Landers, J.E. et al. Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 106, 9004-9009

Cecil B. Day Neuromuscular Research Laboratory, Massachusetts General Hospital-East, Building 114, Navy Yard, Charlestown, MA 02129, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2009; 106(22):9004-9. DOI: 10.1073/pnas.0812937106
Source: PubMed


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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Available from: Ammar Al-Chalabi
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    • "Table 1. Moderate Effect Loci Previously Identified By a GWAS as Contributing Risk to ALS Development Primary Variant Chr Position a Gene(s) Source(s) rs80356717 1 11078893 TARDBP Chiò et al, 9 2009 rs16856202 1 232155151 DISC1 Landers et al, 10 2009 rs179943 6 16398318 ATXN1 Bettens et al, 11 2010 rs2708909 7 48051679 SUN3, HUS1 b Chiò et al, 9 2009 rs10260404 7 154210798 DPP6 b Cronin et al, 12 2008; van Es et al, 13 2007 rs2708851 7 48085802 C7orf57 Chiò et al, 9 2009 rs3849942 9 27543281 C9orf72 b Laaksovirta et al, 14 2010 rs2225389 9 27409264 MOB3B Laaksovirta et al, 14 2010 rs2306677 12 26636386 ITPR2 van Es et al, 13 2007 rs13048019 21 32918294 TIAM1 Laaksovirta et al, 14 2010 "
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    ABSTRACT: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.
    Full-text · Article · Jul 2014 · JAMA Neurology
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    • "Common and rare genetic variants like SNPs and CNVs may contribute to complex disease development. Candidate SNPs in several genes, including DPP6, ITPR2, KIFAP3 and UNC13A, were previously shown to be associated with ALS using the GWAS platform although the contribution of these SNPs to disease pathogenesis remained questionable in different studies [18], [19], [20], [21]. The more recently discovered CNVs, on the other hand, are also abundant and dynamic throughout the genome and they can cause genetic variations even between two closely related individuals. "
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    ABSTRACT: The genome-wide presence of copy number variations (CNVs), which was shown to affect the expression and function of genes, has been recently suggested to confer risk for various human disorders, including Amyotrophic Lateral Sclerosis (ALS). We have performed a genome-wide CNV analysis using PennCNV tool and 733K GWAS data of 117 Turkish ALS patients and 109 matched healthy controls. Case-control association analyses have implicated the presence of both common (>5%) and rare (<5%) CNVs in the Turkish population. In the framework of this study, we identified several common and rare loci that may have an impact on ALS pathogenesis. None of the CNVs associated has been implicated in ALS before, but some have been reported in different types of cancers and autism. The most significant associations were shown for 41 kb and 15 kb intergenic heterozygous deletions (Chr11: 50,545,009-50,586,426 and Chr19: 20,860,930-20,875,787) both contributing to increased risk for ALS. CNVs in coding regions of the MAP4K3, HLA-B, EPHA3 and DPYD genes were detected however, after validation by Log R Ratio (LRR) values and TaqMan CNV genotyping, only EPHA3 deletion remained as a potential protective factor for ALS (p = 0.0065024). Based on the knowledge that EPHA4 has been previously shown to rescue SOD1 transgenic mice from ALS phenotype and prolongs survival, EPHA3 may be a promising candidate for therepuetic interventions.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Methods for identifying SNPs that overlap regulatory elements, such as transcription factor binding sites, are therefore necessary. Approaches based on known transcription factor binding motifs (Xu and Taylor 2009; Macintyre et al. 2010) have been successfully used to refine GWAS results and identify specific loci that have a functional role (Jarinova et al. 2009; Landers et al. 2009). However, the presence of a motif does not imply that a transcription factor is necessarily binding in vivo. "
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    ABSTRACT: Genome-wide association studies have been successful in identifying single nucleotide polymorphisms (SNPs) associated with a large number of phenotypes. However, an associated SNP is likely part of a larger region of linkage disequilibrium. This makes it difficult to precisely identify the SNPs that have a biological link with the phenotype. We have systematically investigated the association of multiple types of ENCODE data with disease-associated SNPs and show that there is significant enrichment for functional SNPs among the currently identified associations. This enrichment is strongest when integrating multiple sources of functional information and when highest confidence disease-associated SNPs are used. We propose an approach that integrates multiple types of functional data generated by the ENCODE Consortium to help identify "functional SNPs" that may be associated with the disease phenotype. Our approach generates putative functional annotations for up to 80% of all previously reported associations. We show that for most associations, the functional SNP most strongly supported by experimental evidence is a SNP in linkage disequilibrium with the reported association rather than the reported SNP itself. Our results show that the experimental data sets generated by the ENCODE Consortium can be successfully used to suggest functional hypotheses for variants associated with diseases and other phenotypes.
    Full-text · Article · Sep 2012 · Genome Research
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