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14

ORIGINAL ARTICLE

Genetic studies of amyotrophic lateral sclerosis: Controversies and

perspectives

ANA BELEZA-MEIRELES & AMMAR AL-CHALABI

MRC Centre for Neurodegeneration Research, King’s College London Institute of Psychiatry, London, UK
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Abstract
The genetic causes of amyotrophic lateral sclerosis (ALS) are slowly being dissected out with the help of recent advances in
genetic technology. Linkage studies and association studies examining candidate genes, candidate pathways, and genome-
wide association have been used, based on direct sequencing and correlations between genetic variations. Copy number and
microsatellite variants have also been examined, although the ideal methods for analysis are still being developed. In this
review we examine the evidence for a genetic basis to ALS, discuss the challenges and difficulties faced and summarize the
support for the reported genetic causes of ALS.

Key words: Genetics, association, linkage, genome-wide association, copy number variation
For personal use only.

Introduction Mutations in the gene for SOD1, an anti-oxidant

Amyotrophic lateral sclerosis (ALS), also called
motor neuron disease, is a devastating, rapidly
progressive neurodegenerative disorder, in which
the primary hallmark is the selective death of motor
neurons resulting in progressive weakness and death
from respiratory failure within a few years (1,2). The
incidence is 1
2 per 100,000 person-years and
prevalence 4
13 per 100,000 (3).
The exact cause of the selective motor neuron
degeneration in ALS remains elusive. To date, and
despite many years of intensive study, very few genes
have been unequivocally implicated in sporadic
ALS. Moreover, it is difficult to determine which
of the hypothesized molecular processes is most
important in triggering cell dysfunction and death.
Familial amyotrophic lateral sclerosis
Between 5 and 10% of ALS cases are familial
(FALS) with a predominantly autosomal dominant
pattern of inheritance. Various genes have been
identified in familial ALS, the most important of
which, superoxide dismutase 1 (SOD1), accounts for
up to 20% of all familial cases (4,5). Several other
genes (6
20) have now been identified (Table I).
enzyme, are diverse and have unexpected effects on
its structure, activity and native state stability. ALS-
causing SOD1 mutants acquire properties that are
selectively toxic to motor neurons. The toxicity
of mutant SOD1 appears to be multifactorial and
operates through multiple interrelated pathways:
it affects DNA/RNA metabolism, mitochondria,
neurofilaments and axonal transport, and the func-
tion of cell organelles. The SOD1-related patholo-
gical processes also involve activation and
dysfunction of astrocytes and microglia, with ex-
cessive extracellular glutamate and excitotoxicity.
These cellular stresses ultimately activate cell death
pathways (4
7).
The role of the other Mendelian ALS genes is
even less clear and far less investigated. However,
some candidate physiological mechanisms have been
proposed. ALS2 is an infantile-to-young adult-onset
spastic paraparesis, with amyotrophy reported in one
family. The ALS2 gene codes for alsin, a guanine-
nucleotide exchange factor for small GTPases,
whose function is not fully understood. It is known
to suppress mutant SOD1-mediated toxicity in
immortalized motor neuron cell lines by binding to
SOD1. Most of the identified mutations in alsin are
predicted to lead to loss of function, and loss of alsin

Correspondence: A. Al-Chalabi, MRC Centre for Neurodegeneration Research, King’s College London Institute of Psychiatry P 043, London SE5 8AF, UK.
E-mail: ammar@iop.kcl.ac.uk

(Received 2 September 2008; accepted 21 October 2008)

ISSN 1748-2968 print/ISSN 1471-180X online # 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS)
DOI: 10.1080/17482960802585469
 2 A. Beleza-Meireles & A. Al-Chalabi

Table I. Monogenic forms of motor neuron disease. Loci identified through linkage have led to the discovery of six ALS-causing genes.
Because linkage is most powerful when large pedigrees of at least three generations are available, most of these identified genes have been in
young-onset slowly progressive forms of ALS. All are transmitted as autosomal dominant, except for ALS2 and ALS5, which are autosomal
recessive.

Onset Name Linkage Gene Protein Reference

Adult ALS1 21q22.1 SOD1 Cu/Zn superoxide dismutase 4, 6, 7

Juvenile ALS2 2q33-35 ALS2 Alsin 8
Adult ALS3 18q21 Unknown 9
Juvenile ALS4 9q34 SETX Senataxin 10
Juvenile ALS5 15q15-q22 Unknown 11
Adult ALS6 16q12 Unknown 12
Adult ALS7 20ptel Unknown 13
Adult ALS8 20q13.33 VAPB VAMP-associated protein B and C 14
Adult ALS9 14q11 ANG Angiogenin 59
Adult ALS10 1q36 TARDBP Tar DNA-binding-protein 43 (TDP-43) 19,20
Adult ALS-FTD 9q21-22 Unknown 15
Juvenile ALS-FTD2 9p13.2-21.3 Unknown 17
Juvenile 7q34-q36 Unknown 18
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in mice predisposes to oxidative stress, causes age- Sporadic amyotrophic lateral sclerosis
dependent neurological defects and results in altered
About 90% of cases of ALS are genetic isolates,
vesicle and endosome trafficking (5,8).
referred to as sporadic ALS. An estimate of sporadic
ALS4 is a slowly progressive, juvenile-onset distal
ALS heritability comes from a 10-year UK study of
motor neuropathy with pyramidal signs. ALS4-
10,872 death certificates in which ‘motor neuron
related missense mutations in the SETX gene, which
disease’ was listed as a cause of death. In this study,
codes for a protein with a DNA/RNA helicase
26 monozygous (MZ) and 51 dizygous (DZ) twin
domain, lead to altered RNA processing, a mechan-
For personal use only.

