Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease
Identifieur interne : 000907 ( Main/Exploration ); précédent : 000906; suivant : 000908Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease
Auteurs : Balaji S. Srinivasan [États-Unis] ; Jaleh Doostzadeh [États-Unis] ; Farnaz Absalan [États-Unis] ; Sharareh Mohandessi [États-Unis] ; Roxana Jalili [États-Unis] ; Saharnaz Bigdeli [États-Unis] ; Justin Wang [États-Unis] ; Jaydev Mahadevan [États-Unis] ; Caroline L. G. Lee [Singapour] ; Ronald W. Davis [États-Unis] ; J. William Langston [États-Unis] ; Mostafa Ronaghi [États-Unis]Source :
- Human Mutation [ 1059-7794 ] ; 2009-02.
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Abstract
It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Toward this end, we have developed a general method for finding pathways associated with traits that control for pathway size. We have applied this method to a new whole genome survey of coding SNP variation in 187 patients afflicted with Parkinson disease (PD) and 187 controls. We show that our dataset provides an independent replication of the axon guidance association recently reported by Lesnick et al. [PLoS Genet 2007;3:e98], and also indicates that variation in the ubiquitin‐mediated proteolysis and T‐cell receptor signaling pathways may predict PD susceptibility. Given this result, it is reasonable to hypothesize that pathway associations are more replicable than individual SNP associations in whole genome association studies. However, this hypothesis is complicated by a detailed comparison of our dataset to the second recent PD association study by Fung et al. [Lancet Neurol 2006;5:911–916]. Surprisingly, we find that the axon guidance pathway does not rank at the very top of the Fung dataset after controlling for pathway size. More generally, in comparing the studies, we find that SNP frequencies replicate well despite technologically different assays, but that both SNP and pathway associations are globally uncorrelated across studies. We thus have a situation in which an association between axon guidance pathway variation and PD has been found in 2 out of 3 studies. We conclude by relating this seeming inconsistency to the molecular heterogeneity of PD, and suggest future analyses that may resolve such discrepancies. Hum Mutat 0,1–11, 2008. © 2008 Wiley‐Liss, Inc.
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DOI: 10.1002/humu.20840
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G." last="Lee">Caroline L. G. Lee</name><affiliation wicri:level="4"><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Biochemistry, Yong Loo School of Medicine, National University of Singapore</wicri:regionArea><orgName type="university">Université nationale de Singapour</orgName></affiliation></author><author><name sortKey="Davis, Ronald W" sort="Davis, Ronald W" uniqKey="Davis R" first="Ronald W." last="Davis">Ronald W. Davis</name><affiliation wicri:level="2"><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Stanford Genome Technology Center, Stanford University, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="William Langston, J" sort="William Langston, J" uniqKey="William Langston J" first="J." last="William Langston">J. William Langston</name><affiliation wicri:level="2"><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>The Parkinson's Institute, Sunnyvale</wicri:cityArea></affiliation></author><author><name sortKey="Ronaghi, Mostafa" sort="Ronaghi, Mostafa" uniqKey="Ronaghi M" first="Mostafa" last="Ronaghi">Mostafa Ronaghi</name><affiliation wicri:level="2"><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Stanford Genome Technology Center, Stanford University, Palo Alto</wicri:cityArea></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Mutation</title><title level="j" type="abbrev">Hum. Mutat.