A large genome scan for rare CNVs in amyotrophic lateral sclerosis

Autor: Eric Strengman, Ruben van 't Slot, Peter C. Sapp, Thomas F. Meyer, Anna Birve, Peter M. Andersen, Martin D. Tobin, Max Koppers, Ewout J N Groen, Albert C. Ludolph, Simon Cronin, Sita H. Vermeulen, Claudia Schulte, Jan H. Veldink, André G. Uitterlinden, Robin Lemmens, Paul W.J. van Vught, Thomas Gasser, Lambertus A. Kiemeney, Christiaan G J Saris, Hylke M. Blauw, Leonard H. van den Berg, Frank P. Diekstra, Fernando Rivadeneira, Karol Estrada, Robert H. Brown, Agnieszka Slowik, Barbara Tomik, Louise V. Wain, Russell L. McLaughlin, Dan Rujescu, Michael A. van Es, Albert Hofman, Wim Robberecht, Ammar Al-Chalabi, Wouter van Rheenen, John Landers, Orla Hardiman, Roel A. Ophoff, Stefan Waibel
Přispěvatelé: Internal Medicine, Epidemiology
Rok vydání: 2010
Předmět:
Potassium Channels
Genome-wide association study
Aetiology
screening and detection [ONCOL 5]
Polymerase Chain Reaction
genetics [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases]
0302 clinical medicine
Risk Factors
Copy-number variation
Amyotrophic lateral sclerosis
genetics [Nerve Tissue Proteins]
NIPA1 protein
human
Genetics (clinical)
Motor Neurons
Genetics
0303 health sciences
education.field_of_study
genetics [Potassium Channels]
DPP6 protein
human
General Medicine
3. Good health
genetics [Amyotrophic Lateral Sclerosis]
genetics [Membrane Proteins]
DNA Copy Number Variations
Population
Nerve Tissue Proteins
Single-nucleotide polymorphism
Locus (genetics)
Biology
Polymorphism
Single Nucleotide
Molecular epidemiology [NCEBP 1]
03 medical and health sciences
ddc:570
genetics [Spastic Paraplegia
Hereditary]
medicine
Humans
Genetic Predisposition to Disease
Allele
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
education
Molecular Biology
030304 developmental biology
Genetic association
Genome
Human
Spastic Paraplegia
Hereditary
Amyotrophic Lateral Sclerosis
Genetic Variation
Membrane Proteins
medicine.disease
Evaluation of complex medical interventions [NCEBP 2]
Case-Control Studies
030217 neurology & neurosurgery
Genome-Wide Association Study
Zdroj: Human Molecular Genetics, 19(20), 4091-4099. Oxford University Press
Human Molecular Genetics, 19, 4091-9
Human Molecular Genetics, 19, 20, pp. 4091-9
Human molecular genetics 19(20), 4091-4099 (2010). doi:10.1093/hmg/ddq323
ISSN: 0964-6906
DOI: 10.1093/hmg/ddq323
Popis: Contains fulltext : 89076.pdf (Publisher’s version ) (Closed access) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 x 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 x 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 x 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 x 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
Databáze: OpenAIRE
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