Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease
We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus
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| creator | Jakobsdottir, Johanna van der Lee, Sven J Bis, Joshua C Chouraki, Vincent Li-Kroeger, David Yamamoto, Shinya Grove, Megan L Naj, Adam Vronskaya, Maria Salazar, Jose L DeStefano, Anita L Brody, Jennifer A Smith, Albert V Amin, Najaf Sims, Rebecca Ibrahim-Verbaas, Carla A Choi, Seung-Hoan Satizabal, Claudia L Lopez, Oscar L Beiser, Alexa Ikram, M Arfan Garcia, Melissa E Hayward, Caroline Varga, Tibor V Ripatti, Samuli Franks, Paul W Hallmans, Göran Rolandsson, Olov Jansson, Jan-Håkon Porteous, David J Salomaa, Veikko Eiriksdottir, Gudny Rice, Kenneth M Bellen, Hugo J Levy, Daniel Uitterlinden, Andre G Emilsson, Valur Rotter, Jerome I Aspelund, Thor O'Donnell, Christopher J Fitzpatrick, Annette L Launer, Lenore J Hofman, Albert Wang, Li-San Williams, Julie Schellenberg, Gerard D Boerwinkle, Eric Psaty, Bruce M Seshadri, Sudha Shulman, Joshua M Gudnason, Vilmundur van Duijn, Cornelia M |
| description | We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus |
| doi_str_mv | 10.1371/journal.pgen.1006327 |
| format | Article |
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We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1006327</identifier><identifier>PMID: 27764101</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age of Onset ; Aged ; Alleles ; Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer's disease ; Alzheimers disease ; Amyloid beta-Protein Precursor - genetics ; Animals ; Apolipoproteins E - genetics ; Basic Medicine ; Biology and Life Sciences ; Clinical medicine ; Colleges & universities ; Drosophila ; Drosophila melanogaster - genetics ; Drosophila Proteins - genetics ; Epidemiology ; Exome - genetics ; Female ; Genetic aspects ; Genetic variation ; Genetics ; Genome-Wide Association Study ; Genomics ; Health aspects ; Heart ; Hospitals ; Humans ; Iceland ; Intracellular Signaling Peptides and Proteins - genetics ; Male ; Medical and Health Sciences ; Medical Genetics ; Medical research ; Medicin och hälsovetenskap ; Medicine ; Medicine and Health Sciences ; Medicinsk genetik ; Medicinska och farmaceutiska grundvetenskaper ; Membrane Proteins - genetics ; Mutation ; Neurology ; Neurosciences ; Phenotype ; Physicians ; Public health ; Receptors, Notch - genetics ; Research and Analysis Methods ; Social Sciences ; Tropomyosin - genetics ; White People</subject><ispartof>PLoS genetics, 2016-10, Vol.12 (10), p.e1006327</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 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: is Associated with Late-Onset Alzheimer's Disease. PLoS Genet 12(10): e1006327. doi:10.1371/journal.pgen.1006327</rights><rights>2016 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: is Associated with Late-Onset Alzheimer's Disease. PLoS Genet 12(10): e1006327. doi:10.1371/journal.pgen.1006327</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c866t-6e7be009a87d5e9b81c5e6388478e392a3b66852b2eaab4c32b77f0a2e9d8f2d3</citedby><cites>FETCH-LOGICAL-c866t-6e7be009a87d5e9b81c5e6388478e392a3b66852b2eaab4c32b77f0a2e9d8f2d3</cites><orcidid>0000-0002-2383-699X ; 0000-0002-1115-4430 ; 0000-0003-2172-8036 ; 0000-0002-8019-9683 ; 0000-0002-1727-306X ; 0000-0003-1606-8643</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072721/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072721/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27764101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-128473$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/2bceeac0-cc27-42d2-8748-be9a02d9841d$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Jakobsdottir, Johanna</creatorcontrib><creatorcontrib>van der Lee, Sven J</creatorcontrib><creatorcontrib>Bis, Joshua C</creatorcontrib><creatorcontrib>Chouraki, Vincent</creatorcontrib><creatorcontrib>Li-Kroeger, David</creatorcontrib><creatorcontrib>Yamamoto, Shinya</creatorcontrib><creatorcontrib>Grove, Megan L</creatorcontrib><creatorcontrib>Naj, Adam</creatorcontrib><creatorcontrib>Vronskaya, Maria</creatorcontrib><creatorcontrib>Salazar, Jose L</creatorcontrib><creatorcontrib>DeStefano, Anita L</creatorcontrib><creatorcontrib>Brody, Jennifer A</creatorcontrib><creatorcontrib>Smith, Albert