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Human Molecular Genetics 2007 16(R2):R233-R242; doi:10.1093/hmg/ddm215
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetics of sporadic amyotrophic lateral sclerosis

J.C. Schymick1,3, K. Talbot3,4 and B.J. Traynor2,5,*

1 Laboratory of Neurogenetics, NIA and 2 Neurogenetics Branch, NINDS, NIH, Bethesda, MD 20892, USA , 3 Department of Physiology, Anatomy and Genetics, University of Oxford, Henry Wellcome Building of Gene Function, South Parks Road, Oxford OX1 3QX, UK, 4 Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK and 5 Neurology Department, Johns Hopkins Hospital, 600 N. Wolfe Street, Meyer 6-109, Baltimore, MD 21287, USA

* To whom correspondence should be addressed. Tel: +1 3014517606; Fax: +1 3014517295; Email: traynorb{at}mail.nih.gov

Received July 26, 2007; Accepted July 27, 2007


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CANDIDATE GENES
 GENOME-WIDE ASSOCIATION STUDIES
 DISCUSSION
 FUNDING
 REFERENCES
 
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CANDIDATE GENES
 GENOME-WIDE ASSOCIATION STUDIES
 DISCUSSION
 FUNDING
 REFERENCES
 
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown aetiology characterized by rapidly progressive paralysis leading to death due to respiratory failure, typically within 3–5 years of symptom onset. It is the most common adult onset motor neuron disease with an incidence of ~2.1 per 100 000 person-years (1). Although it is widely stated that 10% of ALS is familial in nature, population-based prospective epidemiological studies report the true rate of familial ALS to be between 1.5 and 5% (2,3). Familial ALS follows a predominantly autosomal dominant pattern and a number of genes underlying this condition have been identified (4–9). The remaining 95% of cases do not have an obvious family history of ALS and appear to occur sporadically throughout the community.

Although the aetiology of sporadic ALS is largely unknown, familial and epidemiological data indicate that genetic factors contribute to its pathogenesis (10,11). Despite this, no single gene has been definitively shown to cause sporadic ALS, though a number of genes have been implicated (Table 1). The purpose of this article is to critically review published data supporting each candidate gene associated with increased risk of sporadic ALS. Emphasis will be placed on the genetic evidence rather than biological function of the corresponding protein, as it is possible to construct a feasible biological hypothesis for virtually any gene in terms of ALS pathophysiology. We also review whole genome association studies of sporadic ALS and discuss the potential of this methodology for identifying genes relevant to sporadic ALS.


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  		Table 1. Association studies of candidate genes in ALS

 

   CANDIDATE GENES
TOP
 ABSTRACT
 INTRODUCTION
 CANDIDATE GENES
GENOME-WIDE ASSOCIATION STUDIES
 DISCUSSION
 FUNDING
 REFERENCES
 
The results of individual association studies and mutational screening of each candidate gene are detailed in Table 1.

Apurinic endonuclease gene (OMIM 107748)
The DNA repair enzyme apurinic endonuclease (APEX1) was initially selected as a candidate gene for sporadic ALS based on its protective role against oxidative stress. A study of 117 sporadic ALS patients found the G allele of D148E (rs1130409) to be moderately over-represented in cases compared with controls (12). This finding was evaluated by two additional studies, one of which confirmed the association (13) and one of which did not (14). Pooled analysis of all three studies shows a moderate association with sporadic ALS (OR for allelic carriers = 1.51, 95% CI = 1.30–1.75, P = 0.0099 based on a cohort of 303 cases and 228 controls, Table 1). Further evaluation of this locus has been eclipsed by the neighbouring gene angiogenin (ANG), despite the fact that the data supporting APEX are more robust.

Angiogenin (OMIM 105850)
ANG was selected as a candidate gene for sporadic ALS because it is located 229 kb telomeric of the APEX gene on chromosome 14q11.2 and because it shares functional similarity to VEGF, another angiogenesis factor previously implicated in the pathogenesis of ALS. An initial case–control study demonstrated that the synonymous G110G variant (rs11701) was associated with increased risk of disease in the Irish and Scottish ALS populations (13). Follow-up screening confirmed the association of rs11701 with ALS in the same populations, but not in large cohorts of patients drawn from America, Sweden and England (15) or in two independent cohorts of Italian sporadic cases (16,17). Direct sequencing of ANG putatively identified seven missense-coding mutations that the authors considered to be pathogenic (15). However, the families reported in this study were not large enough to conclusively prove that the variants segregated with disease and two of these variants have since been described in normal individuals (15,16).