</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-02">2009-02</date><biblScope unit="volume">30</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="228">228</biblScope><biblScope unit="page" to="238">238</biblScope></imprint><idno type="ISSN">1059-7794</idno></series><idno type="istex">37694CDEB7889ACE9501DB9B732012E71783B9FD</idno><idno type="DOI">10.1002/humu.20840</idno><idno type="ArticleID">HUMU20840</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>PD</term><term>Parkinson</term><term>Parkinson's disease</term><term>axon guidance</term><term>candidate pathways</term><term>pathway association</term><term>whole genome association</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="fr">It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Toward this end, we have developed a general method for finding pathways associated with traits that control for pathway size. We have applied this method to a new whole genome survey of coding SNP variation in 187 patients afflicted with Parkinson disease (PD) and 187 controls. We show that our dataset provides an independent replication of the axon guidance association recently reported by Lesnick et al. [PLoS Genet 2007;3:e98], and also indicates that variation in the ubiquitin‐mediated proteolysis and T‐cell receptor signaling pathways may predict PD susceptibility. Given this result, it is reasonable to hypothesize that pathway associations are more replicable than individual SNP associations in whole genome association studies. However, this hypothesis is complicated by a detailed comparison of our dataset to the second recent PD association study by Fung et al. [Lancet Neurol 2006;5:911–916]. Surprisingly, we find that the axon guidance pathway does not rank at the very top of the Fung dataset after controlling for pathway size. More generally, in comparing the studies, we find that SNP frequencies replicate well despite technologically different assays, but that both SNP and pathway associations are globally uncorrelated across studies. We thus have a situation in which an association between axon guidance pathway variation and PD has been found in 2 out of 3 studies. We conclude by relating this seeming inconsistency to the molecular heterogeneity of PD, and suggest future analyses that may resolve such discrepancies. Hum Mutat 0,1–11, 2008. © 2008 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Singapour</li><li>États-Unis</li></country><region><li>Californie</li><li>État de New York</li></region><orgName><li>Université nationale de Singapour</li></orgName></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Srinivasan, Balaji S" sort="Srinivasan, Balaji S" uniqKey="Srinivasan B" first="Balaji S." last="Srinivasan">Balaji S. Srinivasan</name></region><name sortKey="Absalan, Farnaz" sort="Absalan, Farnaz" uniqKey="Absalan F" first="Farnaz" last="Absalan">Farnaz Absalan</name><name sortKey="Bigdeli, Saharnaz" sort="Bigdeli, Saharnaz" uniqKey="Bigdeli S" first="Saharnaz" last="Bigdeli">Saharnaz Bigdeli</name><name sortKey="Davis, Ronald W" sort="Davis, Ronald W" uniqKey="Davis R" first="Ronald W." last="Davis">Ronald W. Davis</name><name sortKey="Doostzadeh, Jaleh" sort="Doostzadeh, Jaleh" uniqKey="Doostzadeh J" first="Jaleh" last="Doostzadeh">Jaleh Doostzadeh</name><name sortKey="Jalili, Roxana" sort="Jalili, Roxana" uniqKey="Jalili R" first="Roxana" last="Jalili">Roxana Jalili</name><name sortKey="Mahadevan, Jaydev" sort="Mahadevan, Jaydev" uniqKey="Mahadevan J" first="Jaydev" last="Mahadevan">Jaydev Mahadevan</name><name sortKey="Mohandessi, Sharareh" sort="Mohandessi, Sharareh" uniqKey="Mohandessi S" first="Sharareh" last="Mohandessi">Sharareh Mohandessi</name><name sortKey="Ronaghi, Mostafa" sort="Ronaghi, Mostafa" uniqKey="Ronaghi M" first="Mostafa" last="Ronaghi">Mostafa Ronaghi</name><name sortKey="Srinivasan, Balaji S" sort="Srinivasan, Balaji S" uniqKey="Srinivasan B" first="Balaji S." last="Srinivasan">Balaji S. Srinivasan</name><name sortKey="Wang, Justin" sort="Wang, Justin" uniqKey="Wang J" first="Justin" last="Wang">Justin Wang</name><name sortKey="William Langston, J" sort="William Langston, J" uniqKey="William Langston J" first="J." last="William Langston">J. William Langston</name></country><country name="Singapour"><noRegion><name sortKey="Lee, Caroline L G" sort="Lee, Caroline L G" uniqKey="Lee C" first="Caroline L. G." last="Lee">Caroline L. G. Lee</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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