V</creatorcontrib><creatorcontrib>Amin, Najaf</creatorcontrib><creatorcontrib>Sims, Rebecca</creatorcontrib><creatorcontrib>Ibrahim-Verbaas, Carla A</creatorcontrib><creatorcontrib>Choi, Seung-Hoan</creatorcontrib><creatorcontrib>Satizabal, Claudia L</creatorcontrib><creatorcontrib>Lopez, Oscar L</creatorcontrib><creatorcontrib>Beiser, Alexa</creatorcontrib><creatorcontrib>Ikram, M Arfan</creatorcontrib><creatorcontrib>Garcia, Melissa E</creatorcontrib><creatorcontrib>Hayward, Caroline</creatorcontrib><creatorcontrib>Varga, Tibor V</creatorcontrib><creatorcontrib>Ripatti, Samuli</creatorcontrib><creatorcontrib>Franks, Paul W</creatorcontrib><creatorcontrib>Hallmans, Göran</creatorcontrib><creatorcontrib>Rolandsson, Olov</creatorcontrib><creatorcontrib>Jansson, Jan-Håkon</creatorcontrib><creatorcontrib>Porteous, David J</creatorcontrib><creatorcontrib>Salomaa, Veikko</creatorcontrib><creatorcontrib>Eiriksdottir, Gudny</creatorcontrib><creatorcontrib>Rice, Kenneth M</creatorcontrib><creatorcontrib>Bellen, Hugo J</creatorcontrib><creatorcontrib>Levy, Daniel</creatorcontrib><creatorcontrib>Uitterlinden, Andre G</creatorcontrib><creatorcontrib>Emilsson, Valur</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Aspelund, Thor</creatorcontrib><creatorcontrib>O'Donnell, Christopher J</creatorcontrib><creatorcontrib>Fitzpatrick, Annette L</creatorcontrib><creatorcontrib>Launer, Lenore J</creatorcontrib><creatorcontrib>Hofman, Albert</creatorcontrib><creatorcontrib>Wang, Li-San</creatorcontrib><creatorcontrib>Williams, Julie</creatorcontrib><creatorcontrib>Schellenberg, Gerard D</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Psaty, Bruce M</creatorcontrib><creatorcontrib>Seshadri, Sudha</creatorcontrib><creatorcontrib>Shulman, Joshua M</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>van Duijn, Cornelia M</creatorcontrib><creatorcontrib>Cohorts for Heart and Aging Research in Genomic Epidemiology consortium</creatorcontrib><creatorcontrib>Alzheimer’s Disease Genetic Consortium</creatorcontrib><creatorcontrib>Genetic and Environmental Risk in Alzheimer’s Disease consortium</creatorcontrib><title>Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.</description><subject>Age of Onset</subject><subject>Aged</subject><subject>Alleles</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Alzheimers disease</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Animals</subject><subject>Apolipoproteins E - genetics</subject><subject>Basic Medicine</subject><subject>Biology and Life Sciences</subject><subject>Clinical medicine</subject><subject>Colleges & universities</subject><subject>Drosophila</subject><subject>Drosophila melanogaster - genetics</subject><subject>Drosophila Proteins - genetics</subject><subject>Epidemiology</subject><subject>Exome - genetics</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Genetic variation</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Iceland</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medical Genetics</subject><subject>Medical research</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Medicinsk genetik</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>Membrane Proteins - genetics</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Phenotype</subject><subject>Physicians</subject><subject>Public health</subject><subject>Receptors, Notch - genetics</subject><subject>Research and Analysis Methods</subject><subject>Social Sciences</subject><subject>Tropomyosin - genetics</subject><subject>White 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Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease</title><author>Jakobsdottir, Johanna ; van der Lee, Sven J ; Bis, Joshua C ; Chouraki, Vincent ; Li-Kroeger, David ; Yamamoto, Shinya ; Grove, Megan L ; Naj, Adam ; Vronskaya, Maria ; Salazar, Jose L ; DeStefano, Anita L ; Brody, Jennifer A ; Smith, Albert V ; Amin, Najaf ; Sims, Rebecca ; Ibrahim-Verbaas, Carla A ; Choi, Seung-Hoan ; Satizabal, Claudia L ; Lopez, Oscar L ; Beiser, Alexa ; Ikram, M Arfan ; Garcia, Melissa E ; Hayward, Caroline ; Varga, Tibor V ; Ripatti, Samuli ; Franks, Paul W ; Hallmans, Göran ; Rolandsson, Olov ; Jansson, Jan-Håkon ; Porteous, David J ; Salomaa, Veikko ; Eiriksdottir, Gudny ; Rice, Kenneth M ; Bellen, Hugo J ; Levy, Daniel ; Uitterlinden, Andre G ; Emilsson, Valur ; Rotter, Jerome I ; Aspelund, Thor ; O'Donnell, Christopher J ; Fitzpatrick, Annette L ; Launer, Lenore J ; Hofman, Albert ; Wang, Li-San ; Williams, Julie ; Schellenberg, Gerard D ; Boerwinkle, Eric ; Psaty, Bruce M ; Seshadri, Sudha ; Shulman, Joshua M ; Gudnason, Vilmundur ; van Duijn, Cornelia M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c866t-6e7be009a87d5e9b81c5e6388478e392a3b66852b2eaab4c32b77f0a2e9d8f2d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Age of Onset</topic><topic>Aged</topic><topic>Alleles</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Alzheimers disease</topic><topic>Amyloid beta-Protein Precursor - genetics</topic><topic>Animals</topic><topic>Apolipoproteins E - genetics</topic><topic>Basic Medicine</topic><topic>Biology and Life Sciences</topic><topic>Clinical medicine</topic><topic>Colleges & universities</topic><topic>Drosophila</topic><topic>Drosophila melanogaster - genetics</topic><topic>Drosophila Proteins - genetics</topic><topic>Epidemiology</topic><topic>Exome - genetics</topic><topic>Female</topic><topic>Genetic aspects</topic><topic>Genetic variation</topic><topic>Genetics</topic><topic>Genome-Wide Association Study</topic><topic>Genomics</topic><topic>Health aspects</topic><topic>Heart</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Iceland</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Male</topic><topic>Medical and Health Sciences</topic><topic>Medical Genetics</topic><topic>Medical research</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Medicinsk genetik</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>Membrane Proteins - genetics</topic><topic>Mutation</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Phenotype</topic><topic>Physicians</topic><topic>Public health</topic><topic>Receptors, Notch - genetics</topic><topic>Research and Analysis Methods</topic><topic>Social Sciences</topic><topic>Tropomyosin - genetics</topic><topic>White People</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jakobsdottir, Johanna</creatorcontrib><creatorcontrib>van der Lee, Sven J</creatorcontrib><creatorcontrib>Bis, Joshua C</creatorcontrib><creatorcontrib>Chouraki, Vincent</creatorcontrib><creatorcontrib>Li-Kroeger, David</creatorcontrib><creatorcontrib>Yamamoto, Shinya</creatorcontrib><creatorcontrib>Grove, Megan L</creatorcontrib><creatorcontrib>Naj, Adam</creatorcontrib><creatorcontrib>Vronskaya, Maria</creatorcontrib><creatorcontrib>Salazar, Jose L</creatorcontrib><creatorcontrib>DeStefano, Anita L</creatorcontrib><creatorcontrib>Brody, Jennifer A</creatorcontrib><creatorcontrib>Smith, Albert V</creatorcontrib><creatorcontrib>Amin, Najaf</creatorcontrib><creatorcontrib>Sims, Rebecca</creatorcontrib><creatorcontrib>Ibrahim-Verbaas, Carla A</creatorcontrib><creatorcontrib>Choi, Seung-Hoan</creatorcontrib><creatorcontrib>Satizabal, Claudia L</creatorcontrib><creatorcontrib>Lopez, Oscar L</creatorcontrib><creatorcontrib>Beiser, Alexa</creatorcontrib><creatorcontrib>Ikram, M Arfan</creatorcontrib><creatorcontrib>Garcia, Melissa E</creatorcontrib><creatorcontrib>Hayward, Caroline</creatorcontrib><creatorcontrib>Varga, Tibor V</creatorcontrib><creatorcontrib>Ripatti, Samuli</creatorcontrib><creatorcontrib>Franks, Paul W</creatorcontrib><creatorcontrib>Hallmans, Göran</creatorcontrib><creatorcontrib>Rolandsson, Olov</creatorcontrib><creatorcontrib>Jansson, Jan-Håkon</creatorcontrib><creatorcontrib>Porteous, David J</creatorcontrib><creatorcontrib>Salomaa, Veikko</creatorcontrib><creatorcontrib>Eiriksdottir, Gudny</creatorcontrib><creatorcontrib>Rice, Kenneth M</creatorcontrib><creatorcontrib>Bellen, Hugo J</creatorcontrib><creatorcontrib>Levy, Daniel</creatorcontrib><creatorcontrib>Uitterlinden, Andre G</creatorcontrib><creatorcontrib>Emilsson, Valur</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>Aspelund, Thor</creatorcontrib><creatorcontrib>O'Donnell, Christopher J</creatorcontrib><creatorcontrib>Fitzpatrick, Annette L</creatorcontrib><creatorcontrib>Launer, Lenore J</creatorcontrib><creatorcontrib>Hofman, Albert</creatorcontrib><creatorcontrib>Wang, Li-San</creatorcontrib><creatorcontrib>Williams, Julie</creatorcontrib><creatorcontrib>Schellenberg, Gerard D</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Psaty, Bruce M</creatorcontrib><creatorcontrib>Seshadri, Sudha</creatorcontrib><creatorcontrib>Shulman, Joshua M</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>van