Additional genetic data are required to support the hypothesis that ANG is relevant in the pathogenesis of ALS. However, it is already clear that ANG mutations are, at best, a rare cause of sporadic disease, as variants were only found in eight out of 1370 sporadic ALS patients.

Chromatin modifying protein 2b (OMIM 609512)
Chromatin modifying protein 2B (CHMP2B) is involved in endosomal trafficking, which is increasingly recognized as being important in neurodegeneration (18). Mutations in this gene were first identified as a cause of frontotemporal dementia (FTD) after a splice site mutation was found to segregate with disease within a large Danish family (19). However, it is now clear that CHMP2B mutations are a rare cause of FTD accounting for < 1% of cases (19,20). The clinical and neuropathological similarities between ALS and FTD mean that any FTD gene should also be considered to be a candidate gene in the pathogenesis of ALS. Mutational screening of 172 British ALS cases revealed two CHMP2B variants in a small number of familial cases, though one of these had been previously identified as a non-pathogenic population polymorphism (21). Variants were not found in sporadic cases, so we conclude that there is currently insufficient data linking CHMP2B mutations with sporadic ALS.

Dynactin (OMIM 601143)
Dynactin (DCTN1) is the motor protein responsible for retrograde axonal transport of vesicles and organelles along microtubules. In 2003, a G59S mutation located in the microtubule-binding domain of dynactin was described as the cause of an autosomal dominant, late-onset motor neuron disease in a large family of European descent (8). Three DCTN1 mutations were subsequently found in a series of 108 familial and 142 sporadic German ALS patients using single-strand conformational polymorphism analysis (22). One of these, T1249I, was found in a 60-year-old sporadic ALS patient. The other two mutations (M571T and R785W) were identified in familial ALS cases, but it was not possible to demonstrate that the mutations segregated with disease. The same group published a case report of a family with ALS and FTD phenotypes who carried a novel R1101K DCTN1 mutation, though again it was not possible to conclusively prove segregation of this mutation with disease within this family (23). More recently, a case–control association study of DCTN1 and 58 other genes involved in axonal transport did not identify any association in a large cohort of British sporadic ALS patients (24).

Although it is clear that mutations within the DCTN1 gene can be responsible for a familial form of motor neuron disease, additional genetic evidence is required to confirm the association with sporadic ALS.

Haemochromatosis (OMIM 235200)
Mutations in the haemochromatosis (HFE) gene disrupt iron metabolism and have been implicated in the pathogenesis of Alzheimer's disease (25). There are conflicting reports concerning the role of HFE mutations in the pathogenesis of ALS. The odds ratio associated with the H63D allele of the HFE gene has been reported to vary from 0.8 in the Dutch population (26) to 2.5 in the US population (27). However, pooled analysis of four published studies continues to show that the H63D variant of the HFE gene is associated with a significantly increased risk of developing ALS (Table 1).

Despite this, the association between HFE mutations and ALS should be interpreted cautiously. There is a marked geographical variation in its distribution of H63D, which is one of the most frequent mutations observed in the general population and therefore the nature of the control populations used in these studies is a particular potential confounder. Furthermore, HFE lies in a large block of linkage disequilibrium, so it is not clear whether the H63D variant is truly linked with the pathogenesis of ALS or whether it is merely in linkage with the true disease-causing variant. Additional genetic studies are required to delineate the role of HFE mutations in the pathogenesis of sporadic ALS.

Neurofilaments (NEFL, NEFM, NEFH; OMIM 162280, 162230)
Neurofilaments are intermediate filaments that are primarily responsible for maintaining axonal integrity. The presence of neurofilament-containing inclusion bodies within the cell bodies and proximal axons of motor neurons is considered pathonomonic of ALS (28). On the basis of this, and the observation that mutations in the NEFL gene cause the hereditary motor neuropathy Charcot–Marie–Tooth disease type 2E (29), neurofilament subunit genes were obvious candidate genes. However, screening of large numbers of cases has failed to identify variants in any of the three neurofilament subunits which are unambiguously linked to dominantly inherited disease (30–34). Furthermore, although rare insertions and deletions had previously been observed within the highly repetitive KSP repeat domain of NEFH, it is now clear that the most common KSP domain repeat variations are not associated with sporadic disease (30,32,33).

We conclude that mutations in the neurofilament genes are not a common cause of sporadic ALS, though it remains possible that alterations in neurofilament structure and dosage may act as modifiers to SOD1 mediated familial ALS (35).

