Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD....
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| creator | Kauwe, John S K Bailey, Matthew H Ridge, Perry G Perry, Rachel Wadsworth, Mark E Hoyt, Kaitlyn L Staley, Lyndsay A Karch, Celeste M Harari, Oscar Cruchaga, Carlos Ainscough, Benjamin J Bales, Kelly Pickering, Eve H Bertelsen, Sarah Fagan, Anne M Holtzman, David M Morris, John C Goate, Alison M |
| description | Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p |
| doi_str_mv | 10.1371/journal.pgen.1004758 |
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Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1004758</identifier><identifier>PMID: 25340798</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer Disease - blood ; Alzheimer Disease - cerebrospinal fluid ; Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Peptides - cerebrospinal fluid ; Amyloid beta-Peptides - genetics ; Biology and Life Sciences ; Blood Proteins - genetics ; Cerebrospinal fluid ; Chemokine CCL2 - genetics ; Chemokine CCL4 - genetics ; Development and progression ; Female ; Genes ; Genetic aspects ; Genetic polymorphisms ; Genome-Wide Association Study ; Humans ; Male ; Matrix Metalloproteinase 3 - genetics ; Medical research ; Medicine and Health Sciences ; Nerve Growth Factor - genetics ; Physiological aspects ; Polymorphism, Single Nucleotide ; Receptors, Interleukin-6 - genetics ; Receptors, Lipoprotein - genetics ; Renin - genetics ; Studies ; tau Proteins - cerebrospinal fluid ; tau Proteins - genetics</subject><ispartof>PLoS genetics, 2014-10, Vol.10 (10), p.e1004758-e1004758</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Kauwe et al 2014 Kauwe et al</rights><rights>2014 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Kauwe JSK, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL, et al. (2014) Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation. PLoS Genet 10(10): e1004758. doi:10.1371/journal.pgen.1004758</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c698t-d9b95a8bd82e171bf0db0960598afe12ac5134dc3edf4e7886d2ac123c6745f03</citedby><cites>FETCH-LOGICAL-c698t-d9b95a8bd82e171bf0db0960598afe12ac5134dc3edf4e7886d2ac123c6745f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207667/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207667/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25340798$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Geschwind, Daniel H.</contributor><creatorcontrib>Kauwe, John S K</creatorcontrib><creatorcontrib>Bailey, Matthew H</creatorcontrib><creatorcontrib>Ridge, Perry G</creatorcontrib><creatorcontrib>Perry, Rachel</creatorcontrib><creatorcontrib>Wadsworth, Mark E</creatorcontrib><creatorcontrib>Hoyt, Kaitlyn L</creatorcontrib><creatorcontrib>Staley, Lyndsay A</creatorcontrib><creatorcontrib>Karch, Celeste M</creatorcontrib><creatorcontrib>Harari, Oscar</creatorcontrib><creatorcontrib>Cruchaga, Carlos</creatorcontrib><creatorcontrib>Ainscough, Benjamin J</creatorcontrib><creatorcontrib>Bales, Kelly</creatorcontrib><creatorcontrib>Pickering, Eve H</creatorcontrib><creatorcontrib>Bertelsen, Sarah</creatorcontrib><creatorcontrib>Fagan, Anne M</creatorcontrib><creatorcontrib>Holtzman, David M</creatorcontrib><creatorcontrib>Morris, John C</creatorcontrib><creatorcontrib>Goate, Alison M</creatorcontrib><creatorcontrib>Alzheimer's Disease Neuroimaging Initiative</creatorcontrib><creatorcontrib>the Alzheimer's Disease Neuroimaging Initiative</creatorcontrib><title>Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.