Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease
Identifieur interne : 000967 ( Main/Corpus ); précédent : 000966; suivant : 000968Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease
Auteurs : Balaji S. Srinivasan ; Jaleh Doostzadeh ; Farnaz Absalan ; Sharareh Mohandessi ; Roxana Jalili ; Saharnaz Bigdeli ; Justin Wang ; Jaydev Mahadevan ; Caroline L. G. Lee ; Ronald W. Davis ; J. William Langston ; Mostafa RonaghiSource :
- Human Mutation [ 1059-7794 ] ; 2009-02.
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- KwdEn :
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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Srinivasan</name><affiliation><mods:affiliation>Department of Statistics, Stanford University, Stanford, California</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Computer Science, Stanford University, Stanford, California</mods:affiliation></affiliation></author><author><name sortKey="Doostzadeh, Jaleh" sort="Doostzadeh, Jaleh" uniqKey="Doostzadeh J" first="Jaleh" last="Doostzadeh">Jaleh Doostzadeh</name><affiliation><mods:affiliation>The Parkinson's Institute, Sunnyvale, California</mods:affiliation></affiliation></author><author><name sortKey="Absalan, Farnaz" sort="Absalan, Farnaz" uniqKey="Absalan F" first="Farnaz" last="Absalan">Farnaz Absalan</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Mohandessi, Sharareh" sort="Mohandessi, Sharareh" uniqKey="Mohandessi S" first="Sharareh" last="Mohandessi">Sharareh Mohandessi</name><affiliation><mods:affiliation>The Parkinson's Institute, Sunnyvale, California</mods:affiliation></affiliation></author><author><name sortKey="Jalili, Roxana" sort="Jalili, Roxana" uniqKey="Jalili R" first="Roxana" last="Jalili">Roxana Jalili</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Bigdeli, Saharnaz" sort="Bigdeli, Saharnaz" uniqKey="Bigdeli S" first="Saharnaz" last="Bigdeli">Saharnaz Bigdeli</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Wang, Justin" sort="Wang, Justin" uniqKey="Wang J" first="Justin" last="Wang">Justin Wang</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Mahadevan, Jaydev" sort="Mahadevan, Jaydev" uniqKey="Mahadevan J" first="Jaydev" last="Mahadevan">Jaydev Mahadevan</name><affiliation><mods:affiliation>Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York</mods:affiliation></affiliation></author><author><name sortKey="Lee, Caroline L G" sort="Lee, Caroline L G" uniqKey="Lee C" first="Caroline L. 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Srinivasan</name><affiliation><mods:affiliation>Department of Statistics, Stanford University, Stanford, California</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Computer Science, Stanford University, Stanford, California</mods:affiliation></affiliation></author><author><name sortKey="Doostzadeh, Jaleh" sort="Doostzadeh, Jaleh" uniqKey="Doostzadeh J" first="Jaleh" last="Doostzadeh">Jaleh Doostzadeh</name><affiliation><mods:affiliation>The Parkinson's Institute, Sunnyvale, California</mods:affiliation></affiliation></author><author><name sortKey="Absalan, Farnaz" sort="Absalan, Farnaz" uniqKey="Absalan F" first="Farnaz" last="Absalan">Farnaz Absalan</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Mohandessi, Sharareh" sort="Mohandessi, Sharareh" uniqKey="Mohandessi S" first="Sharareh" last="Mohandessi">Sharareh Mohandessi</name><affiliation><mods:affiliation>The Parkinson's Institute, Sunnyvale, California</mods:affiliation></affiliation></author><author><name sortKey="Jalili, Roxana" sort="Jalili, Roxana" uniqKey="Jalili R" first="Roxana" last="Jalili">Roxana Jalili</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Bigdeli, Saharnaz" sort="Bigdeli, Saharnaz" uniqKey="Bigdeli S" first="Saharnaz" last="Bigdeli">Saharnaz Bigdeli</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Wang, Justin" sort="Wang, Justin" uniqKey="Wang J" first="Justin" last="Wang">Justin Wang</name><affiliation><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="Mahadevan, Jaydev" sort="Mahadevan, Jaydev" uniqKey="Mahadevan J" first="Jaydev" last="Mahadevan">Jaydev Mahadevan</name><affiliation><mods:affiliation>Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York</mods:affiliation></affiliation></author><author><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><affiliation><mods:affiliation>Department of Biochemistry, Yong Loo School of Medicine, National University of Singapore, Singapore</mods:affiliation></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><mods:affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</mods:affiliation></affiliation></author><author><name sortKey="William Langston, J" sort="William Langston, J" uniqKey="William Langston J" first="J." last="William Langston">J. 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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><istex><corpusName>wiley</corpusName><author><json:item><name>Balaji S. 