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1.  Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis 
Nature neuroscience  2014;17(5):664-666.
MATR3 is an RNA/DNA binding protein that interacts with TDP-43, a major disease protein linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in the spinal cords of ALS cases with and without MATR3 mutations. Our data provide additional evidence supporting the role of aberrant RNA processing in motor neuron degeneration.
doi:10.1038/nn.3688
PMCID: PMC4000579  PMID: 24686783
3.  Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion☆ 
Neurobiology of Aging  2015;36(1):546.e1-546.e7.
An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Although 0–30 hexanucleotide repeats are present in the general population, expansions >500 repeats are associated with C9ALS/FTD. Large C9ALS/FTD expansions share a common haplotype and whether these expansions derive from a single founder or occur more frequently on a predisposing haplotype is yet to be determined and is relevant to disease pathomechanisms. Furthermore, although cases carrying 50–200 repeats have been described, their role and the pathogenic threshold of the expansions remain to be identified and carry importance for diagnostics and genetic counseling. We present clinical and genetic data from a UK ALS cohort and report the detailed molecular study of an atypical somatically unstable expansion of 90 repeats. Our results across different tissues provide evidence for the pathogenicity of this repeat number by showing they can somatically expand in the central nervous system to the well characterized pathogenic range. Our results support the occurrence of multiple expansion events for C9ALS/FTD.
doi:10.1016/j.neurobiolaging.2014.07.037
PMCID: PMC4270445  PMID: 25179228
Frontotemporal dementia; Somatic instability; Amyotrophic lateral sclerosis
4.  Homozygosity analysis in amyotrophic lateral sclerosis 
European Journal of Human Genetics  2013;21(12):1429-1435.
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering ‘common' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10−5), a greater proportion of cases harboured homozygosity (P=2 × 10−5), a longer average length of segment (P=1 × 10−5), a longer total genome coverage (P=1 × 10−5), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9–4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.
doi:10.1038/ejhg.2013.59
PMCID: PMC3829775  PMID: 23612577
amyotrophic lateral sclerosis; homozygosity; recessive
5.  Genetic comorbidities in Parkinson’s disease 
Human molecular genetics  2013;23(3):831-841.
Parkinson’s disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn’s disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn’s disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn’s disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn’s disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn’s disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.
doi:10.1093/hmg/ddt465
PMCID: PMC3888265  PMID: 24057672
6.  Valosin-containing protein mutations in sporadic amyotrophic lateral sclerosis 
Neurobiology of Aging  2012;33(9):2231.e1-2231.e6.
We recently reported that mutations in the VCP gene are a cause of 1–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three US cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS, but account for less than 1% of this form of disease.
doi:10.1016/j.neurobiolaging.2012.04.005
PMCID: PMC3391327  PMID: 22572540
Amyotrophic lateral sclerosis; valosin-containing protein; mutations; sporadic disease
7.  Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12 
Human mutation  2013;34(10):10.1002/humu.22378.
We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly-conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.
doi:10.1002/humu.22378
PMCID: PMC3819934  PMID: 23857908
SPG43; NBIA; C19orf12; hereditary spastic paraplegia
9.  Frequency of the C9ORF72 hexanucleotide repeat expansion in ALS and FTD in diverse populations: a cross-sectional study 
Lancet Neurology  2012;11(4):323-330.
Background
A hexanucleotide repeat expansion in the C9ORF72 gene has recently been shown to cause a large proportion of amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD).
Methods
We screened 4,448 patients diagnosed with ALS and 1,425 patients diagnosed with FTD drawn from diverse populations for the hexanucleotide expansion using a repeat-primed PCR assay. ALS and FTD were diagnosed according to the El Escorial and Lund-Manchester criteria respectively. Familial status was based on self-reported family history of similar neurodegenerative diseases at the time of sample collection. Haplotype data of 262 patients carrying the expansion were compared with the known Finnish founder risk haplotype across the chromosomal locus. Age-related penetrance was calculated by the Kaplan-Meier method using data from 603 individuals carrying the expansion.
