Multi-Phenotype Association Decomposition: Unraveling Complex Gene-Phenotype Relationships.
Identifieur interne : 000830 ( Main/Exploration ); précédent : 000829; suivant : 000831Multi-Phenotype Association Decomposition: Unraveling Complex Gene-Phenotype Relationships.
Auteurs : Deborah Weighill [États-Unis] ; Piet Jones [États-Unis] ; Carissa Bleker [États-Unis] ; Priya Ranjan [États-Unis] ; Manesh Shah [États-Unis] ; Nan Zhao [États-Unis] ; Madhavi Martin [États-Unis] ; Stephen Difazio [États-Unis] ; David Macaya-Sanz [États-Unis] ; Jeremy Schmutz [États-Unis] ; Avinash Sreedasyam [États-Unis] ; Timothy Tschaplinski [États-Unis] ; Gerald Tuskan [États-Unis] ; Daniel Jacobson [États-Unis]Source :
- Frontiers in genetics [ 1664-8021 ] ; 2019.
Abstract
Various patterns of multi-phenotype associations (MPAs) exist in the results of Genome Wide Association Studies (GWAS) involving different topologies of single nucleotide polymorphism (SNP)-phenotype associations. These can provide interesting information about the different impacts of a gene on closely related phenotypes or disparate phenotypes (pleiotropy). In this work we present MPA Decomposition, a new network-based approach which decomposes the results of a multi-phenotype GWAS study into three bipartite networks, which, when used together, unravel the multi-phenotype signatures of genes on a genome-wide scale. The decomposition involves the construction of a phenotype powerset space, and subsequent mapping of genes into this new space. Clustering of genes in this powerset space groups genes based on their detailed MPA signatures. We show that this method allows us to find multiple different MPA and pleiotropic signatures within individual genes and to classify and cluster genes based on these SNP-phenotype association topologies. We demonstrate the use of this approach on a GWAS analysis of a large population of 882 Populus trichocarpa genotypes using untargeted metabolomics phenotypes. This method should prove invaluable in the interpretation of large GWAS datasets and aid in future synthetic biology efforts designed to optimize phenotypes of interest.
DOI: 10.3389/fgene.2019.00417
PubMed: 31134130
PubMed Central: PMC6522845
Affiliations:
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Relationships.</title><author><name sortKey="Weighill, Deborah" sort="Weighill, Deborah" uniqKey="Weighill D" first="Deborah" last="Weighill">Deborah Weighill</name><affiliation wicri:level="2"><nlm:affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Jones, Piet" sort="Jones, Piet" uniqKey="Jones P" first="Piet" last="Jones">Piet Jones</name><affiliation wicri:level="2"><nlm:affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Bleker, Carissa" sort="Bleker, Carissa" uniqKey="Bleker C" first="Carissa" last="Bleker">Carissa Bleker</name><affiliation wicri:level="2"><nlm:affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Ranjan, Priya" sort="Ranjan, Priya" uniqKey="Ranjan P" first="Priya" last="Ranjan">Priya Ranjan</name><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Department of Plant Sciences, The University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Plant Sciences, The University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Shah, Manesh" sort="Shah, Manesh" uniqKey="Shah M" first="Manesh" last="Shah">Manesh Shah</name><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Zhao, Nan" sort="Zhao, Nan" uniqKey="Zhao N" first="Nan" last="Zhao">Nan Zhao</name><affiliation wicri:level="2"><nlm:affiliation>Department of Plant Sciences, The University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Plant Sciences, The University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Martin, Madhavi" sort="Martin, Madhavi" uniqKey="Martin M" first="Madhavi" last="Martin">Madhavi Martin</name><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Difazio, Stephen" sort="Difazio, Stephen" uniqKey="Difazio S" first="Stephen" last="Difazio">Stephen Difazio</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biology, West Virginia University, Morgantown, WV, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, West Virginia University, Morgantown, WV</wicri:regionArea><placeName><region type="state">Virginie-Occidentale</region></placeName></affiliation></author><author><name sortKey="Macaya Sanz, David" sort="Macaya Sanz, David" uniqKey="Macaya Sanz D" first="David" last="Macaya-Sanz">David Macaya-Sanz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Biology, West Virginia University, Morgantown, WV, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biology, West Virginia University, Morgantown, WV</wicri:regionArea><placeName><region type="state">Virginie-Occidentale</region></placeName></affiliation></author><author><name sortKey="Schmutz, Jeremy" sort="Schmutz, Jeremy" uniqKey="Schmutz J" first="Jeremy" last="Schmutz">Jeremy Schmutz</name><affiliation wicri:level="2"><nlm:affiliation>Department of Energy Joint Genome Institute, Walnut Creek, CA, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Energy Joint Genome Institute, Walnut Creek, CA</wicri:regionArea><placeName><region type="state">Californie</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>HudsonAlpha Institute for Biotechnology, Huntsville, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Sreedasyam, Avinash" sort="Sreedasyam, Avinash" uniqKey="Sreedasyam A" first="Avinash" last="Sreedasyam">Avinash Sreedasyam</name><affiliation wicri:level="2"><nlm:affiliation>HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>HudsonAlpha Institute for Biotechnology, Huntsville, AL</wicri:regionArea><placeName><region type="state">Alabama</region></placeName></affiliation></author><author><name sortKey="Tschaplinski, Timothy" sort="Tschaplinski, Timothy" uniqKey="Tschaplinski T" first="Timothy" last="Tschaplinski">Timothy Tschaplinski</name><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Tuskan, Gerald" sort="Tuskan, Gerald" uniqKey="Tuskan G" first="Gerald" last="Tuskan">Gerald Tuskan</name><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Jacobson, Daniel" sort="Jacobson, Daniel" uniqKey="Jacobson D" first="Daniel" last="Jacobson">Daniel Jacobson</name><affiliation wicri:level="2"><nlm:affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></analytic><series><title level="j">Frontiers in genetics</title><idno type="ISSN">1664-8021</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Various patterns of multi-phenotype associations (MPAs) exist in the results of Genome Wide Association Studies (GWAS) involving different topologies of single nucleotide polymorphism (SNP)-phenotype associations. These can provide interesting