pairs were identified in which at least one member

ism that has already been implicated in other
inherited motor neuron diseases (discussed below)
(5,10).
ALS8 is associated with three different pheno-
types: late-onset spinal muscular atrophy, typical
ALS, and a slowly progressive ALS with tremor.
Mutations in the vesicle-associated membrane pro-
tein (VAMP)/synaptobrevin-associated membrane
protein B gene, VAPB (5,14), which is responsible
for ALS8, affect a protein presumed to regulate
vesicle transport.
ALS10 is a recently described typical form of
ALS linked to the TARDBP gene. The RNA
processing hypothesis has been reinforced by the
finding, in both sporadic and familial ALS cases, of
mutations in TARDBP, a gene coding for TDP-43
protein which binds RNA and DNA and has
proposed functions in transcriptional regulation
(19,20). Gene loci for other forms of ALS are still
being investigated, and the overlap between ALS
and frontotemporal dementia is also providing in-
sights into potential ALS genes.
Overall, analyses of the genes already identified
as contributors to Mendelian inheritance of ALS
have generated new insights into the diverse mole-
cular pathways involved in ALS pathogenesis. Fa-
milial ALS genes encode proteins involved in various
cellular mechanisms, including oxidation, axonal
transport, DNA/RNA processing and apoptotic
signalling. This diversity may indicate that the
pathogenesis of ALS is related to several different
processes, all of which ultimately lead to neurode-
generation (5).
had ALS. Two of the MZ pairs and none of the DZ
twins were concordant for ALS. One MZ concordant
twin pair was from a family with known FALS and
excluded, as were a further four discordant MZ pairs
because the co-twin died before the proband devel-
oped ALS. Seven DZ pairs were also excluded for this
reason. This led the authors to estimate heritability
for sporadic ALS as 0.38
0.85, although the estimate
is essentially based on one twin pair (21). Further
evidence for a familial component to sporadic ALS
(SALS) comes from the demonstration of familial
aggregation of neurodegenerative diseases including
ALS, Parkinson’s disease and dementia (22).
In addition, SOD1 mutations have been found in
1
7% of sporadic ALS (21) and TARDBP mutations
(19,20) are found in between 1 and 5% of sporadic
ALS, confirming that heritable genetic causes are
responsible for at least a proportion of ALS.
Susceptibility to developing ALS can therefore be
considered on a spectrum from familial to appar-
ently sporadic disease, most likely resulting from
complex genetic and environmental interactions.
Dissecting out the genetic factors responsible
requires linkage studies for FALS and association
studies for SALS. Until recently, most association
studies have confined themselves to examining
candidate genes selected on the basis of structure,
function or similarity to known genes. Association
studies are fraught with difficulty because the signal
to be detected is usually weak (odds ratios of the
order of 1.5 or less) and the number of genes to be
tested is large. This means that very many cases and

