Novel late-onset Alzheimer disease loci variants associate with brain gene expression
Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (...
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| Veröffentlicht in: | Neurology 2012-07, Vol.79 (3), p.221-228 |
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| creator | ALLEN, Mariet FANGGENG ZOU MAHARJAN, Sooraj NGUYEN, Thuy LI MA MALPHRUS, Kimberly G PALUSAK, Ryan LINCOLN, Sarah BISCEGLIO, Gina GEORGESCU, Constantin SCHULTZ, Debra RAKHSHAN, Fariborz SENG CHAI, High KOLBERT, Christopher P JIN JEN HAINES, Jonathan L MAYEUX, Richard PERICAK-VANCE, Margaret A FARRER, Lindsay A SCHELLENBERG, Gerard D DISEASE, Alzheimer's CONSORTIUM, Genetics PETERSEN, Ronald C YOUNKIN, Curtis S GRAFF-RADFORD, Neill R DICKSON, Dennis W YOUNKIN, Steven G ERTEKIN-TANER, Niliifer CROOK, Julia SHANE PANKRATZ, V CARRASQUILLO, Minerva M ROWLEY, Christopher N NAIR, Asha A MIDDHA, Sumit |
| description | Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.
We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.
CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).
CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci. |
| doi_str_mv | 10.1212/WNL.0b013e3182605801 |
| format | Article |
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We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.
CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).
CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.</description><identifier>ISSN: 0028-3878</identifier><identifier>EISSN: 1526-632X</identifier><identifier>DOI: 10.1212/WNL.0b013e3182605801</identifier><identifier>PMID: 22722634</identifier><identifier>CODEN: NEURAI</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Aged ; Alleles ; Alzheimer Disease - genetics ; Apolipoprotein E4 - genetics ; Autopsy ; Biological and medical sciences ; Brain Chemistry - genetics ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Female ; Gene Dosage ; Gene Expression - physiology ; Genetic Predisposition to Disease ; Genotype ; Humans ; Linear Models ; Male ; Medical sciences ; Neurology ; Polymorphism, Single Nucleotide ; Risk Factors ; RNA - genetics ; RNA - isolation & purification ; Temporal Lobe - metabolism</subject><ispartof>Neurology, 2012-07, Vol.79 (3), p.221-228</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 by AAN Enterprises, Inc. 2012 AAN Enterprises, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-c3ef0a37ae4e835f16c52597277c5fdf9457dc3e70697925723ca12c07cdf0e3</citedby><cites>FETCH-LOGICAL-c438t-c3ef0a37ae4e835f16c52597277c5fdf9457dc3e70697925723ca12c07cdf0e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26163414$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22722634$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ALLEN, Mariet</creatorcontrib><creatorcontrib>FANGGENG ZOU</creatorcontrib><creatorcontrib>MAHARJAN, Sooraj</creatorcontrib><creatorcontrib>NGUYEN, Thuy</creatorcontrib><creatorcontrib>LI MA</creatorcontrib><creatorcontrib>MALPHRUS, Kimberly G</creatorcontrib><creatorcontrib>PALUSAK, Ryan</creatorcontrib><creatorcontrib>LINCOLN, Sarah</creatorcontrib><creatorcontrib>BISCEGLIO, Gina</creatorcontrib><creatorcontrib>GEORGESCU, Constantin</creatorcontrib><creatorcontrib>SCHULTZ, Debra</creatorcontrib><creatorcontrib>RAKHSHAN, Fariborz</creatorcontrib><creatorcontrib>SENG CHAI, High</creatorcontrib><creatorcontrib>KOLBERT, Christopher P</creatorcontrib><creatorcontrib>JIN JEN</creatorcontrib><creatorcontrib>HAINES, Jonathan L</creatorcontrib><creatorcontrib>MAYEUX, Richard</creatorcontrib><creatorcontrib>PERICAK-VANCE, Margaret