Findings
The mutation was observed among 7·0% (n = 236 of 3,377) of Caucasians, 4·1% (n = 2 of 49) of African-Americans, and 8·3% (n = 6 of 72) of Hispanic individuals diagnosed with sporadic ALS, whereas the rate was 6·0% (n = 59 of 981) among Caucasians diagnosed with sporadic FTD. Among Asians, 5·0% (n = 1 of 20) of familial ALS and 66·6% (n = 2 of 3) of familial FTD cases carried the repeat expansion. In contrast, mutations were not observed among patients of Native American (n = 3 sporadic ALS), Indian (n = 31 sporadic ALS, n = 31 sporadic FTD), and Pacific Islander (n = 90 sporadic ALS) ethnicity. All patients with the repeat expansion carried, either partially or fully, the founder haplotype suggesting that the expansion occurred on a single occasion in the past (~1,500 years ago). The pathogenic expansion was non-penetrant below 35 years of age, increasing to 50·0% penetrance by 58 years of age, and was almost fully penetrant by 80 years of age.
Interpretation
We confirm that a common single Mendelian genetic lesion is implicated in a large proportion of sporadic and familial ALS and FTD. Testing for this pathogenic expansion will be important in the management and genetic counseling of patients with these fatal neurodegenerative diseases.
Funding
See Acknowledgements.
doi:10.1016/S1474-4422(12)70043-1
PMCID: PMC3322422  PMID: 22406228
10.  Large proportion of amyotrophic lateral sclerosis cases in Sardinia are due to a single founder mutation of the TARDBP gene 
Archives of neurology  2011;68(5):594-598.
Objective
To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)–related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.
Design
Population-based, prospective cohort study.
Patients
A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.
Intervention
Patients underwent mutational analysis for SOD1, FUS, and TARDBP.
Results
Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94–single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.
Conclusions
The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.
doi:10.1001/archneurol.2010.352
PMCID: PMC3513278  PMID: 21220647
11.  A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD 
Renton, Alan E. | Majounie, Elisa | Waite, Adrian | Simón-Sánchez, Javier | Rollinson, Sara | Gibbs, J. Raphael | Schymick, Jennifer C. | Laaksovirta, Hannu | van Swieten, John C. | Myllykangas, Liisa | Kalimo, Hannu | Paetau, Anders | Abramzon, Yevgeniya | Remes, Anne M. | Kaganovich, Alice | Scholz, Sonja W. | Duckworth, Jamie | Ding, Jinhui | Harmer, Daniel W. | Hernandez, Dena G. | Johnson, Janel O. | Mok, Kin | Ryten, Mina | Trabzuni, Danyah | Guerreiro, Rita J. | Orrell, Richard W. | Neal, James | Murray, Alex | Pearson, Justin | Jansen, Iris E. | Sondervan, David | Seelaar, Harro | Blake, Derek | Young, Kate | Halliwell, Nicola | Callister, Janis | Toulson, Greg | Richardson, Anna | Gerhard, Alex | Snowden, Julie | Mann, David | Neary, David | Nalls, Michael A. | Peuralinna, Terhi | Jansson, Lilja | Isoviita, Veli-Matti | Kaivorinne, Anna-Lotta | Hölttä-Vuori, Maarit | Ikonen, Elina | Sulkava, Raimo | Benatar, Michael | Wuu, Joanne | Chiò, Adriano | Restagno, Gabriella | Borghero, Giuseppe | Sabatelli, Mario | Heckerman, David | Rogaeva, Ekaterina | Zinman, Lorne | Rothstein, Jeffrey | Sendtner, Michael | Drepper, Carsten | Eichler, Evan E. | Alkan, Can | Abdullaev, Zied | Pack, Svetlana D. | Dutra, Amalia | Pak, Evgenia | Hardy, John | Singleton, Andrew | Williams, Nigel M. | Heutink, Peter | Pickering-Brown, Stuart | Morris, Huw R. | Tienari, Pentti J. | Traynor, Bryan J.
Neuron  2011;72(2):257-268.
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one third of familial ALS cases of outbred European descent making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
doi:10.1016/j.neuron.2011.09.010
PMCID: PMC3200438  PMID: 21944779
12.  RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention 
Neuron  2013;80(2):415-428.