controls need to be examined to achieve a low risk of
false positive results. Thus, although there has been
a steady stream of reported associations (23
98),
replication studies have often been inconsistent
(Table II), even for supposedly genuine associations,
reflecting limited power and investigation of very
small regions of the genome (99). An additional
complication in genetic studies of ALS is the striking
phenotypic variation aggravated by the absence of
biological markers. Disease heterogeneity is likely to
further reduce power to detect association. More-
over, because ALS is a late-onset, short-survival
disorder, obtaining the parental samples that facil-
itate family-based studies is problematic.
Despite these issues, two strategies have been used
in candidate-gene studies of SALS in the recent past.
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The first studies concentrated on single genes and
searched for sequence variants. These studies have
arguably given us our greatest insights into disease
susceptibility, with replicated associations of, for
example, SOD1, NEFH, ANG, VEGF and TARDBP
mutations in a small percentage of cases. Between
them, such variants could account for up to 13% of
SALS cases. TARDBP, ANG and NEFH show a
similar pattern to SOD1 in having mutations found
both in families and those with sporadic disease.
For personal use only.
The second strategy is based on the common-
disease common-variant hypothesis. Because the
lifetime risk of ALS is of the order of 1 in 250 to
1 in 400 (100), it can be considered a common
disease. A consequence of the genetic architecture in
human populations means that genetic associations
can be tested by analysis of a subset of single
nucleotide polymorphism markers (SNPs) that cap-
tures most of the genetic variation in the immediate
region around the SNPs. Since many common
variants are correlated with one another, association
at a tested marker (a tag) will reveal information
about association at untested markers. Using this
approach, large numbers of candidate genes can be
tested for association of common variation with
ALS. One recent large-scale case-control association
study of 822 cases and 872 controls selected
134 genes from pathways hypothesized to be of
importance in ALS and studied 1277 tag and
functional SNPs within those genes (101). This
failed to demonstrate that common variation in the
investigated genes had a major effect on suscept-
ibility to sporadic ALS. Some of the mechanisms
that have been strongly implicated in neurodegen-
eration and motor neuron death, such as defects in
retrograde axonal transport, vesicle trafficking and
xenobiotic metabolism, were targeted.
Genome-wide association studies of ALS
A higher throughput version of this strategy has
recently become possible. Genome-wide association
(GWA) studies (102) offer the potential for mapping
Genetics of ALS review 3
of SALS. These studies differ from candidate gene-
based approaches as they do not make assumptions
about the nature or location of the causative genes.
GWA studies make use of the abundant, naturally
occurring, polymorphic genetic markers, particularly
SNPs and microsatellite markers, which are distrib-
uted throughout the genome (103). The advent of
microchip technology, which types a million com-
mon genetic variants in one test thereby capturing
more than 90% of the common genetic variation in
humans, has made it feasible to perform GWA
studies in hundreds of patients and controls. Today,
the chips are designed to include SNPs at even
spacing across the genome, giving preference to tag
SNPs that have been identified as reliable proxies for
the larger pool of SNPs selected from the Interna-
tional HapMap Project database (104).
The power of this technique is increasingly
recognized. SNP-based genome-wide association
studies undertaken by the Wellcome Trust Case
Control Consortium in 2007 (105) showed that
GWA studies represent a powerful approach to the
identification of genes involved in common complex
genetic disorders. An important factor limiting
genetic studies of sporadic ALS, however, has been
the lack of large sample collections providing enough
power for association analysis, and the lack of
replication and attempts to replicate published
findings. International collaborations are therefore
a necessity.
The first published GWA study in ALS was of
276 ALS cases and 271 controls from the United
States analysed at the National Institutes of Health
(NIH) (106). Although the authors identified 34 loci
they thought might be worth follow-up, no genome-
wide significant findings were observed. One limita-
tion was the low number of patients and controls.
There was zero power to detect an odds ratio of
1.5 at the average minor allele frequency (0.24) on
the chip and at the necessarily stringent multiple test
correction that needed to be applied (107).
A second GWA study was performed using
766,955 SNPs derived from Illumina and Affymetrix
platforms in 386 patients of European ancestry with
sporadic ALS and 542 neurologically normal con-
trols (the discovery series) at the Translational
Genomics Research Institute, Phoenix, USA (108).
The first pass was followed by two independent
replication populations: replication series 1, with
766 people with ALS (136 were classified as not of
European ancestry and 192 as of unknown ancestry)
and 750 neurologically normal controls, and replica-
tion series 2, which were the data from the NIH
study. The most significant association with disease
in cases of European ancestry compared with con-
trols was found for a SNP near an uncharacterized
gene known as FLJ10986 (p 3.0 10
4). Further-
more, the authors confirmed the presence of the
FLJ10986 protein in the cerebrospinal fluid of
 4
Table II. Candidate genes for SALS. There have been many candidate gene studies in SALS, and more recently pathways-based analyses and genome-wide association studies.

Gene Description Reason for investigation Significance Refs

A. Beleza-Meireles & A. Al-Chalabi

Oxidative stress
SOD1 Cu/Zn superoxide dis- A major cytoplasmic antioxidant enzyme that metabolizes superoxide radicals 2
7% sporadic cases have mutations 4, 6, 7
mutase 1 to molecular oxygen and hydrogen peroxide, thus providing a defense against oxygen toxicity.
Mutations in SOD1 account for 20% of familial ALS.
SOD2 Manganese superoxide SOD2 is a related protein of SOD1, found in mitochondria. No association with human ALS demonstrated/ replicated 23, 24
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dismutase
CCS Copper chaperone for Gene responsible for copper insertion into SOD1. No association with human ALS demonstrated/ replicated 25
superoxide
dismutase
HFE Hemochromatosis Oxidative stress is hypothesized to be implicated in neurodegeneration and misregulation of Contradictory results 26, 27
iron induces oxidative stress. Also, abnormal iron levels found
in spinal cords of ALS patients.
Excitotoxicity and glutamate transport
EAAT2 Excitatory amino acid EAAT2 regulates Na/
dependent glutamate levels in the synapse. CSF glutamate levels are No association with human ALS 28
31
transporter 2 elevated in ALS patients. Reports of aberrant RNA demonstrated/replicated
processing of EAAT2 in ALS patients.
VEGF Vascular endothelial Protects spinal cord motor neurons against glutamate-induced excitotoxicity; reduces Association found in some populations 32
37
For personal use only.

