Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred
INTRODUCTION Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS A genetic...
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| Veröffentlicht in: | Alzheimer's & dementia 2023-09, Vol.19 (9), p.3835-3847 |
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| creator | Cochran, Jesse Nicholas Acosta‐Uribe, Juliana Esposito, Bianca T. Madrigal, Lucia Aguillón, David Giraldo, Margarita M. Taylor, Jared W. Bradley, Joseph Fulton‐Howard, Brian Andrews, Shea J. Acosta‐Baena, Natalia Alzate, Diana Garcia, Gloria P. Piedrahita, Francisco Lopez, Hugo E. Anderson, Ashlyn G. Rodriguez‐Nunez, Ivan Roberts, Kevin Dominantly Inherited Alzheimer Network Absher, Devin Myers, Richard M. Beecham, Gary W. Reitz, Christiane Rizzardi, Lindsay F. Fernandez, Maria Victoria Goate, Alison M. Cruchaga, Carlos Renton, Alan E. Lopera, Francisco Kosik, Kenneth S. |
| description | INTRODUCTION
Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.
METHODS
A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies.
RESULTS
13 variants had p |
| doi_str_mv | 10.1002/alz.13021 |
| format | Article |
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Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.
METHODS
A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies.
RESULTS
13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.
DISCUSSION
Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.</description><identifier>ISSN: 1552-5260</identifier><identifier>ISSN: 1552-5279</identifier><identifier>EISSN: 1552-5279</identifier><identifier>DOI: 10.1002/alz.13021</identifier><identifier>PMID: 36951251</identifier><language>eng</language><publisher>United States</publisher><subject>AAO ; ACE ; Age of Onset ; Alzheimer ; Alzheimer Disease - diagnosis ; Amyloid ; AOO ; CLU ; clusterin ; Clusterin - genetics ; Colombia ; E280A ; heparin sulfate ; HS3ST1 ; HSPG2 ; Humans ; LRP1B ; Mutation - genetics ; Presenilin-1 - genetics ; PSEN1 ; SIAH3 ; tetraspanin ; TSPAN10 ; TSPAN14 ; ZC3H13</subject><ispartof>Alzheimer's & dementia, 2023-09, Vol.19 (9), p.3835-3847</ispartof><rights>2023 Alzheimer's Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4161-b8f9abfe6520dc2d4ec595ab7bb26df9edd42ff48e3c9496d45c570c2551cb723</citedby><cites>FETCH-LOGICAL-c4161-b8f9abfe6520dc2d4ec595ab7bb26df9edd42ff48e3c9496d45c570c2551cb723</cites><orcidid>0000-0002-9852-5504</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falz.13021$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falz.13021$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36951251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cochran, Jesse Nicholas</creatorcontrib><creatorcontrib>Acosta‐Uribe, Juliana</creatorcontrib><creatorcontrib>Esposito, Bianca T.</creatorcontrib><creatorcontrib>Madrigal, Lucia</creatorcontrib><creatorcontrib>Aguillón, David</creatorcontrib><creatorcontrib>Giraldo, Margarita M.</creatorcontrib><creatorcontrib>Taylor, Jared W.</creatorcontrib><creatorcontrib>Bradley, Joseph</creatorcontrib><creatorcontrib>Fulton‐Howard, Brian</creatorcontrib><creatorcontrib>Andrews, Shea J.</creatorcontrib><creatorcontrib>Acosta‐Baena, Natalia</creatorcontrib><creatorcontrib>Alzate, Diana</creatorcontrib><creatorcontrib>Garcia, Gloria P.</creatorcontrib><creatorcontrib>Piedrahita, Francisco</creatorcontrib><creatorcontrib>Lopez, Hugo E.</creatorcontrib><creatorcontrib>Anderson, Ashlyn G.</creatorcontrib><creatorcontrib>Rodriguez‐Nunez, Ivan</creatorcontrib><creatorcontrib>Roberts, Kevin</creatorcontrib><creatorcontrib>Dominantly Inherited Alzheimer Network</creatorcontrib><creatorcontrib>Absher, Devin</creatorcontrib><creatorcontrib>Myers, Richard M.</creatorcontrib><creatorcontrib>Beecham, Gary W.</creatorcontrib><creatorcontrib>Reitz, Christiane</creatorcontrib><creatorcontrib>Rizzardi, Lindsay F.</creatorcontrib><creatorcontrib>Fernandez, Maria Victoria</creatorcontrib><creatorcontrib>Goate, Alison M.</creatorcontrib><creatorcontrib>Cruchaga, Carlos</creatorcontrib><creatorcontrib>Renton, Alan E.</creatorcontrib><creatorcontrib>Lopera, Francisco</creatorcontrib><creatorcontrib>Kosik, Kenneth S.</creatorcontrib><title>Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred</title><title>Alzheimer's & dementia</title><addtitle>Alzheimers Dement</addtitle><description>INTRODUCTION
Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.
METHODS
A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies.