SUMMARY
A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.
doi:10.1016/j.neuron.2013.10.015
PMCID: PMC4098943  PMID: 24139042
13.  Homozygosity analysis in amyotrophic lateral sclerosis 
European journal of human genetics : EJHG  2013;21(12):10.1038/ejhg.2013.59.
Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognized dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. 620 ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2Mb were identified, and 3568 rare segments remained after filtering “common” segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, p=0.05). 2017 ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (p=1×10−5), a greater proportion of cases harboured homozygosity (p=2×10−5), a longer average length of segment (p=1×10−5), a longer total genome coverage (p=1×10−5), and a higher rate of these segments overlapped with RefSeq gene regions (p=1×10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9Mb to 4.8Mb, and chromosome 5 in the 65Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS which are not identified as common variants in GWAS.
doi:10.1038/ejhg.2013.59
PMCID: PMC3829775  PMID: 23612577
amyotrophic lateral sclerosis; homozygosity; genetics; recessive
14.  Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study 
Lancet Neurology  2012;11(4):323-330.
Summary
Background
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Methods
We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
Findings
In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
Interpretation
A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
Funding
Full funding sources listed at end of paper (see Acknowledgments).
doi:10.1016/S1474-4422(12)70043-1
PMCID: PMC3322422  PMID: 22406228
15.  FUS mutations in sporadic amyotrophic lateral sclerosis 
Neurobiology of aging  2010;32(3):550.e1-550.e4.
Mutations in the FUS gene have recently been described as a cause of familial ALS, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of all coding exons of FUS in 228 sporadic ALS cases, and, as previous reports suggest that exon 15 represents a mutational hotspot, we sequenced this exon in an additional 1,295 sporadic cases. Six variants in six different cases were found, indicating that FUS mutations can underlie apparently sporadic ALS, but account for less than 1% of this form of disease.
doi:10.1016/j.neurobiolaging.2009.12.020
PMCID: PMC2891336  PMID: 20138404
amyotrophic lateral sclerosis; sporadic disease; FUS; Italy; United States of America
16.  Exome sequencing reveals VCP mutations as a cause of familial ALS 
Neuron  2010;68(5):857-864.
Summary
Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget’s disease and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically-proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ~1–2% of familial ALS, and represent the first evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
doi:10.1016/j.neuron.2010.11.036
PMCID: PMC3032425  PMID: 21145000
17.  The p.A382T TARDBP gene mutation in Sardinian patients affected by Parkinson’s disease and other degenerative parkinsonisms 
Neurogenetics  2013;14(2):161-166.
Background
Based on our previous finding of the p.A382T founder mutation in ALS patients with concomitant parkinsonism in the Sardinian population, we hypothesized that the same variant may underlie PD and/or other forms of degenerative parkinsonism on this Mediterranean island.
Design
We screened a cohort of 611 patients with PD (544 cases) and other forms of degenerative parkinsonism (67 cases), and 604 unrelated controls for the c.1144G>A (p.A382T) missense mutation of the TARDBP gene.
Results
The p.A382T mutation was identified in 9 patients with parkinsonism. Of these, 5 (0.9% of PD patients) presented a typical PD (2 with familiar forms), while 4 patients (6.0% of all other forms of parkinsonism) presented a peculiar clinical presentation quite different from classical atypical parkinsonism with an overlap of extrapyramidal-pyramidal-cognitive clinical signs. The mutation was found in 8 Sardinian controls (1.3%) consistent with a founder mutation in the island population.
Conclusions
Our findings suggest that the clinical presentation of the p.A382T TARDBP gene mutation may include forms of parkinsonism in which the extrapyramidal signs are the crucial core of the disease at onset. These forms can present PSP or CBD-like clinical signs, with bulbar and/or extrabulbar pyramidal signs and cognitive impairment. No evidence of association has been found between TARDBP gene mutation and typical PD.
doi:10.1007/s10048-013-0360-2
PMCID: PMC3661017  PMID: 23546887
TARDBP gene mutation; degenerative parkinsonism; TDP-43 Proteinopathies; Sardinia
18.  Chromosome 9p21 in Amyotrophic Lateral Sclerosis in Finland: A Genome-Wide Association Study 
Lancet neurology  2010;9(10):978-985.