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William Langston</name><affiliations><json:string>The Parkinson's Institute, Sunnyvale, California</json:string></affiliations></json:item><json:item><name>Mostafa Ronaghi</name><affiliations><json:string>Stanford Genome Technology Center, Stanford University, Palo Alto, California</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>whole genome association</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PD</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pathway association</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>axon guidance</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>candidate pathways</value></json:item></subject><articleId><json:string>HUMU20840</json:string></articleId><language><json:string>eng</json:string></language><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. 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Mathew</note><note>Department of Defense (DOD) - No. W81XWH‐04‐1‐0404;</note><note>National Institutes of Health (NIH) - No. P01 HG000205;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease</title><author><persName><forename type="first">Balaji S.</forename><surname>Srinivasan</surname></persName><affiliation>Department of Statistics, Stanford University, Stanford, California</affiliation><affiliation>Department of Computer Science, Stanford University, Stanford, California</affiliation></author><author><persName><forename type="first">Jaleh</forename><surname>Doostzadeh</surname></persName><affiliation>The Parkinson's Institute, Sunnyvale, California</affiliation></author><author><persName><forename type="first">Farnaz</forename><surname>Absalan</surname></persName><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation></author><author><persName><forename type="first">Sharareh</forename><surname>Mohandessi</surname></persName><affiliation>The Parkinson's Institute, Sunnyvale, California</affiliation></author><author><persName><forename type="first">Roxana</forename><surname>Jalili</surname></persName><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation></author><author><persName><forename type="first">Saharnaz</forename><surname>Bigdeli</surname></persName><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation></author><author><persName><forename type="first">Justin</forename><surname>Wang</surname></persName><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation></author><author><persName><forename type="first">Jaydev</forename><surname>Mahadevan</surname></persName><affiliation>Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York</affiliation></author><author><persName><forename type="first">Caroline L.G.</forename><surname>Lee</surname></persName><affiliation>Department of Biochemistry, Yong Loo School of Medicine, National University of Singapore, Singapore</affiliation></author><author><persName><forename type="first">Ronald W.</forename><surname>Davis</surname></persName><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation></author><author><persName><forename type="first">J.</forename><surname>William Langston</surname></persName><affiliation>The Parkinson's Institute, Sunnyvale, California</affiliation></author><author><persName><forename type="first">Mostafa</forename><surname>Ronaghi</surname></persName><note type="correspondence"><p>Correspondence: Stanford University, Stanford Genome Technology Center, 855 California Ave, Palo Alto, CA 94304</p></note><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation></author></analytic><monogr><title level="j">Human Mutation</title><title level="j" type="abbrev">Hum. 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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.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>whole genome association</term></item><item><term>Parkinson's disease</term></item><item><term>PD</term></item><item><term>Parkinson</term></item><item><term>pathway association</term></item><item><term>axon guidance</term></item><item><term>candidate pathways</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2008-03-08">Received</change><change when="2008-05-15">Registration</change><change when="2009-02">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/37694CDEB7889ACE9501DB9B732012E71783B9FD/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1098-1004</doi><issn type="print">1059-7794</issn><issn type="electronic">1098-1004</issn><idGroup><id type="product" value="HUMU"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="HUMAN MUTATION">Human Mutation</title><title type="short">Hum. 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number="4"></count><count type="tableTotal" number="4"></count><count type="referenceTotal" number="46"></count></countGroup><titleGroup><title type="main" xml:lang="en">Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease<link href="#fn1"></link></title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Balaji S.</givenNames><familyName>Srinivasan</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Jaleh</givenNames><familyName>Doostzadeh</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Farnaz</givenNames><familyName>Absalan</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Sharareh</givenNames><familyName>Mohandessi</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Roxana</givenNames><familyName>Jalili</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Saharnaz</givenNames><familyName>Bigdeli</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Justin</givenNames><familyName>Wang</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Jaydev</givenNames><familyName>Mahadevan</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Caroline L.G.</givenNames><familyName>Lee</familyName></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Ronald W.