A</creatorcontrib><creatorcontrib>FARRER, Lindsay A</creatorcontrib><creatorcontrib>SCHELLENBERG, Gerard D</creatorcontrib><creatorcontrib>DISEASE, Alzheimer's</creatorcontrib><creatorcontrib>CONSORTIUM, Genetics</creatorcontrib><creatorcontrib>PETERSEN, Ronald C</creatorcontrib><creatorcontrib>YOUNKIN, Curtis S</creatorcontrib><creatorcontrib>GRAFF-RADFORD, Neill R</creatorcontrib><creatorcontrib>DICKSON, Dennis W</creatorcontrib><creatorcontrib>YOUNKIN, Steven G</creatorcontrib><creatorcontrib>ERTEKIN-TANER, Niliifer</creatorcontrib><creatorcontrib>CROOK, Julia</creatorcontrib><creatorcontrib>SHANE PANKRATZ, V</creatorcontrib><creatorcontrib>CARRASQUILLO, Minerva M</creatorcontrib><creatorcontrib>ROWLEY, Christopher N</creatorcontrib><creatorcontrib>NAIR, Asha A</creatorcontrib><creatorcontrib>MIDDHA, Sumit</creatorcontrib><creatorcontrib>Alzheimer's Disease Genetics Consortium (ADGC)</creatorcontrib><title>Novel late-onset Alzheimer disease loci variants associate with brain gene expression</title><title>Neurology</title><addtitle>Neurology</addtitle><description>Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.
We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.
CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).
CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.</description><subject>Aged</subject><subject>Alleles</subject><subject>Alzheimer Disease - genetics</subject><subject>Apolipoprotein E4 - genetics</subject><subject>Autopsy</subject><subject>Biological and medical sciences</subject><subject>Brain Chemistry - genetics</subject><subject>Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases</subject><subject>Female</subject><subject>Gene Dosage</subject><subject>Gene Expression - physiology</subject><subject>Genetic Predisposition to Disease</subject><subject>Genotype</subject><subject>Humans</subject><subject>Linear Models</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Neurology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Risk Factors</subject><subject>RNA - genetics</subject><subject>RNA - isolation & purification</subject><subject>Temporal Lobe - metabolism</subject><issn>0028-3878</issn><issn>1526-632X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1PGzEQhq2qqATKP6gqXyr1suCPXdt7qYQQLUgRXEDlZjneWeLKsVPPJi38-roi0I_TaDTP-85oXkLecXbMBRcnX6_mx2zBuATJjVCsM4y_IjPeCdUoKe5ekxljwjTSaLNPDhC_MVaHun9D9oXQQijZzsjtVd5CpNFN0OSEMNHT-LiEsIJCh4DgEGjMPtCtK8GlCalDrH3l6Y8wLemiuJDoPSSg8HNdADHk9JbsjS4iHO3qIbn5fH5zdtHMr79cnp3OG99KMzVewsic1A5aMLIbufKd6HottPbdOIx92-mhQpqpXvei00J6x4Vn2g8jA3lIPj3ZrjeLFQwe0lRctOsSVq482OyC_XeSwtLe562VsjetFNXg486g5O8bwMmuAnqI0SXIG7ScCWWUqp-qaPuE-pIRC4wvazizvwOxNRD7fyBV9v7vE19EzwlU4MMOcOhdHItLPuAfTvFK8Vb-Akbhlhg</recordid><startdate>20120717</startdate><enddate>20120717</enddate><creator>ALLEN, Mariet</creator><creator>FANGGENG ZOU</creator><creator>MAHARJAN, Sooraj</creator><creator>NGUYEN, Thuy</creator><creator>LI MA</creator><creator>MALPHRUS, Kimberly G</creator><creator>PALUSAK, Ryan</creator><creator>LINCOLN, Sarah</creator><creator>BISCEGLIO, Gina</creator><creator>GEORGESCU, Constantin</creator><creator>SCHULTZ, Debra</creator><creator>RAKHSHAN, Fariborz</creator><creator>SENG CHAI, High</creator><creator>KOLBERT, Christopher P</creator><creator>JIN JEN</creator><creator>HAINES, Jonathan L</creator><creator>MAYEUX, Richard</creator><creator>PERICAK-VANCE, Margaret A</creator><creator>FARRER, Lindsay A</creator><creator>SCHELLENBERG, Gerard