Duijn, Cornelia M</creatorcontrib><creatorcontrib>Cohorts for Heart and Aging Research in Genomic Epidemiology consortium</creatorcontrib><creatorcontrib>Alzheimer’s Disease Genetic Consortium</creatorcontrib><creatorcontrib>Genetic and Environmental Risk in Alzheimer’s Disease consortium</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints in Context (Gale)</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 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titles)</collection><collection>SWEPUB Umeå universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Umeå universitet</collection><collection>SwePub Articles full text</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SWEPUB Lunds universitet</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>Jakobsdottir, Johanna</au><au>van der Lee, Sven J</au><au>Bis, Joshua C</au><au>Chouraki, Vincent</au><au>Li-Kroeger, David</au><au>Yamamoto, Shinya</au><au>Grove, Megan L</au><au>Naj, Adam</au><au>Vronskaya, Maria</au><au>Salazar, Jose L</au><au>DeStefano, Anita L</au><au>Brody, Jennifer A</au><au>Smith, Albert V</au><au>Amin, Najaf</au><au>Sims, Rebecca</au><au>Ibrahim-Verbaas, Carla A</au><au>Choi, Seung-Hoan</au><au>Satizabal, Claudia L</au><au>Lopez, Oscar L</au><au>Beiser, Alexa</au><au>Ikram, M Arfan</au><au>Garcia, Melissa E</au><au>Hayward, Caroline</au><au>Varga, Tibor V</au><au>Ripatti, Samuli</au><au>Franks, Paul W</au><au>Hallmans, Göran</au><au>Rolandsson, Olov</au><au>Jansson, Jan-Håkon</au><au>Porteous, David J</au><au>Salomaa, Veikko</au><au>Eiriksdottir, Gudny</au><au>Rice, Kenneth M</au><au>Bellen, Hugo J</au><au>Levy, Daniel</au><au>Uitterlinden, Andre G</au><au>Emilsson, Valur</au><au>Rotter, Jerome I</au><au>Aspelund, Thor</au><au>O'Donnell, Christopher J</au><au>Fitzpatrick, Annette L</au><au>Launer, Lenore J</au><au>Hofman, Albert</au><au>Wang, Li-San</au><au>Williams, Julie</au><au>Schellenberg, Gerard D</au><au>Boerwinkle, Eric</au><au>Psaty, Bruce M</au><au>Seshadri, Sudha</au><au>Shulman, Joshua M</au><au>Gudnason, Vilmundur</au><au>van Duijn, Cornelia M</au><aucorp>Cohorts for Heart and Aging Research in Genomic Epidemiology consortium</aucorp><aucorp>Alzheimer’s Disease Genetic Consortium</aucorp><aucorp>Genetic and Environmental Risk in Alzheimer’s Disease consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2016-10-01</date><risdate>2016</risdate><volume>12</volume><issue>10</issue><spage>e1006327</spage><pages>e1006327-</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27764101</pmid><doi>10.1371/journal.pgen.1006327</doi><orcidid>https://orcid.org/0000-0002-2383-699X</orcidid><orcidid>https://orcid.org/0000-0002-1115-4430</orcidid><orcidid>https://orcid.org/0000-0003-2172-8036</orcidid><orcidid>https://orcid.org/0000-0002-8019-9683</orcidid><orcidid>https://orcid.org/0000-0002-1727-306X</orcidid><orcidid>https://orcid.org/0000-0003-1606-8643</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1553-7404 |
| ispartof | PLoS genetics, 2016-10, Vol.12 (10), p.e1006327 |
| issn | 1553-7404 1553-7390 1553-7404 |
| language | eng |
| recordid | cdi_plos_journals_1840927990 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; SWEPUB Freely available online; Public Library of Science (PLoS) Journals Open Acc |
| subjects | Age of Onset Aged Alleles Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease Alzheimers disease Amyloid beta-Protein Precursor - genetics Animals Apolipoproteins E - genetics Basic Medicine Biology and Life Sciences Clinical medicine Colleges & universities Drosophila Drosophila melanogaster - genetics Drosophila Proteins - genetics Epidemiology Exome - genetics Female Genetic aspects Genetic variation Genetics Genome-Wide Association Study Genomics Health aspects Heart Hospitals Humans Iceland Intracellular Signaling Peptides and Proteins - genetics Male Medical and Health Sciences Medical Genetics Medical research Medicin och hälsovetenskap Medicine Medicine and Health Sciences Medicinsk genetik Medicinska och farmaceutiska grundvetenskaper Membrane Proteins - genetics Mutation Neurology Neurosciences Phenotype Physicians Public health Receptors, Notch - genetics Research and Analysis Methods Social Sciences Tropomyosin - genetics White People |
| title | Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease |
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