RESULTS
13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.
DISCUSSION
Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.</description><subject>AAO</subject><subject>ACE</subject><subject>Age of Onset</subject><subject>Alzheimer</subject><subject>Alzheimer Disease - diagnosis</subject><subject>Amyloid</subject><subject>AOO</subject><subject>CLU</subject><subject>clusterin</subject><subject>Clusterin - genetics</subject><subject>Colombia</subject><subject>E280A</subject><subject>heparin sulfate</subject><subject>HS3ST1</subject><subject>HSPG2</subject><subject>Humans</subject><subject>LRP1B</subject><subject>Mutation - genetics</subject><subject>Presenilin-1 - genetics</subject><subject>PSEN1</subject><subject>SIAH3</subject><subject>tetraspanin</subject><subject>TSPAN10</subject><subject>TSPAN14</subject><subject>ZC3H13</subject><issn>1552-5260</issn><issn>1552-5279</issn><issn>1552-5279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kUFPwjAYhhujEUQP_gHTox7Atms3djKEIJoQNREvXpqu_QbVbcV1SPDXWwWJHjz1S74nT7-8L0KnlPQoIexSFR89GhFG91CbCsG6giXp_m6OSQsdef9CCCd9Kg5RK4pTQZmgbTQdQwWN1Vh577RVjXWVxyvbzLGaAVYNNlBC1ViFwwIabCvczAE_PI7uKB6xPhngoStcmVlV4VdbmRrMMTrIVeHhZPt20NP1aDq86U7ux7fDwaSrOY1pN-vnqcpyiAUjRjPDQYtUqCzJMhabPAVjOMtz3odIpzyNDRdaJEQzIajOEhZ10NXGu1hmJRgd7qxVIRe1LVW9lk5Z-XdT2bmcuXdJiaCcRUkwnG8NtXtbgm9kab2GolAVuKWXIceQWkp4HNCLDapr530N-e4fSuRXDTLUIL9rCOzZ78N25E_uAbjcACtbwPp_kxxMnjfKTxvKkdQ</recordid><startdate>202309</startdate><enddate>202309</enddate><creator>Cochran, Jesse Nicholas</creator><creator>Acosta‐Uribe, Juliana</creator><creator>Esposito, Bianca T.</creator><creator>Madrigal, Lucia</creator><creator>Aguillón, David</creator><creator>Giraldo, Margarita M.</creator><creator>Taylor, Jared W.</creator><creator>Bradley, Joseph</creator><creator>Fulton‐Howard, Brian</creator><creator>Andrews, Shea J.</creator><creator>Acosta‐Baena, Natalia</creator><creator>Alzate, Diana</creator><creator>Garcia, Gloria P.</creator><creator>Piedrahita, Francisco</creator><creator>Lopez, Hugo E.</creator><creator>Anderson, Ashlyn G.</creator><creator>Rodriguez‐Nunez, Ivan</creator><creator>Roberts, Kevin</creator><creator>Dominantly Inherited Alzheimer Network</creator><creator>Absher, Devin</creator><creator>Myers, Richard M.</creator><creator>Beecham, Gary W.</creator><creator>Reitz, Christiane</creator><creator>Rizzardi, Lindsay F.</creator><creator>Fernandez, Maria Victoria</creator><creator>Goate, Alison M.</creator><creator>Cruchaga, Carlos</creator><creator>Renton, Alan E.</creator><creator>Lopera, Francisco</creator><creator>Kosik, Kenneth S.</creator><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><orcidid>https://orcid.org/0000-0002-9852-5504</orcidid></search><sort><creationdate>202309</creationdate><title>Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred</title><author>Cochran, Jesse Nicholas ; Acosta‐Uribe, Juliana ; Esposito, Bianca T. ; Madrigal, Lucia ; Aguillón, David ; Giraldo, Margarita M. ; Taylor, Jared W. ; Bradley, Joseph ; Fulton‐Howard, Brian ; Andrews, Shea J. ; Acosta‐Baena, Natalia ; Alzate, Diana ; Garcia, Gloria P. ; Piedrahita, Francisco ; Lopez, Hugo E. ; Anderson, Ashlyn G. ; Rodriguez‐Nunez, Ivan ; Roberts, Kevin ; Dominantly Inherited Alzheimer Network ; Absher, Devin ; Myers, Richard M. ; Beecham, Gary W. ; Reitz, Christiane ; Rizzardi, Lindsay F. ; Fernandez, Maria Victoria ; Goate, Alison M. ; Cruchaga, Carlos ; Renton, Alan E. ; Lopera, Francisco ; Kosik, Kenneth S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4161-b8f9abfe6520dc2d4ec595ab7bb26df9edd42ff48e3c9496d45c570c2551cb723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>AAO</topic><topic>ACE</topic><topic>Age of Onset</topic><topic>Alzheimer</topic><topic>Alzheimer Disease - diagnosis</topic><topic>Amyloid</topic><topic>AOO</topic><topic>CLU</topic><topic>clusterin</topic><topic>Clusterin - genetics</topic><topic>Colombia</topic><topic>E280A</topic><topic>heparin sulfate</topic><topic>HS3ST1</topic><topic>HSPG2</topic><topic>Humans</topic><topic>LRP1B</topic><topic>Mutation - genetics</topic><topic>Presenilin-1 - genetics</topic><topic>PSEN1</topic><topic>SIAH3</topic><topic>tetraspanin</topic><topic>TSPAN10</topic><topic>TSPAN14</topic><topic>ZC3H13</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cochran, Jesse Nicholas</creatorcontrib><creatorcontrib>Acosta‐Uribe, Juliana</creatorcontrib><creatorcontrib>Esposito, Bianca T.