Introduction
The genetic etiology of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well-suited location for a genome-wide association study of ALS, as the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci.
Methods
We performed a genome-wide association study of 442 Finnish patients diagnosed with ALS, and 521 Finnish control subjects using Illumina genome-wide genotyping arrays. DNA was collected from patients attending an ALS specialty clinic that receives referrals from neurologists throughout Finland, whereas the control samples were obtained from a population-based study of elderly Finnish individuals. Individuals known to carry D90A alleles of the SOD1 gene (n = 40) were included in the final analysis as positive controls to determine if our GWAS was able to detect an association signal at this locus.
Findings
We identified two association peaks that exceeded genome-wide significance. One of these was located on chromosome 21q22 (rs13048019, p = 2·58×10−8) that corresponded to the known autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium (rs3849942, p = 9·11×10−11) in a region of chromosome 9p that has been previously identified by linkage studies of ALS families. Within this region, we defined a 42-SNP haplotype that significantly increased risk of developing ALS (p = 4·2×10−33 among familial cases, odds ratio = 21·0, 95% CI = 11·2–39·1), and which overlapped with an association locus recently reported for fronto-temporal dementia (FTD). Based on the 93 familial ALS cases included in the analysis, population attributable risk percent for the chromosome 9p21 locus was 37.9% (95% CI, 27·7 – 48·1%), and for D90A homozygosity was 25·5% (95% CI, 16·9 – 34·1%).
Interpretation
In summary, we present evidence that the chromosome 9p21 ALS-FTD locus is a major cause of familial ALS in the Finnish population.
doi:10.1016/S1474-4422(10)70184-8
PMCID: PMC2965392  PMID: 20801718
19.  Age associated changes in gene expression in human brain and isolated neurons 
Neurobiology of aging  2012;34(4):1199-1209.
Previous studies have suggested that there are genes whose expression levels are associated with chronological age. However, which genes show consistent age association across studies, and which are specific to a given organism or tissue remains unresolved. Here, we re-assessed this question using two independently ascertained series of human brain samples from two anatomical regions, the frontal lobe of the cerebral cortex and cerebellum. Using microarrays to estimate gene expression, we found sixty associations between expression and chronological age that were statistically significant and were replicated in both series in at least one tissue. There were a greater number of significant associations in the frontal cortex compared to the cerebellum. We then repeated the analysis in a subset of samples using laser capture microdissection to isolate purkinje neurons from the cerebellum. We were able to replicate five gene associations from either frontal cortex or cerebellum in the Purkinje cell dataset, suggesting that there is a subset of genes have robust changes withs aging. Of these, the most consistent and strongest association was with expression of RHBDL3, a rhomboid protease family member. We confirmed several hits using an independent technique (qRT-PCR) and in an independent published sample series that used a different array platform. We also interrogated larger patterns of age related gene expression using weighted gene correlation network analysis (WGCNA). We found several modules that showed significant associations with chronological age and, of these, several that showed negative associations were enriched for genes encoding components of mitochondria. Overall, our results show that there is a distinct and reproducible gene signature for aging in the human brain.
doi:10.1016/j.neurobiolaging.2012.10.021
PMCID: PMC3545059  PMID: 23177596
20.  Incidence of Amyotrophic Lateral Sclerosis in Europe 
Background
Geographical differences in amyotrophic lateral sclerosis (ALS) incidence have been reported in the literature, but comparisons across previous studies are limited by different methods in case ascertainment and by the relatively small size of the studied populations. To address these issues, the authors undertook a pooled-analysis of European population-based ALS registries.
Methods
All new incident ALS cases in subjects 18 years old and older were identified prospectively in six population-based registries in three European countries (Ireland, United Kingdom, Italy) in the two year period 1998-1999 with a reference population of almost 24 million.