D</creator><creator>DISEASE, Alzheimer's</creator><creator>CONSORTIUM, Genetics</creator><creator>PETERSEN, Ronald C</creator><creator>YOUNKIN, Curtis S</creator><creator>GRAFF-RADFORD, Neill R</creator><creator>DICKSON, Dennis W</creator><creator>YOUNKIN, Steven G</creator><creator>ERTEKIN-TANER, Niliifer</creator><creator>CROOK, Julia</creator><creator>SHANE PANKRATZ, V</creator><creator>CARRASQUILLO, Minerva M</creator><creator>ROWLEY, Christopher N</creator><creator>NAIR, Asha A</creator><creator>MIDDHA, Sumit</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120717</creationdate><title>Novel late-onset Alzheimer disease loci variants associate with brain gene expression</title><author>ALLEN, Mariet ; FANGGENG ZOU ; MAHARJAN, Sooraj ; NGUYEN, Thuy ; LI MA ; MALPHRUS, Kimberly G ; PALUSAK, Ryan ; LINCOLN, Sarah ; BISCEGLIO, Gina ; GEORGESCU, Constantin ; SCHULTZ, Debra ; RAKHSHAN, Fariborz ; SENG CHAI, High ; KOLBERT, Christopher P ; JIN JEN ; HAINES, Jonathan L ; MAYEUX, Richard ; PERICAK-VANCE, Margaret A ; FARRER, Lindsay A ; SCHELLENBERG, Gerard D ; DISEASE, Alzheimer's ; CONSORTIUM, Genetics ; PETERSEN, Ronald C ; YOUNKIN, Curtis S ; GRAFF-RADFORD, Neill R ; DICKSON, Dennis W ; YOUNKIN, Steven G ; ERTEKIN-TANER, Niliifer ; CROOK, Julia ; SHANE PANKRATZ, V ; CARRASQUILLO, Minerva M ; ROWLEY, Christopher N ; NAIR, Asha A ; MIDDHA, Sumit</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-c3ef0a37ae4e835f16c52597277c5fdf9457dc3e70697925723ca12c07cdf0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Aged</topic><topic>Alleles</topic><topic>Alzheimer Disease - genetics</topic><topic>Apolipoprotein E4 - genetics</topic><topic>Autopsy</topic><topic>Biological and medical sciences</topic><topic>Brain Chemistry - genetics</topic><topic>Degenerative and inherited degenerative diseases of the nervous system. 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Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.
We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.
CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).
CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>22722634</pmid><doi>10.1212/WNL.0b013e3182605801</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Neurology, 2012-07, Vol.79 (3), p.221-228 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3398432 |
| source | MEDLINE; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Aged Alleles Alzheimer Disease - genetics Apolipoprotein E4 - genetics Autopsy Biological and medical sciences Brain Chemistry - genetics Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Female Gene Dosage Gene Expression - physiology Genetic Predisposition to Disease Genotype Humans Linear Models Male Medical sciences Neurology Polymorphism, Single Nucleotide Risk Factors RNA - genetics RNA - isolation & purification Temporal Lobe - metabolism |
| title | Novel late-onset Alzheimer disease loci variants associate with brain gene expression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T03%3A55%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Novel%20late-onset%20Alzheimer%20disease%20loci%20variants%20associate%20with%20brain%20gene%20expression&rft.jtitle=Neurology&rft.au=ALLEN,%20Mariet&rft.aucorp=Alzheimer's%20Disease%20Genetics%20Consortium%20(ADGC)&rft.date=2012-07-17&rft.volume=79&rft.issue=3&rft.spage=221&rft.epage=228&rft.pages=221-228&rft.issn=0028-3878&rft.eissn=1526-632X&rft.coden=NEURAI&rft_id=info:doi/10.1212/WNL.0b013e3182605801&rft_dat=%3Cproquest_pubme%3E1026866634%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1026866634&rft_id=info:pmid/22722634&rfr_iscdi=true |