growth factor astrogliosis and preserves neuromuscular junctions in ALS transgenic mice. Suggests also
abnormalities in hypoxia-regulated genes.
Neurofilaments, cytoskeleton and microtubule defects
MAPT Microtubule-associated Microtubule-associated protein tau involved in other neurodegenerativediseases and Guam Association reported but p-values were weak 16, 38
protein tau variant of ALS has neurofibrillary tangles containing aggregates of tau.
NEFH Neurofilament, heavy Deletions within the C-terminal KSP repeat region of the NEFH have been found in some Significant association, tail domain deletions present in 1% 39
41
chain human ALS patients. Dramatic defects of axonal transport of neurofilament proteins and ALS patients, not in controls. Findings have replicated in
motor neuron degeneration observed in mice that overexpress neurofilament proteins. several studies
PRPH Peripherin Transgenic mice overexpressing peripherin, an intermediate filament protein that is expressed Few mutations found, not a common cause of ALS 42, 43
chiefly in motor neurons, develop motor neuron degeneration.
SNCG Persyn Persyn plays a role in neurofilament network integrity. It is a member of the synuclein family, ?- No association with human ALS demonstrated/ replicated 44
synuclein. Mutations in a-synuclein found in Parkinson’s disease.
SPG4 Hereditary spastic para- Mutations in spastin and paraplegin are the most common causes of hereditary spastic Associated with early-onset ALS with long survival 45, 46
paresis paraparesis. Possibly involved in the fine regulation of microtubule dynamics and organization. (1 case).
Altered axonal transport and vesicle trafficking
DCTN1 Dynactin Disruption of dynein/dynactin complex produces motor neuron disease phenotype in mice. One reported association, not yet replicated 47
The cytoplasmic dynein-dynactin complex has essential neuronal role in the trafficking of
cargo. Defects in retrograde transport hypothesis of ALS aetiology.
DNCH1 Dynein heavy chain DNCH1 has an essential neuronal role in the retrograde axonal transport of cargoes, such as No association with human ALS demonstrated/ replicated 48, 49
trophic factors, from synapse to cell body. Mutations in Dnch1 result in progressive motor
neuron degeneration in heterozygous mice,
homozygotes also have Lewy-like inclusion bodies.
VAPB Vesicle-associated mem- VAPB plays a role in the unfolded protein response. Expression is reduced in human ALS New familial gene, not yet tested in SALS. 14
brane patients and superoxide dismutase 1 (SOD1)-ALS-transgenic mice. Mutations in VAPB cause
protein-associated pro- an autosomal dominant, slowly progressive ALS (ALS8).
tein B
 Table II (Continued)
Gene Description Reason for investigation Significance Refs

poor metabolism of xenobiotics

ALAD Alfa-aminolevulinic acid Lead exposure may be associated with increased risk of ALS. Polymorphisms in ALAD may No association with human ALS demonstrated/ replicated 50, 51
dehydratase affect susceptibility to lead exposure.
CYP2D6 Cytochrome p450, sub- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. One reported association, not replicable 51, 52
family IID, Hypothesized poor metabolism of xenobiotics as risk factor.
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polypeptide 6
LOX Lysyl oxidase LOX is a copper containing enzyme and copper-induced cytotoxicity is a hypothetical No association with human ALS demonstrated/ replicated 54
mechanism of motor neuron degeneration.
MAO-B Monoamine oxidase B MAO-B is a mitochondrial enzyme involved in the oxidative deamination of biogenic and Association with age at onset modification reported, not yet 55
xenobiotic amines. If dysfunctional, it generates free radicals and these are implicated in replicated
neuronal damage.
PON1-3 Paraoxonases Major protective role both against environmental toxins and as part of the antioxidant defense Evidence that genetic variation across the paroxanase loci 56, 57
system. may be susceptibility factors for SALS.
VDR Vitamin D receptor Polymorphisms in VDR may affect susceptibility to lead induced ALS. Not significant 50
Altered DNA/RNA processing
ANG Angiogenin ANG is functionally similar to VEGF. Suggested to function as a tRNA-specific ribonuclease. Association found in European and US populations 58
62
ALS associated ANG variants affect neurite extension/pathfinding and survival of motor
For personal use only.

neurons. Suggests also abnormalities in hypoxia-regulated genes.

APEX Apurinic endonuclease Defective DNA repair hypothesis of ALS etiology. May have small but not major factor 63, 64
GARS Glycyl tRNA synthetase Mutated in distal hereditary motor neuropathy type V. Role for tRNA-charging enzymes in Not yet tested in SALS, but an interesting candidate 65, 66
peripheral axons.
SETX Senataxin Contains a DNA/ RNA helicase domain, which may suggest defects in RNA processing, cause New familial gene, not yet tested in sporadics 10, 46,
autosomal dominant juvenile ALS (ALS4). 67
SMN1/2 Survival of motor neuron Component of an import snRNP complex, interacts with several spliceosomal snRNP core Sm SMN genotypes which reduce SMN protein levels asso- 68
70
1/2 proteins. SMN protects cells against mutant SOD1 toxicity by increasing chaperone activity. ciated with SALS
TDP43 TAR DNA-binding pro- TDP43 is a human low molecular weight neurofilament mRNA-binding protein. Inclusions of TDP43 mutations found in FALS and SALS patients 19,69,
tein 43 TDP-43 described in MND and FTD. Anterior horn cells with abnormal TDP-43 71
73
immunoreactivities show fragmentation of the Golgi apparatus in ALS.
Mitochondrial defects
Mito Mitochondrial DNA de- Accumulation of mitochondrial DNA mutations associated with aging, Associations reported, but all studies very small 74
77
letions development of degenerative diseases. In ALS, abnormal mitochondria are often found in
spinal motor neurons.

