JNNP Online First, published on February 16, 2017 as 10.1136/jnnp-2016-315469 Editorial commentary J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-315469 on 16 February 2017. Downloaded from

traditionally under-represented in large ALS genetic ‘How simplex is genomics efforts. The samples are there, the international expertise is there, the the genetic epidemiology of ALS?’ ICT solutions are there, but there are still a number of challenges that need to Jan H Veldink be met: setting up prospective cohorts in many countries to collect biosamples and clinical data, getting proper informed consent on all samples, so these can be First, how genetic is amyotrophic lateral common risk haplotype in C9orf72 repeat used for research purposes and last but not sclerosis (ALS)? We know that there are expansion carriers.5 6 The consequence of least, funding to generate the data. Recent clear ‘Mendelian’ forms of the disease this finding is that in Euro- crowd funding events have shown how where the classic Mendelian rules of inher- pean populations need to first focus on successful these can be to generate funds itance apply, and several first-degree and C9orf72 using a combination of repeat- (swimming, hiking or cycling for ALS). second-degree relatives are affected by primed PCR and fluorescent PCR, while With the advent of gene-specific therapies, the disease. Prospective population-based in Asian populations, non-synonymous this seems to be an urgent matter for all registries show that the rate of this Mende- screening in SOD1 (and other patients with ALS. lian form of ALS is about 5% (and not 10% ALS genes) is the first step. Contributors JHV wrote the manuscript. as most often is assumed).1 The far majority Second, the authors also show through of patients, therefore, cannot be classi- meta-regression that besides popula- Competing interests None declared. fied as such, but twin studies in ALS have tion type (Asian vs European), the type Provenance and peer review Commissioned; shown that explain about 61% of of cohort (population-based vs hospital internally peer reviewed liability in ALS, suggesting that a substan- based) is a strong determinant of muta- © Article author(s) (or their employer(s) unless tial genetic contribution is available for tion frequencies. This suggests that popu- otherwise stated in the text of the article) [2017]. All discovery, even in patients with no family lation-based cohorts provide less biased rights reserved. No commercial use is permitted unless otherwise expressly granted. history.2 Also, patients with ‘sporadic’ ALS estimates compared with hospital-based show in major ALS genes. series, since these are typically character- In their JNNP manuscript, Zou et al3 ized by younger patients, a phenomenon very elegantly describe the genetic epide- well known in ALS epidemiology.

miology of sporadic and ‘familial’ ALS, Last, this paper again shows strong indica- copyright. applying a clear definition for familial tions for the existence of an oligogenic basis To cite: Veldink JH. J Neurol Neurosurg Psychiatry versus sporadic disease.4 Using guidelines for ALS: the co-occurence of two mutations in Published Online First: [please include Day Month Year]. for meta-analyses and systematic reviews, the big four was 0.4% in familial ALS, which doi:10.1136/jnnp-2016-315469 the authors have screened over 6000 arti- is much higher compared with expected cles dealing with mutation frequencies in by chance. It mostly concerned combina- Received 17 January 2017 Accepted 25 January 2017 the ‘big four’ in ALS: C9orf72, SOD1, tions between TARDBP, FUS or SOD1 with TARDBP and FUS. C9orf72 repeat expansions. There are three important observations What can we learn from these observa- REFERENCES 1 Byrne S, Walsh C, Lynch C, et al. Rate of familial to take home from this huge effort. tions? amyotrophic lateral sclerosis: a systematic review First, Asian and European ALS cohorts Recent insights show that the genetics and meta-analysis. J Neurol Neurosurg Psychiatry show a striking divergent genetic back- of all ALS (both sporadic and familial) 2011;82:623–7. http://jnnp.bmj.com/ ground, which is not due to publication is characterised by a disproportionate 2 Al-Chalabi A, Fang F, Hanby MF, et al. An estimate of amyotrophic lateral sclerosis heritability bias. The most common ALS mutation contribution of rare genetic variation, as using twin data. J Neurol Neurosurg Psychiatry in European patients, both sporadic and opposed to common complex diseases 2010;81:1324–6. familial, is the C9orf72 repeat expan- such as schizophrenia,7 and popula- 3 Zou Z, Zhou Z, Che Z, et al. Genetic epidemiology sion, while non-synonymous mutations in tion-based incidence figures appear to fit of amyotrophic lateral sclerosis: a systematic review SOD1 are the most common mutations in well with a so-called discrete multistep and meta-analysis. J Neurol Neurosurg Psychiatry. Published Online First: 5 January 2017. Asia. Frequencies of C9orf72 mutations process.8 Indeed, rare genetic variation

4 Byrne S, Bede P, Elamin M, et al. Proposed on September 23, 2021 by guest. Protected in familial disease were most common in is much more geographically stratified criteria for familial amyotrophic lateral sclerosis. Belgium and Greece (both 50%), followed compared with common genetic variation, Amyotroph Lateral Scler 2011;12:157–9. by Finland (46.4%), while SOD1 mutations which is in agreement with the findings in 5 Smith BN, Newhouse S, Shatunov A, et al. The C9ORF72 expansion mutation is a common cause were highest in Korean (54.7%), Russian ALS by Zou et al. The combination of the of ALS+/-FTD in Europe and has a single founder. (50%) and Finnish (42.9%) cohorts. This importance of rare genetic variation with Eur J Hum Genet 2013;21:102–8. shows that the genetic origin of ALS in a multistep model suggests that ALS is 6 He J, Tang L, Benyamin B, et al. C9orf72 different populations is not uniform across somewhere in between common complex hexanucleotide repeat expansions in Chinese the globe and suggests the occurrence of diseases and simple Mendelian diseases. In sporadic amyotrophic lateral sclerosis. Neurobiol Aging 2015;36:2660.e1–e8. many independent founder mutations that sense, ALS can be regarded as a'sim- 7 van Rheenen W, Shatunov A, Dekker AM, et al. in the past, as has been shown with the plex’ disease. Given the strong influence Genome-wide association analyses identify new risk of geography, rare genetic variation and variants and the genetic architecture of amyotrophic study type in assessing mutation frequen- lateral sclerosis. Nat Genet 2016;48:1043–8. Correspondence to Professor Jan H Veldink, 8 Al-Chalabi A, Calvo A, Chio A, et al. Analysis of Department of Neurology, University Medical Center cies, this truly calls for a global effort to amyotrophic lateral sclerosis as a multistep process: Utrecht, P.O. Box 85500, GA 3508 Utrecht, The do ALS genomics. We need to include a population-based modelling study. Lancet Neurol Netherlands; j.​ ​h.veldink@​ ​umcutrecht.nl​ more populations from countries that are 2014;13:1108–13.

Veldink JH. J Neurol Neurosurg Psychiatry 2017;0:1. doi:10.1136/jnnp-2016-315469 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd under licence.