Paraoxonase (OMIM 168820, 602447)
Paraoxonase (PON) is a serum enzyme involved in the detoxification of organophosphate insecticides and neurotoxins (36,37). There is weak epidemiological evidence suggesting that chemical exposure may increase risk of developing ALS among farmers (38) and among Gulf War Veterans (39). The PON genes, PON1, PON2 and PON3, are located together within an 80 kb block on chromosome 7q21.2–q22.1. A case–control association study performed in a cohort of 185 Polish sporadic cases and 437 matched controls reported that the non-synonymous SNPs rs662 in PON1 and rs6954345 in PON2 were positively associated with increased risk of ALS. These associations were not significant after multiple test correction (Bonferroni corrected P-value for rs662 and rs854560 = 0.09 and 0.36) (40). Furthermore, the finding was not confirmed in two subsequent case–control studies (41,42) and rs662 was not associated with disease in a whole genome association study of American ALS cases and controls (43).

Peripherin (OMIM 602447)
Peripherin (PRPH) is an intermediate filament similar to neurofilaments, but expressed primarily in autonomic nerves and peripheral sensory neurons. PRPH mutations have been identified in two sporadic ALS patients: a 228delC frameshift mutation that truncated the last 386 amino acids of the protein was found in a 60-year-old sporadic ALS patient, but was not observed in control samples (44). The second variant (homozygous D141Y) was identified in a 42-year-old male with spinal-onset disease (45). Interestingly, immunocytochemical analysis of his spinal cord revealed large peripherin-containing aggregates within surviving spinal motor neurons.

The genetic evidence supporting PRPH mutations as a cause of sporadic ALS is preliminary. The fact that the two identified variants, 228delC and D141Y, have different mode of inheritance is obviously concerning. Furthermore, a larger number of controls from different ethnic backgrounds need to be screened to determine whether these variants are merely rare population polymorphisms. Nevertheless, the concept of selecting patients for PRPH mutational screening based on their neuropathological analysis is intriguing.

Progranulin (OMIM 138945)
Progranulin (PGRN) is a 68.5 kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. Truncating and nonsense mutations of PGRN were recently discovered to be the cause of ubiquitin-positive, tau-negative FTD (FTDU) (46). To date, there is only a single published report of an individual with a definitively pathogenic progranulin mutation who also fulfilled the El Escorial criteria for ALS (47). No truncating PGRN mutations were identified in a series of 48 patients with sporadic ALS or in a separate series of 272 sporadic cases indicating that mutations in this gene only rarely (if ever) cause a ‘pure’ ALS phenotype (48,49).

Cu/Zn superoxide dismutase (OMIM 147450)
SOD 1 mutations account for one-fifth of familial ALS cases (50) and it is widely quoted that SOD1 mutations are a cause of sporadic ALS in 1% of cases (51). However, there has been no systematic screen in a population-based sample to eliminate the biases inherent in screening a clinic-based sample. Many of these mutations could be explained by low penetrance (52), de novo mutations (53) or even non-paternity and therefore do not necessarily provide clear evidence of a true association with sporadic ALS. One association study suggests that specific SOD1 polymorphisms do not confer an increased risk of sporadic ALS (54).

Survival motor neuron 1 and 2 (OMIM 600354, 601627)
Humans contain two copies of the survival motor neuron (SMN) gene located on chromosome 5q13.3, telomeric SMN1 and centromeric SMN2, which has only 20% of the biological function of SMN1 (55). Deletions or mutations of SMN1 cause child-onset spinal muscular atrophy (56), whereas variations in SMN2 copy number affect disease severity (57). Five studies have demonstrated that the typical deletions seen in SMA do not occur in ALS patients (58–62). A large study of 600 sporadic ALS patients found that an ‘abnormal’ number of SMN1 copies (one or three rather than two) occurred more frequently in cases than controls (OR = 2.8, 95% CI 1.8–4.4) (59,61). Given that this predicts either an increased or a decreased amount of total SMN protein, this is a potentially confusing result, though either one or three SMN1 copies could indicate disruptions to the genomic organization of the SMN region resulting in lower total SMN protein levels. In keeping with this possibility, one study, which used predicted total SMN protein levels based on SMN1 and SMN2 copy number, indicated that reduced total SMN protein levels occurred in 61% of ALS patients versus 36% of controls (60).

