A genome-wide association study of sporadic ALS in a homogenous Irish population

Cronin, Simon; Berger, Stephen; Ding, Jinhui; Schymick, Jennifer C.; Washecka, Nicole; Hernandez, Dena G.; Greenway, Matthew; Bradley, Daniel G.; Traynor, Bryan J.; Hardiman, Orla

doi:10.1093/hmg/ddm361

Cited by 180 publications

(132 citation statements)

References 36 publications

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“…At the level of D¢ and r 2 , the populations seemed indistinguishable, consistent with our own and other authors' previous results. 10,32 However, it is interesting to note that using the LDU parameter, we observed increased levels of LD and reduced numbers of 'LD holes' in Irish and Swedish populations (see Figure 3, Table 2). However, it should be stressed that the increase in LD is marginal.…”

Section: Discussionmentioning

confidence: 73%

Population structure and genome-wide patterns of variation in Ireland and Britain

et al. 2010

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Located off the northwestern coast of the European mainland, Britain and Ireland were among the last regions of Europe to be colonized by modern humans after the last glacial maximum. Further, the geographical location of Britain, and in particular of Ireland, is such that the impact of historical migration has been minimal. Genetic diversity studies applying the Y chromosome and mitochondrial systems have indicated reduced diversity and an increased population structure across Britain and Ireland relative to the European mainland. Such characteristics would have implications for genetic mapping studies of complex disease. We set out to further our understanding of the genetic architecture of the region from the perspective of (i) population structure, (ii) linkage disequilibrium (LD), (iii) homozygosity and (iv) haplotype diversity (HD). Analysis was conducted on 3654 individuals from Ireland, Britain (with regional sampling in Scotland), Bulgaria, Portugal, Sweden and the Utah HapMap collection. Our results indicate a subtle but clear genetic structure across Britain and Ireland, although levels of structure were reduced in comparison with average cross-European structure. We observed slightly elevated levels of LD and homozygosity in the Irish population compared with neighbouring European populations. We also report on a cline of HD across Europe with greatest levels in southern populations and lowest levels in Ireland and Scotland. These results are consistent with our understanding of the population history of Europe and promote Ireland and Scotland as relatively homogenous resources for genetic mapping of rare variants.

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Section: Discussionmentioning

confidence: 73%

Population structure and genome-wide patterns of variation in Ireland and Britain

et al. 2010

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“…Few genetic factors that modify ALS survival are reported (19,20,47); none were identified in the previous ALS genome analyses (21)(22)(23)(24)46). The identification of KIFAP3 as a determinant of progression rate of sporadic ALS is therefore promising; insights into this pathway may provide new targets for therapies to slow this devastating disease, for example, by reducing levels of KIFAP3 expression or modifying its interactions with 1 or more protein binding partners.…”

Section: Discussionmentioning

confidence: 99%

“…The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies.…”

mentioning

confidence: 99%

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Landers

Melki

Meininger

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

168

110

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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 genomewide significant result (P ‫؍‬ 1.84 ؋ 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.genome-wide association study ͉ single nucleotide polymorphism A myotrophic lateral sclerosis (ALS) is an age-dependent, degenerative disorder of motor neurons (1) that typically develops in the 6th decade and is uniformly fatal, usually within 5 years (2). Approximately 10% of ALS cases are dominantly inherited (3); 20% of these are caused by mutations in the gene encoding copper/zinc superoxide dismutase 1 (SOD1) (4); mutations in the TARDBP gene (5, 6) account for Ϸ5% of cases. Rare familial cases arise from mutations in genes encoding the vesicle-associated membrane associated protein B (7), alsin (a RAB5-guanine nucleotide exchange factor) (8, 9), senataxin (10) or dynactin (11). Recently, we reported that Ϸ5% of familial ALS cases are due to mutations in the FUS/TLS gene (12, 13) whose product binds DNA and RNA, as does TARDBP. The cause of sporadic ALS is thought to be multifactorial, with environmental, infectious and genetic etiologies. Reported associations with variants in diverse genes (14-25) have proven difficult to replicate. Advances in the technology for large-scale genotyping of single nucleotide polymorphisms (SNPs) have facilitated unbiased, genome-wide association studies. Examples include the identification of IL2RA and IL7RA variants as risk factors for multiple sclerosis (26-28) and the recent reports of 6 new gene regions associated with type 2 diabetes (29)(30)(31)(32)(33)(34)(35). To test the hypothesis that commonly occurring genetic

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“…This somewhat controversial study is subject to extensive follow-up before solid conclusions can be drawn. There is, however, a growing consensus that the primary genetic association for ALS is in fact to variation in DPP6 (dipeptidyl-peptidase 6), as a consequence of 2 further published GWA studies of the disease (64,65 ).…”

Section: Neurologymentioning

confidence: 99%

Microarray Technology and Applications in the Arena of Genome-Wide Association

Grant

Hákonarson

2008

Clinical Chemistry

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BACKGROUND:There is a revolution occurring in single nucleotide polymorphism (SNP) genotyping technology, with high-throughput methods now allowing large numbers of ) to be genotyped in large cohort studies. This has enabled large-scale genome-wide association (GWA) studies in complex diseases, such as diabetes, asthma, and inflammatory bowel disease, to be undertaken for the first time.CONTENT: The GWA approach serves the critical need for a comprehensive and unbiased strategy to identify causal genes related to complex disease, and is rapidly replacing the more traditional candidate gene studies and microsatellite-based linkage mapping approaches that have dominated gene discovery attempts for common diseases. As a consequence of employing array-based technologies, over the last 3 years dramatic discoveries of key variants involved in multiple complex diseases and related traits have been reported in the top scientific literature and, most importantly, have been largely replicated by independent investigator groups. As a consequence, several novel genes have been identified, most notably in the metabolic, cardiovascular, autoimmune, and oncology disease areas, that are clearly rooted in the biology of these disorders. These discoveries have opened up new avenues for investigators to address novel molecular pathways that were not previously linked to or thought of in relation with these diseases.

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A genome-wide association study of sporadic ALS in a homogenous Irish population

Cited by 180 publications

References 36 publications

Population structure and genome-wide patterns of variation in Ireland and Britain

Population structure and genome-wide patterns of variation in Ireland and Britain

Reduced expression of the Kinesin-Associated Protein 3 ( KIFAP3 ) gene increases survival in sporadic amyotrophic lateral sclerosis

Microarray Technology and Applications in the Arena of Genome-Wide Association

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