Genetics of ALS review

ND2 Subunit 2 of mitochon- A mitochondrially encoded NADH dehydrogenase, in the oxidative No association with human ALS demonstrated/ replicated 78
drial NADH phosphorylation and ubiquinone biosynthesis pathways. Mutations were detected in patients
dehydrogenase (Complex with ALS and Alzheimer’s.
I)
SPG7/ Paraplegin Mutations in spastin and paraplegin are the most common causes of hereditary spastic No association demonstrated/ replicated 19, 46,
PGN paraparesis. Paraplegin is a nuclear encoded mitochondrial with paraplegin 79
metalloprotease.
Regeneration, trophism and motoneuronal death
ALS2 Alsin Causes autosomal recessive juvenile ALS (ALS2). ALS2 leads to the suppression of No association with human SALS demonstrated/ replicated 8, 80, 81
motoneuronal death induced by ALS-related mutant superoxide dismutase-1 (SOD1), via
activation of Akt3.

5
 6
A. Beleza-Meireles & A. Al-Chalabi
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Table II (Continued)
Gene Description Reason for investigation Significance Refs

APOE Apolipoprotein E Major apolipoprotein in the CNS. Implicated in several other neurodegenerative disorders. Not associated with susceptibility. May be associated with 82
84
Possible isoform specific role of apoE in regeneration and trophism. age of onset, presentation and survival
CNTF Ciliary neurotrophic fac- Mice lacking CNTF develop mild, progressive motor neuron loss. Contradictory results 85,88
tor
LIF Leukaemia inhibitory LIF is same cytokine family as CNTF, involved in motor neuron survival, and positive in the One reported association, not yet replicated 89, 90
factor spinal cord of ALS patients.
PSEN1 Presenilin-1 PSEN1, a transmembrane protein, seems to be implicated in apoptosis, a postulated Weak association found, small study, not replicated 91
mechanism for neuronal death
NAIP Neuronal apoptosis inhi- Often mutated in severe cases of spinal muscular atrophy, it is strongly expressed in anterior No association. Mutations in NAIP now considered 92
94
For personal use only.

bitory protein horn and motor cortex neurons of normal brains. specific for SMA
Other processes
AR Androgen receptor Causes Kennedy spinal and bulbar muscular atrophy. No association with human ALS demonstrated/ replicated 95
HexA Hexosaminidase A Abnormalities of GM2 ganglioside metabolism owing to Hex A deficiency have been Occasionally causes rare ALS-like syndrome 96
associated with ALS phenotypes.
PVR Poliovirus receptor Hypothesis of persistent non-lytic enteroviral infection in ALS: poliovirus attacks motor Association with lower motor neuron disease found in one
neurons selectively, enteroviral nucleic acids found in spinal cord of ALS patients. small study, not yet replicated
97,98

