期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 22, 页码 9004-9009出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812937106
关键词
genome-wide association study; single nucleotide polymorphism
资金
- The Netherlands Organisation for Scientific Research
- Adessium Foundation
- Howard Hughes Medical Institute
- Packard Center for ALS Research
- Muscular Dystrophy Association
- National Center for Research Resources [U54 RR020278-01]
- Howard Hughes Medical Institute Investigator
- ALS Family Charitable Foundation
- Al-Athel ALS Research Foundation
- Pierre L. de Bourgknecht ALS Research Foundation
- Angel Fund
- ALS Therapy Alliance
- National Institute of Neurological Disorders and Stroke
- American Academy of Neurology Foundation/ALS Association
- Harvard Business School Class of 2007
- Medical Research Council
- Wellcome Trust
- Psychiatry Research Trust
- MRC [G0500289, G0600974, MC_G1000733, G0900688] Funding Source: UKRI
- Medical Research Council [G0900688, MC_G1000733, G0500289B, G0600974, G0500289] Funding Source: researchfish
Amyotrophic lateral sclerosis is a degenerative disorder of motor neurons that typically develops in the 6th decade and is uniformly fatal, usually within 5 years. To identify genetic variants associated with susceptibility and phenotypes in sporadic ALS, we performed a genome-wide SNP analysis in sporadic ALS cases and controls. A total of 288,357 SNPs were screened in a set of 1,821 sporadic ALS cases and 2,258 controls from the U. S. and Europe. Survival analysis was performed using 1,014 deceased sporadic cases. Top results for susceptibility were further screened in an independent sample set of 538 ALS cases and 556 controls. SNP rs1541160 within the KIFAP3 gene (encoding a kinesin-associated protein) yielded a genome-wide significant result ( P = 1.84 x 10(-8)) that withstood Bonferroni correction for association with survival. Homozygosity for the favorable allele (CC) conferred a 14.0 months survival advantage. Sequence, genotypic and functional analyses revealed that there is linkage disequilibrium between rs1541160 and SNP rs522444 within the KIFAP3 promoter and that the favorable alleles of rs1541160 and rs522444 correlate with reduced KIFAP3 expression. No SNPs were associated with risk of sporadic ALS, site of onset, or age of onset. We have identified a variant within the KIFAP3 gene that is associated with decreased KIFAP3 expression and increased survival in sporadic ALS. These findings support the view that genetic factors modify phenotypes in this disease and that cellular motor proteins are determinants of motor neuron viability.
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