</givenNames><familyName>Davis</familyName></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af4"><personName><givenNames>J.</givenNames><familyName>William Langston</familyName></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af3" corresponding="yes"><personName><givenNames>Mostafa</givenNames><familyName>Ronaghi</familyName></personName><contactDetails><email>mostafa@stanford.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="US" type="organization"><unparsedAffiliation>Department of Statistics, Stanford University, Stanford, California</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="US" type="organization"><unparsedAffiliation>Department of Computer Science, Stanford University, Stanford, California</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>The Parkinson's Institute, Sunnyvale, California</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="US" type="organization"><unparsedAffiliation>Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="SG" type="organization"><unparsedAffiliation>Department of Biochemistry, Yong Loo School of Medicine, National University of Singapore, Singapore</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">whole genome association</keyword><keyword xml:id="kwd2">Parkinson's disease</keyword><keyword xml:id="kwd3">PD</keyword><keyword xml:id="kwd4">Parkinson</keyword><keyword xml:id="kwd5">pathway association</keyword><keyword xml:id="kwd6">axon guidance</keyword><keyword xml:id="kwd7">candidate pathways</keyword></keywordGroup><fundingInfo><fundingAgency>Department of Defense (DOD)</fundingAgency><fundingNumber>W81XWH‐04‐1‐0404</fundingNumber></fundingInfo><fundingInfo><fundingAgency>National Institutes of Health (NIH)</fundingAgency><fundingNumber>P01 HG000205</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="fr"><title type="main">Abstract</title><p>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. [<i>PLoS Genet</i> 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. [<i>Lancet Neurol</i> 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.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Communicated by Christopher G. Mathew</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease</title></titleInfo><name type="personal"><namePart type="given">Balaji S.</namePart><namePart type="family">Srinivasan</namePart><affiliation>Department of Statistics, Stanford University, Stanford, California</affiliation><affiliation>Department of Computer Science, Stanford University, Stanford, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jaleh</namePart><namePart type="family">Doostzadeh</namePart><affiliation>The Parkinson's Institute, Sunnyvale, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Farnaz</namePart><namePart type="family">Absalan</namePart><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sharareh</namePart><namePart type="family">Mohandessi</namePart><affiliation>The Parkinson's Institute, Sunnyvale, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Roxana</namePart><namePart type="family">Jalili</namePart><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Saharnaz</namePart><namePart type="family">Bigdeli</namePart><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Justin</namePart><namePart type="family">Wang</namePart><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jaydev</namePart><namePart type="family">Mahadevan</namePart><affiliation>Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Caroline L.G.</namePart><namePart type="family">Lee</namePart><affiliation>Department of Biochemistry, Yong Loo School of Medicine, National University of Singapore, Singapore</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ronald W.</namePart><namePart type="family">Davis</namePart><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J.</namePart><namePart type="family">William Langston</namePart><affiliation>The Parkinson's Institute, Sunnyvale, California</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mostafa</namePart><namePart type="family">Ronaghi</namePart><affiliation>Stanford Genome Technology Center, Stanford University, Palo Alto, California</affiliation><description>Correspondence: Stanford University, Stanford Genome Technology Center, 855 California Ave, Palo Alto, CA 94304</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2009-02</dateIssued><dateCaptured encoding="w3cdtf">2008-03-08</dateCaptured><dateValid encoding="w3cdtf">2008-05-15</dateValid><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="tables">4</extent><extent unit="references">46</extent></physicalDescription><abstract 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.</abstract><note type="content">*Communicated by Christopher G. Mathew</note><note type="funding">Department of Defense (DOD) - No. W81XWH‐04‐1‐0404; </note><note type="funding">National Institutes of Health (NIH) - No. P01 HG000205; </note><subject lang="en"><genre>Keywords</genre><topic>whole genome association</topic><topic>Parkinson's disease</topic><topic>PD</topic><topic>Parkinson</topic><topic>pathway association</topic><topic>axon guidance</topic><topic>candidate pathways</topic></subject><relatedItem type="host"><titleInfo><title>Human Mutation</title></titleInfo><titleInfo type="abbreviated"><title>Hum. 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