. Genome-wide analysis of the heritability of amyotrophic lateral sclerosis. JAMA Neurol. 2014 Sep;71(9):1123-34. PubMed.


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  1. GCTA is now a well-established technique, but the result can be affected considerably by the estimate of disease prevalence used. At the prevalence used here by Margaux Keller and colleagues, the 21 percent heritability estimate is identical to the result we published earlier this year using the same method and an overlapping data set (Fogh et al., 2014). When a prevalence estimate of five per 100,000 is used however, the heritability estimate is closer to 12 percent. Without doubt there remains some genetic contribution to ALS that remains unidentified, and this is true for apparently sporadic as well as familial ALS. For example, it is easy to show that every familial disease gene should be found in apparently sporadic cases and that the distinction between familial and sporadic disease is not clear-cut (Al-Chalabi et al., 2011; Byrne et al., 2012; Hanby et al., 2011). What is novel about this study is the use of GCTA to attempt to localize the genomic regions that might hold the relevant gene variants, and it will be interesting to see if the predictions hold up.

    It is likely that future ALS gene discoveries will include some with high and some with modest penetrance, and the contribution to risk in any individual is probably a combination of multiple gene variants and other risk exposures (Al-Chalabi et al., 2013). We already have examples of gene variants of low penetrance in UNC13A and ANG, moderate penetrance in C9orf72 and high penetrance in SOD1, TARDBP, FUS etc., and this trend will continue. A combination of patient engagement in research, large research collaborations, stupendous advances in gene technology and the availability of supercomputing make the discovery of the complete genetic architecture of ALS a realistic possibility.


    . A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2014 Apr 15;23(8):2220-31. Epub 2013 Nov 20 PubMed.

    . Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Hum Hered. 2011;71(4):281-8. PubMed.

    . Absence of consensus in diagnostic criteria for familial neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2012 Apr;83(4):365-7. PubMed.

    . The risk to relatives of patients with sporadic amyotrophic lateral sclerosis. Brain. 2011 Dec;134(Pt 12):3454-7. Epub 2011 Sep 20 PubMed.

    . The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013 Nov;9(11):617-28. Epub 2013 Oct 15 PubMed.

    View all comments by Ammar Al-Chalabi
  2. This paper shows that sporadic ALS is indeed caused by genetic factors, as had been implied by previous twin studies. The method used in this paper shows that the contribution of genes is considerable and higher than estimated previously using GWAS data. This reinforces the need for genetic research in ALS.

    The missing heritability in ALS is likely to be in rarer genetic variants with relatively large effect. The way to find these variants is by performing even larger GWAS (see our own effort: project MINE) using better chips with higher SNPs densities and imputation, analyzing pedigrees and extended pedigrees. As genotyping methods improve and costs drop, we will likely be able to perform large whole exome-/genome-sequencing studies allowing us to find these rare variants with large effects. Luckily, there are many collaborative efforts within the field of ALS which make it possible to get these large studies done.

    View all comments by Michael van Es

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  1. Fishing for the ‘Missing Heritability’ of ALS