Results
Based on 1,028 identified incident cases, the crude annual incidence rate of ALS in the general European population was 2.16 per 100,000 person-years; 95% CI 2.0-2.3), with similar incidence rates across all registries. The incidence was higher among men (3.0 per 100,000 person-years; 95% CI = 2.8 to 3.3) than among women (2.4 per 100,000 person-years; 95% CI=2.2 to 2.6). Spinal onset ALS was more common among men compared to women, particularly in the 70-80 year age group. Disease occurrence decreases rapidly after 80 years of age.
Conclusions
ALS incidence is homogeneous across Europe. Sex differences in incidence may be explained by the higher incidence of spinal onset ALS among males and the age-related disease pattern suggests that ALS occurs within a susceptible group within the population rather than being a disease of aging.
doi:10.1136/jnnp.2009.183525
PMCID: PMC2850819  PMID: 19710046
21.  A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease 
Holmans, Peter | Moskvina, Valentina | Jones, Lesley | Sharma, Manu | Vedernikov, Alexey | Buchel, Finja | Sadd, Mohamad | Bras, Jose M. | Bettella, Francesco | Nicolaou, Nayia | Simón-Sánchez, Javier | Mittag, Florian | Gibbs, J. Raphael | Schulte, Claudia | Durr, Alexandra | Guerreiro, Rita | Hernandez, Dena | Brice, Alexis | Stefánsson, Hreinn | Majamaa, Kari | Gasser, Thomas | Heutink, Peter | Wood, Nicholas W. | Martinez, Maria | Singleton, Andrew B. | Nalls, Michael A. | Hardy, John | Morris, Huw R. | Williams, Nigel M. | Arepalli, Sampath | Barker, Roger | Barrett, Jeffrey | Ben-Shlomo, Yoav | Berendse, Henk W. | Berg, Daniela | Bhatia, Kailash | de Bie, Rob M.A. | Biffi, Alessandro | Bloem, Bas | Brice, Alexis | Bochdanovits, Zoltan | Bonin, Michael | Bras, Jose M. | Brockmann, Kathrin | Brooks, Janet | Burn, David J. | Charlesworth, Gavin | Chen, Honglei | Chinnery, Patrick F. | Chong, Sean | Clarke, Carl E. | Cookson, Mark R. | Cooper, Jonathan M. | Corvol, Jen-Christophe | Counsell, Carl | Damier, Philippe | Dartigues, Jean Francois | Deloukas, Panagiotis | Deuschl, Günther | Dexter, David T. | van Dijk, Karin D. | Dillman, Allissa | Durif, Frank | Durr, Alexandra | Edkins, Sarah | Evans, Jonathan R. | Foltynie, Thomas | Gao, Jianjun | Gardner, Michelle | Gasser, Thomas | Gibbs, J. Raphael | Goate, Alison | Gray, Emma | Guerreiro, Rita | Gústafsson, Ómar | Hardy, John | Harris, Clare | Hernandez, Dena G. | Heutink, Peter | van Hilten, Jacobus J. | Hofman, Albert | Hollenbeck, Albert | Holmans, Peter | Holton, Janice | Hu, Michele | Huber, Heiko | Hudson, Gavin | Hunt, Sarah E. | Huttenlocher, Johanna | Illig, Thomas | Langford, Cordelia | Lees, Andrew | Lesage, Suzanne | Lichtner, Peter | Limousin, Patricia | Lopez, Grisel | Lorenz, Delia | Martinez, Maria | McNeill, Alisdair | Moorby, Catriona | Moore, Matthew | Morris, Huw | Morrison, Karen E. | Moskvina, Valentina | Mudanohwo, Ese | Nalls, Michael A. | Pearson, Justin | Perlmutter, Joel S. | Pétursson, Hjörvar | Plagnol, Vincent | Pollak, Pierre | Post, Bart | Potter, Simon | Ravina, Bernard | Revesz, Tamas | Riess, Olaf | Rivadeneira, Fernando | Rizzu, Patrizia | Ryten, Mina | Saad, Mohamad | Sawcer, Stephen | Schapira, Anthony | Scheffer, Hans | Sharma, Manu | Shaw, Karen | Sheerin, Una-Marie | Shoulson, Ira | Schulte, Claudia | Sidransky, Ellen | Simón-Sánchez, Javier | Singleton, Andrew B. | Smith, Colin | Stefánsson, Hreinn | Stefánsson, Kári | Steinberg, Stacy | Stockton, Joanna D. | Sveinbjornsdottir, Sigurlaug | Talbot, Kevin | Tanner, Carlie M. | Tashakkori-Ghanbaria, Avazeh | Tison, François | Trabzuni, Daniah | Traynor, Bryan J. | Uitterlinden, André G. | Velseboer, Daan | Vidailhet, Marie | Walker, Robert | van de Warrenburg, Bart | Wickremaratchi, Mirdhu | Williams, Nigel | Williams-Gray, Caroline H. | Winder-Rhodes, Sophie | Wood, Nicholas
Human Molecular Genetics  2012;22(5):1039-1049.
