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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: firstname.lastname@example.org
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
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