patients with sporadic ALS by immunoprecipitation.
However, the protein levels in spinal cord samples
from controls and patients with sporadic ALS were
found to be similar.
Two further GWA studies were performed by a
Dutch-led consortium using slightly different study
designs and overlapping sample sets. In the first, a
three-stage GWA study was performed in 461
patients with ALS and 450 controls from the
Netherlands, using Illumina 330K HumHap chips.
SNPs with p B0.1 in this stage were then retested in
a replication set of 876 patients and 906 controls
from the Netherlands, Belgium, and Sweden. In the
second stage, a variant with p 0.0007 (uncor-
rected) was identified in the inositol 1,4,5-tripho-
sphate receptor 2 gene (ITPR2) and the combined
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significance was p3.28 106 (p 0.012 after
Bonferroni correction). Adding in the data from
the NIH study improved the p-value further to
1.48 106. Functional evidence in support of a
true positive was a greater expression of ITPR2
in the peripheral blood of 126 ALS patients than in
that of 126 healthy controls (109). ITPR2 is
involved in glutamate-mediated neurotransmission.
It is also one of the main regulators of intracellular
calcium concentrations, and has an important role in
For personal use only.
apoptosis. ITPR2 is a therefore strong candidate
susceptibility gene for ALS and replication studies
are urgently needed.
The association of polymorphisms in the dipep-
tidyl-peptidase 6 (DPP6) gene with ALS has been
reported using overlapping sample sets. An Irish
GWA study of 222 patients and 217 controls found
no significantly associated variants in the first pass.
However, combination of the results with the NIH
study samples and some Dutch samples led to the
highest ranked SNP being in DPP6 (p 2.5 106)
(110). Analysis of the Dutch and NIH study samples
(total 737 cases and 721 controls) led to identifica-
tion in the first pass of a putative ALS susceptibility
associated variant in the DPP6 gene (111). The
p-value in stage 1 was 4.3 10 5 which does not
achieve genome-wide significance. This and
14 additional SNPs were selected for analysis in
the same replication populations as in the first study
with the addition of three additional independent
populations consisting of 272 cases and 336 controls
from the Netherlands, 467 cases and 437 controls
from Sweden and 291 cases and 420 controls from
Belgium. The overall p-value for SNP rs10260404 in
DPP6 was 5.4 10 8, which is 0.017 after Bonfer-
roni correction.
DPP6 binds specific voltage-gated type A neuro-
nal transmembrane potassium channels and alters
their expression and biophysical properties; it is
predicted to be involved in the physiological pro-
cesses of brain function and is a functionally
attractive candidate gene for ALS. Interestingly,
both the Irish-led and Dutch-led studies found
Genetics of ALS review 7
association with the same SNP, rs10260404, which
is located within an intron of the gene. No known
functional variants within the gene have been
identified. The presence of splicing variants in this
gene (112) may indicate splicing regulation as a
potential explanatory mechanism for this gene
variant or, perhaps more likely, it is in linkage
disequilibrium with the true causal variant. Alter-
natively, it may be a proxy for a copy number
variation. Truly independent replication is required
in new samples to test if this association is false.
Some preliminary conclusions may be reached
from these studies. First, the previously selected
physiologically relevant candidate genes have to date
not been identified in a whole-genome, unbiased
approach. Secondly, no signal is seen under identi-
fied linkage peaks. Thirdly, the GWA studies do not
all detect the same signal, and the Irish study, which
looks as if it might be a replication of the Dutch
DPP6 signal, leaves room for doubt when the data
are examined in more detail. A further replication
would be very helpful in bolstering this evidence.
Only a few possible explanations follow from
these observations. The key possibility is that there is
no important genetic component to ALS suscept-
ibility. The evidence for a genetic component is
given in the introductory paragraphs and, certainly,
absence of evidence for a genetic signal should not at
this stage be taken as evidence of absence of a
genetic signal. A second possibility is that any
genetic factors for sporadic ALS have a low odds
ratio for causing disease and the sample sizes
required for reliable detection are in the tens of
thousands or more, a factor worsened by ‘the
multiple testing problem’ produced because gene
chips contain probes for between 300,000 and one
million SNPs. Other factors might have worsened
the power to detect a variant further, such as disease
or allelic heterogeneity (the latter is sometimes called
the rare variant hypothesis).
The final possibility is that tag-SNP based
approaches are not the correct ones to identify
relevant genes. For example, ALS might be caused
by structural genomic variation in the form of copy
number variants (CNVs), and these are not well
captured using the current chips. While the optimal
methods for identifying these variants are still under
evaluation (113,114), and there is still a paucity of
data on population frequency and distribution of
CNVs, structural genomic variation might represent
a major factor in the aetiology of complex, multi-
factorial ALS. These possibilities are discussed in
more detail below.
The multiple testing correction issue
An important issue in GWA studies is the problem of
multiple testing. Error rates increase with the
number of tests carried out, and since GWA studies
 8 A. Beleza-Meireles & A. Al-Chalabi
involve testing hundreds of thousands of SNPs,