information about the different impacts of a gene on closely related phenotypes or disparate phenotypes (pleiotropy). In this work we present MPA Decomposition, a new network-based approach which decomposes the results of a multi-phenotype GWAS study into three bipartite networks, which, when used together, unravel the multi-phenotype signatures of genes on a genome-wide scale. The decomposition involves the construction of a phenotype powerset space, and subsequent mapping of genes into this new space. Clustering of genes in this powerset space groups genes based on their detailed MPA signatures. We show that this method allows us to find multiple different MPA and pleiotropic signatures within individual genes and to classify and cluster genes based on these SNP-phenotype association topologies. We demonstrate the use of this approach on a GWAS analysis of a large population of 882 <i>Populus trichocarpa</i> genotypes using untargeted metabolomics phenotypes. This method should prove invaluable in the interpretation of large GWAS datasets and aid in future synthetic biology efforts designed to optimize phenotypes of interest.</div></front></TEI><pubmed><MedlineCitation Status="PubMed-not-MEDLINE" Owner="NLM"><PMID Version="1">31134130</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>01</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Print">1664-8021</ISSN><JournalIssue CitedMedium="Print"><Volume>10</Volume><PubDate><Year>2019</Year></PubDate></JournalIssue><Title>Frontiers in genetics</Title><ISOAbbreviation>Front Genet</ISOAbbreviation></Journal><ArticleTitle>Multi-Phenotype Association Decomposition: Unraveling Complex Gene-Phenotype Relationships.</ArticleTitle><Pagination><MedlinePgn>417</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.3389/fgene.2019.00417</ELocationID><Abstract><AbstractText>Various patterns of multi-phenotype associations (MPAs) exist in the results of Genome Wide Association Studies (GWAS) involving different topologies of single nucleotide polymorphism (SNP)-phenotype associations. These can provide interesting information about the different impacts of a gene on closely related phenotypes or disparate phenotypes (pleiotropy). In this work we present MPA Decomposition, a new network-based approach which decomposes the results of a multi-phenotype GWAS study into three bipartite networks, which, when used together, unravel the multi-phenotype signatures of genes on a genome-wide scale. The decomposition involves the construction of a phenotype powerset space, and subsequent mapping of genes into this new space. Clustering of genes in this powerset space groups genes based on their detailed MPA signatures. We show that this method allows us to find multiple different MPA and pleiotropic signatures within individual genes and to classify and cluster genes based on these SNP-phenotype association topologies. We demonstrate the use of this approach on a GWAS analysis of a large population of 882 <i>Populus trichocarpa</i> genotypes using untargeted metabolomics phenotypes. This method should prove invaluable in the interpretation of large GWAS datasets and aid in future synthetic biology efforts designed to optimize phenotypes of interest.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Weighill</LastName><ForeName>Deborah</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jones</LastName><ForeName>Piet</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bleker</LastName><ForeName>Carissa</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ranjan</LastName><ForeName>Priya</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Plant Sciences, The University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shah</LastName><ForeName>Manesh</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhao</LastName><ForeName>Nan</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Plant Sciences, The University of Tennessee Institute of Agriculture, University of Tennessee, Knoxville, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martin</LastName><ForeName>Madhavi</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>DiFazio</LastName><ForeName>Stephen</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Biology, West Virginia University, Morgantown, WV, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Macaya-Sanz</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Biology, West Virginia University, Morgantown, WV, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schmutz</LastName><ForeName>Jeremy</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Energy Joint Genome Institute, Walnut Creek, CA, United States.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sreedasyam</LastName><ForeName>Avinash</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tschaplinski</LastName><ForeName>Timothy</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tuskan</LastName><ForeName>Gerald</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jacobson</LastName><ForeName>Daniel</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>The Bredesen Center for Interdisciplinary Research and Graduate Education, University of Tennessee, Knoxville, TN, United States.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN, United States.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2019</Year><Month>05</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>Switzerland</Country><MedlineTA>Front Genet</MedlineTA><NlmUniqueID>101560621</NlmUniqueID><ISSNLinking>1664-8021</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">GWAS</Keyword><Keyword MajorTopicYN="N">SNP clustering</Keyword><Keyword MajorTopicYN="N">hypothesis generation</Keyword><Keyword MajorTopicYN="N">multi-phenotype associations</Keyword><Keyword MajorTopicYN="N">networks</Keyword><Keyword MajorTopicYN="N">pleiotropic signature</Keyword><Keyword MajorTopicYN="N">pleiotropy</Keyword><Keyword MajorTopicYN="N">powerset space</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>10</Month><Day>19</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2019</Year><Month>04</Month><Day>16</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2019</Year><Month>5</Month><Day>29</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2019</Year><Month>5</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>5</Month><Day>28</Day><Hour>6</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">31134130</ArticleId><ArticleId IdType="doi">10.3389/fgene.2019.00417</ArticleId><ArticleId IdType="pmc">PMC6522845</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Science. 2000 Jul 21;289(5478):436-8</Citation><ArticleIdList><ArticleId 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