Replication in a large cohort of several thousand cases drawn from different populations is required to definitively determine whether SMN1 copy number, or predicted total SMN protein level, is linked with ALS. Alternatively, SMN copy variants may be specifically relevant to the pathogenesis of lower motor neuron-predominant ALS. A study of 14 patients with pure lower motor neuron ALS found that half had either SMN1 or SMN2 deletions (62). Given that what we consider to be ALS is likely to be a clinically and genetically heterogeneous disease, closer attention to endophenotype may be a valuable tool in dissecting the genetic basis of motor neuron degeneration.

Vascular endothelial cell growth factor (OMIM 192240)
Vascular endothelial cell growth factor (VEGF) was identified as a candidate gene based on a mouse model that displayed progressive motor neuron degeneration arising from deletion of the hypoxia response element in the promoter region of VEGF (63). Initial mutation screenings of ALS patients did not find pathogenic variants within the HRE promoter region or coding regions (64,65). Subsequently, a large study of nearly 2000 individuals from Sweden, Belgium and England (Birmingham and London) found a variety of locus and haplotye associations with increased risk of ALS. For example, the – 1154A/A promoter region recessive genotype was positively associated with disease in the Swedish and Birmingham populations, but not in Belgium or London populations. The AAG/AAG promoter haplotype increased the risk of ALS in the Swedish and Birmingham populations, whereas the AGG/AGG haplotype was significantly associated in the Belgium population. These associations were not significant after correction for multiple testing and several subsequent studies have not confirmed the reported findings (66–69). We conclude that VEGF is not a common genetic cause of sporadic ALS, though it remains possible that population-specific or rare familial effects exist.


   GENOME-WIDE ASSOCIATION STUDIES
TOP
 ABSTRACT
 INTRODUCTION
 CANDIDATE GENES
 GENOME-WIDE ASSOCIATION STUDIES
DISCUSSION
 FUNDING
 REFERENCES
 
We recently completed a whole genome association study in a cohort of 276 American sporadic ALS patients and 275 neurologically normal American control samples (43). Analysis of our data found 34 SNPs that were significantly associated with increased risk of developing ALS, though none of these SNPs exceed the Bonferroni threshold. However, speculation on the plausibility and biological significance of these candidate loci is premature, because of the inevitably high false-positive rate that occurs whenever several hundred thousand tests are performed on the same data set. Replication of these findings in a separate cohort is currently underway.

The paradigm of our initial whole genome association study was not to find loci, but rather to provide publicly accessible data. Over 300 million genotypes generated for ALS cases and for normal controls were made publicly available on the Coriell website at the time of manuscript publication (43) and these sample-level raw genotype data have been downloaded several hundred times since April 2007. The release of the raw genotype data and not just the allele frequency data means that other researchers do not have to genotype the same samples, thereby reducing the expense of future whole genome association studies. Furthermore, it established a powerful, unique resource for the ALS research community that can be augmented with other whole genome association data sets in the future. Furthermore, public availability of this data allows researchers to have greater confidence in the results of their candidate gene association studies, as they can instantly determine whether their putative candidate gene is also associated with disease in a separate American cohort. We encourage other ALS researchers to make the raw genotype data from their whole genome association studies publicly available through NCBI's dbGap website (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap). This database is specifically designed to archive and distribute genotype and phenotype information and will soon broadcast data from the initial genome wide association study of ALS.

Although the era of whole genome association studies is in its infancy, a number of important lessons are already evident. The genetic factors that underlie common diseases, such as type 2 diabetes (70), coronary artery disease (71) and breast cancer (72), can clearly be identified using SNP chip technology. However, these variants tend to have a modest effect with odds ratios significantly less than 2.0 and initial whole genome association studies indicate that this is also the case in ALS (43). Identification of variants that increase the risk by 10–15% could require genotyping of more than 7000 well-phenotyped samples (73). Although such a study would require ~$10 million to complete, it may be cost-effective given the total annual expenditure on ALS research and the potential for understanding the fundamental pathogenesis of this fatal neurodegenerative disorder. A number of whole genome association studies of sporadic ALS are currently nearing completion and efforts are underway to merge the different data sets consisting of ~3500 ALS cases. Results of this pooled analysis are expected in early 2008 and a clearer picture of the genetics underlying sporadic ALS and the magnitude of the task of identifying these genes will hopefully emerge at that time.

Apart from the cost, the availability of several thousand well-phenotyped samples is a key bottleneck to undertaking a whole genome association study of the magnitude required to find genetic factors with modest effects. The NINDS Coriell repository was funded to collect and distribute DNA from nearly 2000 ALS cases and 2000 controls. The rate of sample deposition has been extraordinary and there are now a number of pre-compiled plates available for purchase (http://ccr.coriell.org/Sections/Collections/NINDS/?SsId=10). The Veterans Administration ALS Registry (74) and the British ALS Biobank have been ostensibly less well utilized, mainly because access to the DNA samples is regulated by scientific committees, rather than operating on a first come/first serve, or an egalitarian fee-based manner. Clearly, the availability of DNA samples should be a topic of open debate within the ALS research community.