</description><subject>Alzheimer Disease - blood</subject><subject>Alzheimer Disease - cerebrospinal fluid</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - cerebrospinal fluid</subject><subject>Amyloid beta-Peptides - genetics</subject><subject>Biology and Life Sciences</subject><subject>Blood Proteins - genetics</subject><subject>Cerebrospinal fluid</subject><subject>Chemokine CCL2 - genetics</subject><subject>Chemokine CCL4 - genetics</subject><subject>Development and progression</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic polymorphisms</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Male</subject><subject>Matrix Metalloproteinase 3 - genetics</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Nerve Growth Factor - genetics</subject><subject>Physiological aspects</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Receptors, Interleukin-6 - genetics</subject><subject>Receptors, Lipoprotein - genetics</subject><subject>Renin - genetics</subject><subject>Studies</subject><subject>tau Proteins - cerebrospinal fluid</subject><subject>tau Proteins - genetics</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVk11rFDEUhgdRbF39B6IBwY-LXZP5SuKFUIqthWLBqrchm5yZTckk20lm6_qr_IlmutuyC14owzCZc573zeEkJ8ueEzwjBSXvr_zQO2lnyxbcjGBc0oo9yA5JVRVTWuLy4c76IHsSwhXGRcU4fZwd5FVRYsrZYfb7FJzvYHpjNCAZgldGRuMdCnHQa-QbdHx5giyswIbxr-JI2l8LMB30bwLSJoAMgJR02mgZAS17H8G48AEF0zrTmJSKu84B3Zi4uOeQcStvV6DTAslubb3RY1JBCMa1KBmnTGNl193Kn2aPGmkDPNt-J9n3k0_fjj9Pzy9Oz46Pzqeq5ixONZ_zSrK5ZjkQSuYN1nPMa1xxJhsguVQVKUqtCtBNCZSxWqcYyQtV07JqcDHJXm58l9YHsW12EKRmFck5L3kizjaE9vJKLHvTyX4tvDTiNuD7Vsg-GmVBMDw6K4nTTmVdKF7Qqixo3RCpNK518vq43W2Yd6AVuNhLu2e6n3FmIVq_EmWOaV3TZPB2a9D76wFCFJ0JCqyVDvww1k1YevNUxyR7tUFbmUpLvfXJUY24OCoYZxjTdD8m2ewvVHo0dEZ5B41J8T3Buz1BYiL8jK0cQhBnl1__g_3y7-zFj3329Q67AGnjIng73N67fbDcgKr3IfTQ3LeaYDGO192Ji3G8xHa8kuzF7jHdi-7mqfgDoTMjjw</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Kauwe, John S K</creator><creator>Bailey, Matthew H</creator><creator>Ridge, Perry G</creator><creator>Perry, Rachel</creator><creator>Wadsworth, Mark E</creator><creator>Hoyt, Kaitlyn L</creator><creator>Staley, Lyndsay A</creator><creator>Karch, Celeste M</creator><creator>Harari, Oscar</creator><creator>Cruchaga, Carlos</creator><creator>Ainscough, Benjamin J</creator><creator>Bales, Kelly</creator><creator>Pickering, Eve H</creator><creator>Bertelsen, Sarah</creator><creator>Fagan, Anne M</creator><creator>Holtzman, David M</creator><creator>Morris, John C</creator><creator>Goate, Alison M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141001</creationdate><title>Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation</title><author>Kauwe, John S K ; Bailey, Matthew H ; Ridge, Perry G ; Perry, Rachel ; Wadsworth, Mark E ; Hoyt, Kaitlyn L ; Staley, Lyndsay A ; Karch, Celeste M ; Harari, Oscar ; Cruchaga, Carlos ; Ainscough, Benjamin J ; Bales, Kelly ; Pickering, Eve H ; Bertelsen, Sarah ; Fagan, Anne M ; Holtzman, David M ; Morris, John C ; Goate, Alison M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c698t-d9b95a8bd82e171bf0db0960598afe12ac5134dc3edf4e7886d2ac123c6745f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Alzheimer Disease - 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genetics</topic><topic>Receptors, Lipoprotein - genetics</topic><topic>Renin - genetics</topic><topic>Studies</topic><topic>tau Proteins - cerebrospinal fluid</topic><topic>tau Proteins - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kauwe, John S K</creatorcontrib><creatorcontrib>Bailey, Matthew H</creatorcontrib><creatorcontrib>Ridge, Perry G</creatorcontrib><creatorcontrib>Perry, Rachel</creatorcontrib><creatorcontrib>Wadsworth, Mark