hundreds of thousands of tests are carried out even
before factors such as testing for association with
different phenotypes or subgroups are considered.
Because p-values follow the uniform distribution, the
probability that the smallest of n p-values is smaller
than some specified value a by chance is 1
(1
a)n
(115). This means that, as the number of tests
increases, the probability of having an apparently
significant p-value increases rapidly.
Various strategies can be employed to guard
against this multiple testing problem, which would
otherwise lead to false positive associations. The
simplest, such as Bonferroni correction, involves
dividing the threshold for significance by n, the
number of independent tests, but tends to lead to
Amyotroph Lateral Scler Downloaded from informahealthcare.com by 186.67.46.230 on 05/20/14
type 2 errors (false negatives) and may be too
conservative (116). Classical multiple testing theory
in statistics is concerned with the problem of multi-
ple tests of a single global null hypothesis (in other
words, the assumption is there is at best only one
true positive to find). In GWA studies, we are
probably facing the problem of testing multiple
hypotheses since there are likely to be multiple small
effect genes all of which contribute. Moreover, the
closely spaced SNPs frequently have high correla-
For personal use only.
tions because of extensive linkage disequilibrium
among them (117). This violates the requirement for
disease-associated SNPs to operate independently of
each other, which is a basic assumption in the Šidák
and Bonferroni corrections, and they are probably
therefore not appropriate methods for GWA studies
(118). Alternatively, permutation test correction is
very robust and has the advantage of drawing the
threshold directly from the experimental data (119)
but at the expense of computationally intensive
work.
Some other methods have been suggested based
on the False Discovery Rate (120
122), aiming to
keep the false positive rate within acceptable limits in
GWA studies. Another approach is to use a gene-
based correction, since genes are the functional units
that cause disease (123). No consensus has been
achieved within the statistical genetics community
on what correction method to use, and it might be
more advisable to set the significance threshold on
the a priori probability that there is a true association
at any specified location in the genome, rather than
the number of tests performed. Replication in
independent samples by independent laboratories
with confirmatory functional data are additional
levels of evidence that should be used to support a
positive result in a GWA study.
Mapping and the architecture of complex
genetic disorders
Case-control GWA studies are based on the common-
disease common-variant hypothesis. This hypothesis
states that what influences the risk of complex
disorders is common, invisible-to-selection, weakly
associated alleles (124). These alleles, although
medically detrimental at the present time, reached
high frequencies in human populations because they
were not evolutionarily deleterious. The common-
disease common-variant hypothesis also assumes
little allelic heterogeneity within loci. Moreover,
gene variants that affect the risk of complex disorders
under the common-disease common-variant hypoth-
esis have low penetrance and are probably little
affected by selection even when they are associated
with onset before menopause (125), a likely scenario
in late onset ALS (126,127). This is the basis of the
current chip-based genome-wide association studies,
but it is only one way by which genetic variation might
predispose to disease.
We do not yet know if susceptibility alleles in
ALS are neutral or deleterious, common or rare, few
or many (128,129). Modelling of complex diseases
taking into account aspects such as genetic variation
at disease loci, evolutionary processes, including
genetic drift, mutation and possibility of selection,
predicted that common, neutral susceptibility alleles
do not contribute much to the genetic variance
underlying disease and that they tend to be either
lost or close to fixation in the population (130,131).
Instead, the accumulation of mildly deleterious
missense mutations in individual human genomes
might underlie the genetic basis for complex diseases
since the observed frequency of disease-predisposing
genetic variation is at least in part the result of
mutation-selection balance (132
142).
One study (143) has found that around 20% of
new missense mutations in humans result in a loss of
function, whereas about 27% are effectively neutral.
Thus, the remaining 53% of new missense muta-
tions have mildly deleterious effects since the prior
probability of improving a protein function by
random mutation is very low. These mutations give
rise to many low-frequency deleterious allelic var-
iants in the human population, with low selection
coefficients. Thus, the low allele frequency of an
amino acid variant can, by itself, serve as a predictor
of its functional significance, with lower frequencies
indicating greater pathogenicity on average. The
demonstration of a large fraction of mildly deleter-
ious mutations observed among missense mutations
in humans suggests that mutation-selection balance
is a plausible explanation for the existence of
common disease with complex inheritance, at least
in some cases (144). This means allelic heterogene-
ity (in other words different rare variants responsible
for disease in each person) may be greater in more
physiologically complex disorders (130,131) and
would not be detectable using tag SNPs.
Such rare variants would be predicted to have an
effect size intermediate between the small effect of
common variants (odds ratios typically B1.3) and

