper in Nature Reviews Genetics in which Teri Manolio proposes that the missing heritability in human disease might be hiding in rare variants (Manolio et al., 2013). This still remains to be demonstrated for ALS. Many diseases in which GWAS were initially not so successful have made tremendous breakthroughs with increasing sample size (for example, Parkinson’s and schizophrenia). It may be that common variants are involved in ALS, but we just need bigger studies to prove this. On the other hand, the Cady study shows that sporadic cases carry multiple rare variants and therefore that rare variation is perhaps important in sporadic ALS.

    In all, I think the big picture that is forming suggests that a substantial number of ALS patients carry multiple variants and it is probably the nature of these variants that determines whether the disease presents as sporadic or familial. In the Manolio paper they present genetic variants on a sliding scale from disease-causing to risk factors with small effect. I think this model fits ALS genetics well. The division in familial and sporadic ALS is probably artificial.

    References:

    . Bringing genome-wide association findings into clinical use. Nat Rev Genet. 2013 Aug;14(8):549-58. Epub 2013 Jul 9 PubMed.

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  1. Multiple Mutations Hasten ALS Onset, Suggests Genetic Study