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10−16) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the ‘regulation of leucocyte/lymphocyte activity’ and also ‘cytokine-mediated signalling’ as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
doi:10.1093/hmg/dds492
PMCID: PMC3561909  PMID: 23223016
22.  Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis 
Neurobiology of aging  2010;33(2):418-420.
Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca2+-permeable AMPA-type of glutamate receptors and Ca2+ permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no non-synonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3,157 cases and 5,397 controls from 6 additional populations no association with susceptibility, age at onset or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.
doi:10.1016/j.neurobiolaging.2010.03.007
PMCID: PMC2949683  PMID: 20409611
Amyotrophic lateral sclerosis; excitotoxicity; GluR2; motor neuron
23.  The Era of Genomic Epidemiology 
Neuroepidemiology  2009;33(3):276-279.
The recent revolution in genomics is already having a profound impact on the practice of epidemiology. The purpose of this commentary is to demonstrate how genomics and epidemiology will continue to rely heavily on each other, now and in the future, by illustrating a number of interaction points between these 2 disciplines: (1) the use of genomics to estimate disease heritability; (2) the impact of genomics on analytical study design; (3) how genome-wide data can be employed to effectively overcome residual population stratification arising from selection bias; (4) the importance of genomics as a tool in epidemiological investigation; (5) the importance of epidemiology in the collection of adequately phenotyped samples for genomics studies, and (6) for unraveling the clinical and therapeutic relevance of genetic variants once they are discovered.
doi:10.1159/000235639
PMCID: PMC2826447  PMID: 19696518
Genetics; Genomics; Epidemiology
24.  UNC13A influences survival in Italian ALS patients: a population-based study 
Neurobiology of aging  2012;34(1):357.e1-357.e5.
The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to ALS, as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1,457 Italian control samples. Although rs12608932 was not associated to ALS susceptibility in our series (p=0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [IQR 2.2–6.4]; CC = 2.5 years [IQR 1.6–4.2]; p=0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p=0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an ~1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression.
doi:10.1016/j.neurobiolaging.2012.07.016
PMCID: PMC3483408  PMID: 22921269
25.  Frontotemporal dementia with a C9ORF72 expansion in a Swedish family: clinical and neuropathological characteristics 
Background: In 2011 the C9ORF72 repeat expansion was identified as the most frequent genetic mutation underlying FTD and ALS. The main aim of this study was to investigate clinical characteristics in a large C9ORF72-positive FTD family, and to compare these with the neuropathological findings. Methods: The clinical records of 12 related FTD patients were thoroughly evaluated. The five neuropathologically examined cases were revised using additional TDP-43 immuno-stainings. Four cases were screened for the C9ORF72 expansion. Results: All 12 patients fulfilled the criteria for bvFTD. Restlessness and social neglect were often among the first reported symptoms. Psychotic symptoms were reported in 8 patients. Somatic complaints were seen in 7 cases. All the neuropathologically examined cases were TDP-43 positive. Conclusions: The phenotype of this C9ORF72 hexanucleotide expansion carrier family was bvFTD. The clinical symptom profile was strikingly homogenous. Psychotic symptoms and somatic complaints were observed in most of the cases.
PMCID: PMC3852567  PMID: 24319645
Genetics; FTD; longitudinal study; psychotic symptoms; TDP-43

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