Elsevier

Brain Research

Volume 1607, 14 May 2015, Pages 75-93
Brain Research

Review
Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges

https://doi.org/10.1016/j.brainres.2014.10.009Get rights and content

Highlights

  • Amyotrophic lateral sclerosis constitutes a heterogeneous neurodegenerative disorder.

  • Genetics factors play a significant role in ALS etiology and pathogenesis.

  • Genetic causes of ~65% of familial and ~10% of sporadic ALS have been identified.

  • Different genetic mechanisms underlie ALS etiology.

  • NGS techniques may favor the discovery of new genes.

Abstract

The genetic architecture of amyotrophic lateral sclerosis (ALS) is being increasingly understood. In this far-reaching review, we examine what is currently known about ALS genetics and how these genes were initially identified. We also discuss the various types of mutations that might underlie this fatal neurodegenerative condition and outline some of the strategies that might be useful in untangling them. These include expansions of short repeat sequences, common and low-frequency genetic variations, de novo mutations, epigenetic changes, somatic mutations, epistasis, oligogenic and polygenic hypotheses.

This article is part of a Special Issue entitled ALS complex pathogenesis.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons leading to rapidly progressive paralysis and eventually death from respiratory failure. Although this core definition is remarkably straightforward, it is becoming increasingly apparent that ALS is not a monolithic entity, but rather represents a heterogeneous group of diseases that share clinical features.

Examples of the heterogeneity associated with ALS are easy to find: the majority of cases die within three to four years of disease onset, but up to 10% of ALS patients survive for more than 10 years (Chiò et al., 2009a); there is wide variability in disease from population to population and across geographical region (Cronin et al., 2007); age at onset ranges from early twenties to the ninth decade of life; the clinical manifestation of disease differs from patient to patient in terms of clinical onset (bulbar-onset versus spinal-onset disease, proximal versus distal weakness, upper limb versus lower limb predominant), course (upper motor neuron versus lower motor neuron predominant), and frontotemporal lobe involvement (normal cognition versus mild cognitive impairment and/or dementia), to name but a few. Variability in neuropathology has also been observed with TDP-43 positive inclusions dominating most cases, but other cases lacking these inclusions.

Genetics offers a means to dissect out this heterogeneity and understand the cellular mechanisms leading to motor neuron degeneration. Paradoxically, however, it is this very heterogeneity associated with ALS that is the biggest obstacle to unraveling the genetics (Singleton et al., 2010).

For decades after its initial description in the half of 19th century (Aran, 1848, Cruveilhier, 1852, Charcot and Joffroy, 1869), ALS was thought to be a non-hereditary disease. It was not until Kurland and Mulder (1955) reported on familial aggregation in the 1950s that heritable factors were considered important in ALS etiology. Today, a family history of disease is recognized in 10% of cases, whereas the remaining 90% of cases are labeled as sporadic as they appear to occur randomly in the community. Even here, however, the sands are shifting, with an increasing portion of cases recognized as having a family history of related neurodegenerative diseases such as frontotemporal dementia. Autosomal dominant inheritance is by far the most common, but incomplete penetrance appears to be the rule.

To date, the genetic etiology of approximately two thirds of familial ALS and about 10% of sporadic disease has been identified (Renton et al., 2014). Genetic mutations are clearly responsible for the remaining one third of familial disease, but it is not known how much of the remaining sporadic disease is genetic and how much is due to other factors such as environmental exposures, aging or lifestyle choices. Genome-wide data suggest that genetic factors contribute to at least 23% of sporadic ALS (Keller et al., 2014). Even this high value, however, is likely to be an underestimate as the calculation was based on common variants in the human genome and would not capture the portion of disease arising from rare variants.

To date, more than 25 genes linked to ALS have been identified (Table 1, Fig. 1). We present these genes in two categories, namely (a) genes identified using linkage analysis and positional cloning, and (b) genes identified through the application of advanced genome-wide technologies. Though not every gene fits neatly into this framework, describing the genetic discoveries in ALS in this way provides a historical context and highlights how advances in genomic technologies are revolutionizing the way we think about this fatal neurodegenerative disease.

Section snippets

SOD1

In 1993, an international consortium identified SOD1 as a gene responsible for autosomal dominant FALS cases, by means of linkage analysis in 18 ALS pedigrees (Rosen et al., 1993). Through this method is possible to map the location of disease-causing loci by testing the co-segregation of genetic markers with the phenotype of interest. Multiple markers across the whole genome are usually screened in large families and a statistical test is performed to determine which markers are inherited by

Genome-wide association studies of ALS

Association studies involve comparison of the frequencies of genetic variants between groups of unrelated affected individuals and control subjects. Initial association studies were based on a candidate gene approach, but, with advances in genomic assay technology, several million markers across the genome can now be interrogated in a single experiment. This is known as genome-wide association study (GWAS).

Several GWAS have been published in ALS (Schymick et al., 2007, van Es et al., 2007, van

Epigenetics

Epigenetic modifications influence the expression pattern of the genome, Alteration of epigenetic processes, including DNA methylation, have been long known as causes of human diseases (e.g. imprinting syndromes, conditions caused by mutation in genes regulating epigenetic modifications, and cancer). Epigenetic mechanisms also appear to be involved in motor neuron cell death (Chestnut et al. 2011). Furthermore, epigenetics changes are the consequence of a dynamic process influenced by the

Unraveling the genetics of ALS: The way forward

Recent years have seen a boom in the identification of new ALS genes. The discovery of the C9orf72 repeat expansion had the biggest impact, explaining a significant proportion of both FALS and SALS cases and of the observed overlap between ALS and FTD. It has been argued that are unlikely to be other genetic discoveries with as high a frequency as the C9orf72 mutation and that, given the high cost of genetic studies, the ALS research community should focus their efforts elsewhere. Perhaps not

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