A number of factors confound the ability of whole genome association studies to identify causative alleles. It is likely that sporadic ALS, a phenotypically variable syndrome, is a genetically heterogeneous disease with multiple genes initiating motor neuron degeneration through separate but convergent biological pathway. Different disease-causing alleles may also exist within the same gene, as is the case with SOD1 pathogenic mutations (i.e. allelic heterogeneity) (75). As each mutant allele will exist on its own distinct chromosomal background, the strength of association signal for that gene will be diluted. Secondly, the best statistical method of correcting for multiple testing is not yet clear (76) and it may be that the only true solution is to replicate the study in separate cohorts. Rather than focusing on the most significantly SNPs, which are likely to be spurious associations, a more robust method of identifying disease-causing alleles involves follow-up of several thousand SNPs in a larger cohort. Finally, it is possible that ALS is caused by multiple rare variants, rather than following the common disease/common variant hypothesis. The variants are rare because they occurred more recently in human history and therefore each one accounts for only a small percentage of cases and are not found at an appreciable rate among the general population (e.g. minor allele frequency < 0.01 %) (77,78). Standard association approaches will likely fail in this instance, even when the relative risk of the variant is high (78).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 CANDIDATE GENES
 GENOME-WIDE ASSOCIATION STUDIES
 DISCUSSION
FUNDING
 REFERENCES
 
The volume of genetic data that are currently being generated makes it increasingly difficult for non-geneticist readers to interpret the literature. This problem is compounded by the manner in which data are sometimes presented. Although apparent pathogenicity is a more saleable entity, spurious associations can mislead a field for many years resulting in wasted time and resources (79,80). One potential solution is for scientific journals to adopt industry-wide consensus guidelines for the publication of genetic studies and case–control association studies, in particular. This would be analogous to the CONSORT guidelines, which have standardized reporting of randomized clinical trials allowing the validity of the data to be more appropriately evaluated (http://www.consort-statement.org/index.html). Key issues to be considered include: an initial report of association between a variant and a disease should be considered to be hypotheses-generating. Proof of this hypothesis will rely on subsequent replication in large, independent cohorts, preferably drawn from separate regions/populations; emphasis should be placed on correction for multiple testing, especially in an era when high-throughput technology allows several million genotypes to be generated in a short period of time; journals should place more emphasis on publication of negative studies, which are often more informative; raw, sample-level, genotype data should be routinely made publicly available through the dbGaP website (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap). The availability of these data will facilitate future pooled analysis and allow more robust interpretation of putative associations. Finally, a major issue currently facing the field is that resequencing of a gene in large cohorts will inevitably identify rare population polymorphisms that are not disease causing, but it can be subsequently very difficult to disprove their pathogenicity. One method of overcoming this problem is to sequence a large number of controls from more than one ethnic background rather than the more common practice of screening for mutation occurrence in a single ethnic background (79).

In conclusion, we predict that whole genome association studies will identify a number of genes associated with increased risk of ALS over the next 12 to 18 months, but that they will have modest effects and it is likely that there are many such genes waiting to be found. In the longer term, current SNP chip-based technologies will ultimately be superseded by whole genome sequencing (81), which will be a particularly powerful technique for identifying rare variants underlying ALS. Of course, this level of ultra-deep resequencing will carry with it its own set of problems, particularly the thorny issue as to how to determine whether rare population polymorphisms are truly pathogenic or merely innocent bystanders.


   FUNDING
TOP
 ABSTRACT
 INTRODUCTION
 CANDIDATE GENES
 GENOME-WIDE ASSOCIATION STUDIES
 DISCUSSION
 FUNDING
REFERENCES
 
This research was supported (in part) by the Intramural Program of the National Institute of Neurological Diseases and Stroke (B.J.T.) and by the Intramural Program of the National Institute on Aging (J.C.S.).


   ACKNOWLEDGEMENTS
 
The authors would like to thank Andrew B. Singleton, Stephen Berger, Sonja W. Scholz and John Hardy for reviewing the manuscript.

Conflict of Interest statement. The authors report no conflicts of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 CANDIDATE GENES
 GENOME-WIDE ASSOCIATION STUDIES
 DISCUSSION
 FUNDING
 REFERENCES
 

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