the large effect of familial variants (odds ratios
typically well over 5) and on current evidence have
odds ratios 2 and averaging about 3.8. Rare
variants need not be familial, and exploration with
probability theory provides some valuable insights.
For example, in a sibship of size three, a rare
dominant variant with quite a high penetrance of
0.5 results in just one affected sib 84% of the time,
thus appearing sporadic if the parental status is
unknown (not unusual in a late onset disease). Even
if the parents are alive, more than half the pedigrees
manifesting the phenotype will appear to have
sporadic disease. A nuclear family with three chil-
dren is becoming less common in Europe and the
US, where the average family size is now 1.8
children. In families with both parents and two
Amyotroph Lateral Scler Downloaded from informahealthcare.com by 186.67.46.230 on 05/20/14
children, 65% of those manifesting the disease
phenotype will appear sporadic. With lower pene-
trance, such as 0.2, about 87% of such families will
appear to have sporadic ALS. Thus, the rare variant
hypothesis is a strong contender for a genetic model
of ALS, either alone or in combination with the
common-disease common-variant hypothesis.
Between the common-disease common-variant
and the rare-variant (mutation-selection balance)
hypotheses, the answers and paths that define the
For personal use only.
best approach to map complex diseases will be trait
specific, and probably no single approach will be
sufficient. The Wellcome Trust Case Control Con-
sortium genome-wide association studies (105) un-
covered novel variants, characterized by very modest
effect size. The distribution of effect sizes observed
indicated that we should expect a few large effect
genes, a handful of modest effects and a substantial
number of genes generating small or very small
increases in disease risk, which will require very large
population sets, and re-sequencing of other genes in
the relevant pathways or of the entire genome (133).
Furthermore, there is the added complexity of the
effects of structural variation, such as insertions,
deletions and copy number variations (134
136),
and interactions between variants and between
genetic and environmental factors, aspects that
have been poorly addressed in genetic studies to
date.
Copy number variation
CNVs are the most prevalent type of structural
variation in the human genome. Whereas we have
two copies of genes (one from each parent) for
autosomal genes, in some cases deletions and inser-
tions of 1Mb or larger result in loss of gene copies or
multiple copies, and the corresponding change in
gene dose may have an effect on susceptibility to
disease. For some genes, such as the haemoglobin
alpha chain gene, multiple copies are the usual state,
and loss of one or more of the four copies that
should be present results in alpha-thalassaemia trait
Genetics of ALS review 9
or disease. In other cases, duplication or deletion can
each result in different disease. For example, dose
changes of the PMP22 gene result either in heredi-
tary neuropathy with liability to pressure palsy (gene
deletion) or Charcot-Marie-Tooth disease (gene
duplication). Similarly, dose changes in the SMN
genes are risk factors for ALS and risk and prog-
nostic factors in spinal muscular atrophy. CNVs are
now emerging as risk factors for many disorders,
particularly schizophrenia and neurodevelopmental
disorders, and may be susceptibility factors for
infections (134
136).
To date only two studies have sought to identify
the contribution of CNVs to sporadic ALS on a large
scale (145,146), and both were unable to identify
common CNV loci significantly associated with ALS
risk. However, the data supported the hypothesis
that multiple rare CNVs might be commoner in
those with ALS, which encourages further studies.
The first report identified genes deleted specifically
in patients with sporadic ALS, including proteins
involved in oxidative phosphorylation, regulation of
the actin cytoskeleton, and interactions between
cytokines and their receptors (145). The second
report implicated ataxin genes, the hereditary hae-
mochromatosis locus, and an uncharacterized gene
on chromosome 14 (146).
The current challenges in CNV research are the
development of methods for detecting and catalo-
guing CNVs in human populations at increasing
resolution, and appropriate statistical and bioinfor-
matics strategies to accurately assess the association
of CNVs with biological function, recent human
evolution and common and complex human disease.
Convergent methods
The use of evidence from multiple sources to
support a finding is a powerful one. Genomic
convergence is the term used to describe results
from gene expression profiling that support a GWA
study finding. Post mortem analysis of brains of
patients with Alzheimer’s disease, for example, has
led to diverse theories about the causes of Alzhei-
mer’s disease pathology (137) and similar ap-
proaches have been applied in ALS. The strength
of such studies is in highlighting pathways and gene
networks that could be analysed in future genetic
studies.
Several studies have examined expression profiles
of brain, motor neurons or motor cortex in ALS and
suggest many metabolic pathways (147
149). How-
ever, the difficulties in knowing which are true and
which false positives bedevil expression profiling as
much as genome-wide association studies. Much of
this is because of the post mortem nature of the
study samples, which leads to lack of control over
molecular changes taking place during the time gap
between death and the experimental procedure.
 10 A. Beleza-Meireles & A. Al-Chalabi
Furthermore, different studies examine different
structures, and this is compounded by how difficult
it is to individualize and study different microana-
tomic structures. This makes intra-study compar-
isons extremely troublesome. Therefore, despite the
undeniable importance of gene expression profiling
of human post mortem samples in revealing path-
ways that might be implicated in ALS in humans,
there remain difficulties in their interpretation.
Conclusions
Human genetic studies in ALS, including GWA
studies and the study of structural genetic variation,
still represent the strongest tool to identify the
Amyotroph Lateral Scler Downloaded from informahealthcare.com by 186.67.46.230 on 05/20/14
molecular pathways involved in ALS. The accumu-
lated weight of evidence from all motor neuron
diseases suggests that genes encoding proteins that
are involved in axonal transport or play a role in
RNA processing are over-represented. While the
idea that axonal transport is important has been
evident for many years, the RNA processing theme is
only becoming apparent now. For example, the
following genes are linked to motor neuron diseases
and involved in RNA processing: TARDBP, SETX,
For personal use only.
SMN, GARS, ATXN7, IGHMBP2 and ANG. This
has led some to hypothesize that axonal mRNA
translation followed by retrograde transport of the
signal back to the nucleus could be the underlying
mechanism in ALS (150), and we expect that this
aspect will become a clear target for ALS research in
the near future. Genetic studies in ALS are still in
their infancy but the rapid advance in gene-hunting
technologies mean that a greater genetic under-
standing is coming closer every day.
Note
A genome-wide association study using 1,884 mi-
crosatellite markers has identified variants of a
component of RNA polymerase II, elongator protein
3, as associated with ALS in three different popula-
tions, furthur supporting the RNA processing hy-
pothesis. Simpson CL, Lemmens R, Miskiewicz K,
Broom WJ, Hansen VK, van Vught PW, et al.
Variants of the elongator protein 3 ELP3) gene are
associated with motor neuron degeneration. Hum
Mol Genet. 2008 Nov 7. [Epub ahead of print].
Acknowledgements
We thank the Motor Neurone Disease Association
and the Medical Research Council for support.
Declaration of interest: The authors report no
conflicts of interest. The authors alone are respon-
sible for the content and writing of the paper.
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