</creatorcontrib><creatorcontrib>Madrigal, Lucia</creatorcontrib><creatorcontrib>Aguillón, David</creatorcontrib><creatorcontrib>Giraldo, Margarita M.</creatorcontrib><creatorcontrib>Taylor, Jared W.</creatorcontrib><creatorcontrib>Bradley, Joseph</creatorcontrib><creatorcontrib>Fulton‐Howard, Brian</creatorcontrib><creatorcontrib>Andrews, Shea J.</creatorcontrib><creatorcontrib>Acosta‐Baena, Natalia</creatorcontrib><creatorcontrib>Alzate, Diana</creatorcontrib><creatorcontrib>Garcia, Gloria P.</creatorcontrib><creatorcontrib>Piedrahita, Francisco</creatorcontrib><creatorcontrib>Lopez, Hugo E.</creatorcontrib><creatorcontrib>Anderson, Ashlyn G.</creatorcontrib><creatorcontrib>Rodriguez‐Nunez, Ivan</creatorcontrib><creatorcontrib>Roberts, Kevin</creatorcontrib><creatorcontrib>Dominantly Inherited Alzheimer Network</creatorcontrib><creatorcontrib>Absher, Devin</creatorcontrib><creatorcontrib>Myers, Richard M.</creatorcontrib><creatorcontrib>Beecham, Gary W.</creatorcontrib><creatorcontrib>Reitz, Christiane</creatorcontrib><creatorcontrib>Rizzardi, Lindsay F.</creatorcontrib><creatorcontrib>Fernandez, Maria Victoria</creatorcontrib><creatorcontrib>Goate, Alison M.</creatorcontrib><creatorcontrib>Cruchaga, Carlos</creatorcontrib><creatorcontrib>Renton, Alan E.</creatorcontrib><creatorcontrib>Lopera, Francisco</creatorcontrib><creatorcontrib>Kosik, Kenneth S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Alzheimer's & dementia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cochran, Jesse Nicholas</au><au>Acosta‐Uribe, Juliana</au><au>Esposito, Bianca T.</au><au>Madrigal, Lucia</au><au>Aguillón, David</au><au>Giraldo, Margarita M.</au><au>Taylor, Jared W.</au><au>Bradley, Joseph</au><au>Fulton‐Howard, Brian</au><au>Andrews, Shea J.</au><au>Acosta‐Baena, Natalia</au><au>Alzate, Diana</au><au>Garcia, Gloria P.</au><au>Piedrahita, Francisco</au><au>Lopez, Hugo E.</au><au>Anderson, Ashlyn G.</au><au>Rodriguez‐Nunez, Ivan</au><au>Roberts, Kevin</au><au>Dominantly Inherited Alzheimer Network</au><au>Absher, Devin</au><au>Myers, Richard M.</au><au>Beecham, Gary W.</au><au>Reitz, Christiane</au><au>Rizzardi, Lindsay F.</au><au>Fernandez, Maria Victoria</au><au>Goate, Alison M.</au><au>Cruchaga, Carlos</au><au>Renton, Alan E.</au><au>Lopera, Francisco</au><au>Kosik, Kenneth S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred</atitle><jtitle>Alzheimer's & dementia</jtitle><addtitle>Alzheimers Dement</addtitle><date>2023-09</date><risdate>2023</risdate><volume>19</volume><issue>9</issue><spage>3835</spage><epage>3847</epage><pages>3835-3847</pages><issn>1552-5260</issn><issn>1552-5279</issn><eissn>1552-5279</eissn><abstract>INTRODUCTION
Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.
METHODS
A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies.
RESULTS
13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.
DISCUSSION
Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.</abstract><cop>United States</cop><pmid>36951251</pmid><doi>10.1002/alz.13021</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-9852-5504</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | AAO ACE Age of Onset Alzheimer Alzheimer Disease - diagnosis Amyloid AOO CLU clusterin Clusterin - genetics Colombia E280A heparin sulfate HS3ST1 HSPG2 Humans LRP1B Mutation - genetics Presenilin-1 - genetics PSEN1 SIAH3 tetraspanin TSPAN10 TSPAN14 ZC3H13 |
| title | Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred |
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