E</creatorcontrib><creatorcontrib>Hoyt, Kaitlyn L</creatorcontrib><creatorcontrib>Staley, Lyndsay A</creatorcontrib><creatorcontrib>Karch, Celeste M</creatorcontrib><creatorcontrib>Harari, Oscar</creatorcontrib><creatorcontrib>Cruchaga, Carlos</creatorcontrib><creatorcontrib>Ainscough, Benjamin J</creatorcontrib><creatorcontrib>Bales, Kelly</creatorcontrib><creatorcontrib>Pickering, Eve H</creatorcontrib><creatorcontrib>Bertelsen, Sarah</creatorcontrib><creatorcontrib>Fagan, Anne M</creatorcontrib><creatorcontrib>Holtzman, David M</creatorcontrib><creatorcontrib>Morris, John C</creatorcontrib><creatorcontrib>Goate, Alison M</creatorcontrib><creatorcontrib>Alzheimer's Disease Neuroimaging Initiative</creatorcontrib><creatorcontrib>the Alzheimer's Disease Neuroimaging Initiative</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kauwe, John S K</au><au>Bailey, Matthew H</au><au>Ridge, Perry G</au><au>Perry, Rachel</au><au>Wadsworth, Mark E</au><au>Hoyt, Kaitlyn L</au><au>Staley, Lyndsay A</au><au>Karch, Celeste M</au><au>Harari, Oscar</au><au>Cruchaga, Carlos</au><au>Ainscough, Benjamin J</au><au>Bales, Kelly</au><au>Pickering, Eve H</au><au>Bertelsen, Sarah</au><au>Fagan, Anne M</au><au>Holtzman, David M</au><au>Morris, John C</au><au>Goate, Alison M</au><au>Geschwind, Daniel H.</au><aucorp>Alzheimer's Disease Neuroimaging Initiative</aucorp><aucorp>the Alzheimer's Disease Neuroimaging Initiative</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>10</volume><issue>10</issue><spage>e1004758</spage><epage>e1004758</epage><pages>e1004758-e1004758</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25340798</pmid><doi>10.1371/journal.pgen.1004758</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2014-10, Vol.10 (10), p.e1004758-e1004758 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_1685129949 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Public Library of Science (PLoS) |
| subjects | Alzheimer Disease - blood Alzheimer Disease - cerebrospinal fluid Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Peptides - cerebrospinal fluid Amyloid beta-Peptides - genetics Biology and Life Sciences Blood Proteins - genetics Cerebrospinal fluid Chemokine CCL2 - genetics Chemokine CCL4 - genetics Development and progression Female Genes Genetic aspects Genetic polymorphisms Genome-Wide Association Study Humans Male Matrix Metalloproteinase 3 - genetics Medical research Medicine and Health Sciences Nerve Growth Factor - genetics Physiological aspects Polymorphism, Single Nucleotide Receptors, Interleukin-6 - genetics Receptors, Lipoprotein - genetics Renin - genetics Studies tau Proteins - cerebrospinal fluid tau Proteins - genetics |
| title | Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T14%3A08%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome-wide%20association%20study%20of%20CSF%20levels%20of%2059%20alzheimer's%20disease%20candidate%20proteins:%20significant%20associations%20with%20proteins%20involved%20in%20amyloid%20processing%20and%20inflammation&rft.jtitle=PLoS%20genetics&rft.au=Kauwe,%20John%20S%20K&rft.aucorp=Alzheimer's%20Disease%20Neuroimaging%20Initiative&rft.date=2014-10-01&rft.volume=10&rft.issue=10&rft.spage=e1004758&rft.epage=e1004758&rft.pages=e1004758-e1004758&rft.issn=1553-7404&rft.eissn=1553-7404&rft_id=info:doi/10.1371/journal.pgen.1004758&rft_dat=%3Cgale_plos_%3EA389800725%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1618161212&rft_id=info:pmid/25340798&rft_galeid=A389800725&rft_doaj_id=oai_doaj_org_article_80123cca0e78463c93754376f1acd06d&rfr_iscdi=true |