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Amyotrophic Lateral Sclerosis Taking Genetics of Amyotrophic Lateral Sclerosis to Next Steps Orla Hardiman, BSc, MD, FRCPI, FAAN, FTCD, MRIA Professor of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute Abstract Great advances have been made in understanding the genetics of amyotrophic lateral sclerosis, but we are really merely at the end of the beginning. Many new genes have been discovered, but these need to be contextualized within populations and across different phenotypes. Increased international collaboration through whole-genome sequencing initiatives, such as Project MinE (www.projectMinE.com), combined with detailed clinical phenotyping is most likely to drive future research in disease pathogenesis and new drug development. Keywords ALS, genetics, genomics, deep phenotyping, genetic pleiotropy Disclosure: Orla Hardiman, BSc, MD, FRCPI, FAAN, FTCD, MRIA, has no conflicts of interest to declare. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: July 10, 2015 Published Online: August 28, 2015 Citation: US Neurology, 2015;11(2):108–9 Correspondence: Orla Hardiman, BSc, MD, FRCPI, FAAN, FTCD, MRIA, Professor of Neurology, Trinity College Dublin, Room 5.41, Trinity Biomedical Sciences Institute, Pearse Street, Dublin 2, Ireland. E: hardimao@tcd.ie Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that is frequently described as being either familial or sporadic. Since the discovery of mutations in SOD1 as a cause of ALS, there has been an explosion in genetics research, leading to the discovery of at least 22 genes of major effect, of which C9orf72, SOD1, TDP43 and FUS are most prevalent in populations of European extraction. However, genetic risk factors play a role in the aetiology of a substantial portion of apparently non-familial disease. 4 This is supported by heritability estimates based on twin (38–78 %) and trio data (41–60 %), as well as the genetic epidemiology observations that Mendelian genes in familial ALS are also found as disease-causing mutations in apparently sporadic cases. 5 Known Genes and Population Diversity In addition there is much that is yet to be discovered about ALS, and to move the genetics of ALS to the next steps, we must address at least five major dilemmas: (a) the precise definition of familial ALS; (b) the characterization of known genes and their distribution within different populations; (c) the likelihood that not all reported, apparently disease- associated variants are pathologic; (d) the utility or otherwise of genome-wide association studies in identifying new variants; and (e) the unexpected presence of genetic pleiotropy. Familial versus Sporadic Disease There is currently no accepted definition of familial ALS. ALS and frontotemporal dementia (FTD) are biologically related, and the definition of familial ALS should also allow for the presence of FTD. However, we must remember that the frequency of familial disease can be underestimated by the late onset of disease phenotype, incomplete penetrance and small kindreds, and that because the lifetime risk is 1:400, in kindred of 17, there is a 5 % chance that another family member will also have ALS who is not familial. 1,2 Notwithstanding, detailed family history studies estimate that 15 % of people with ALS have another affected member, and in populations of European extraction, 50 % of these families will harbour a repeat expansion in C9orf72. 3 108 It is no longer correct to consider that the genetic risk for developing ALS is uniform across the world, because known genes are not uniformly distributed across the world. We know that the C9orf72 variant is rare outside of European populations, and that mutations in SOD1 are also population-specific, occurring with low frequency in familial and sporadic disease in the Netherlands and Ireland, and with higher frequency in Italy and the US. 5 There is strong evidence now that founder effects of single genes can increase the frequency of ALS in some regions (e.g. Sardinia and the Kii peninsula of Japan 6 ), and that oligogenic inheritance (the likelihood of two or more variants combining to increase the risk for disease) can also affect risk within populations, as has been shown in Guam. 7 Conversely, genetically diverse populations, such as Cuba and Latin America, exhibit lower rates of disease. 8 These factors must be taken into account when studying ALS in diverse populations, and when advising patients in a genetic counselling setting. Are All Variants Pathogenic? Population-based studies of ‘at-risk’ genes that increase disease susceptibility suggest that up to 17 % of patients with ALS carry an ‘at-risk’ variant, although the relative contribution of each identified gene rarely exceeds an odds ratio of 2.0, and in most cases the mechanism by which Touch ME d ica l ME d ia