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Research Letters |

Analysis of the UNC13A Gene as a Risk Factor for Sporadic Amyotrophic Lateral Sclerosis FREE

Hussein Daoud, PhD; Véronique Belzil, MSc; Anne Desjarlais, BSc; William Camu, MD; Patrick A. Dion, PhD; Guy A. Rouleau, MD, PhD
[+] Author Affiliations

Author Affiliations: Centre of Excellence in Neuromics, CHUM Research Center and the Department of Medicine, Université de Montréal, Montréal, Canada (Drs Daoud, Dion, and Rouleau and Mss Belzil and Desjarlais); and the ALS Center, Department of Neurology, CHU Gui de Chauliac, Montpellier, France (Dr Camu).


Arch Neurol. 2010;67(4):516-517. doi:10.1001/archneurol.2010.46.
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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons from the spinal cord, brainstem, and cerebral cortex that typically results in death 2 to 5 years following onset. Approximately 10% of patients with ALS have a family history, of which 15% to 20% are linked to mutations in the SOD1 gene; these patients most frequently inherit the disease in an autosomal dominant manner. Mutations in other genes including ALS2, ANG, DCTN1, SETX, VAPB, TARDBP, and FUS have also been reported in familial cases.1 The remaining 90% of cases have no obvious family history and are referred to as sporadic ALS (SALS). The etiology of these sporadic cases is considered multifactorial, with environmental and genetic factors contributing to disease susceptibility. Although candidate gene studies have identified potential risk factors for SALS, replication of these associations in different populations have often failed. Similarly, several genome-wide association studies for SALS have identified novel candidate susceptibility genes including ITPR2,2FGGY,3 and DPP64; however, these associations have not been consistently replicated.1 Recently, a large-scale genome-wide association study that included 19 838 subjects showed that the variant rs12608932 located in the unc-13 homologue A gene (UNC13A) is strongly associated with SALS.5 The aim of this study is to investigate the variant as a possible risk factor for developing ALS in a French population.

A total of 285 patients with ALS and 285 controls were included in this study. All individuals were recruited through clinics in France and ascertained by experienced neurologists. Informed written consent was obtained from each participant and samples were collected with the approval of the relevant institutional ethic boards. All patients fulfilled the El Escorial criteria for probable or definite ALS, and familial cases were excluded. Controls were matched for age and ethnicity. The DNA was extracted from peripheral blood samples using standard methods. The rs12608932 variant was genotyped by TaqMan SNP Genotyping Assay using the Applied Biosystems 7900HT Fast Real-Time PCR machine and the Sequence Detection System (vs2.2.2; Foster City, California) for allele calling. The case-control association analysis was performed using Haploview 4.1 (Broad Institute of MIT and Harvard, Cambridge, Massachusetts).6

The clinical data of the study population are provided in the Table. A total of 570 samples (285 cases and 285 controls) were genotyped for rs12608932, which is located in intron 21 of the UNC13A gene on chromosome 19p13.11. The genotyping success rate was 96.6%. Hardy-Weinberg equilibrium testing was performed and revealed no significant deviation from equilibrium (P = .93). A χ2 test on basic allele counts showed no significant association between sporadic ALS and the rs12608932 variant (P = .85).

Table Graphic Jump LocationTable. Characteristics of the Studied Populations and the Results From Association Analyses for rs12608932

A recent 2-stage genome-wide association study demonstrated that the rs12608932 variant is a risk factor for sporadic ALS.5 The rs12608932 variant is located within an intronic region of the UNC13A gene that encodes a member of the UNC13 family. The UNC13 proteins are presynaptic proteins found in central and neuromuscular synapses that regulate the release of neurotransmitters, peptides, and hormones. We evaluated this variant as a possible genetic risk factor for SALS in a French population. This revealed no significant association between SALS and the rs12608932 variant. Although the sample size of the present study is not large enough to exclude rs12608932 as a risk factor for SALS, our data does not provide evidence of an association between this variant in the UNC13A gene and susceptibility to sporadic ALS in a French homogeneous population.

ARTICLE INFORMATION

Correspondence: Dr Rouleau, Centre for Excellence in Neuromics, Notre Dame Hospital CHUM Research Center and the Department of Medicine, Université de Montréal, J. A. de Seve Pavillion 1560 Sherbrooke St E, Room Y-3633, Montreal, QC H2L 4MI, Canada (guy.rouleau@umontreal.ca).

Author Contributions:Study concept and design: Daoud, Dion, and Rouleau. Acquisition of data: Daoud, Belzil, Desjarlais, and Camu. Analysis and interpretation of data: Daoud. Drafting the manuscript: Daoud and Desjarlais. Critical revision of the manuscript for important intellectual content: Belzil, Camu, Dion, and Rouleau. Obtained funding: Rouleau. Administrative, technical, and material support: Daoud, Belzil, Desjarlais, Camu, Dion, and Rouleau. Study supervision: Rouleau.

Financial Disclosure: None reported.

Funding/Support: This study is supported by the Muscular Dystrophy Association USA, ALS Association, and the Canadian Institute of Health Research (Dr Rouleau).

Dion  PADaoud  HRouleau  GA Genetics of motor neuron disorders: new insights into pathogenic mechanisms. Nat Rev Genet 2009;10 (11) 769- 782
PubMed Link to Article
van Es  MAVan Vught  PWBlauw  HM  et al.  ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol 2007;6 (10) 869- 877
PubMed Link to Article
Dunckley  THuentelman  MJCraig  DW  et al.  Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007;357 (8) 775- 788
PubMed Link to Article
van Es  MAvan Vught  PWBlauw  HM  et al.  Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet 2008;40 (1) 29- 31
PubMed Link to Article
van Es  MAVeldink  JHSaris  CG  et al.  Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 2009;41 (10) 1083- 1087
PubMed Link to Article
Barrett  JCFry  BMaller  JDaly  MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21 (2) 263- 265
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable. Characteristics of the Studied Populations and the Results From Association Analyses for rs12608932

References

Dion  PADaoud  HRouleau  GA Genetics of motor neuron disorders: new insights into pathogenic mechanisms. Nat Rev Genet 2009;10 (11) 769- 782
PubMed Link to Article
van Es  MAVan Vught  PWBlauw  HM  et al.  ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study. Lancet Neurol 2007;6 (10) 869- 877
PubMed Link to Article
Dunckley  THuentelman  MJCraig  DW  et al.  Whole-genome analysis of sporadic amyotrophic lateral sclerosis. N Engl J Med 2007;357 (8) 775- 788
PubMed Link to Article
van Es  MAvan Vught  PWBlauw  HM  et al.  Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis. Nat Genet 2008;40 (1) 29- 31
PubMed Link to Article
van Es  MAVeldink  JHSaris  CG  et al.  Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 2009;41 (10) 1083- 1087
PubMed Link to Article
Barrett  JCFry  BMaller  JDaly  MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21 (2) 263- 265
PubMed Link to Article

Correspondence

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