Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI
BACKGROUND—The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted...
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| Veröffentlicht in: | Circulation. Cardiovascular genetics 2015-04, Vol.8 (2), p.398-409 |
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| creator | Verhaaren, Benjamin F.J Debette, Stéphanie Bis, Joshua C Smith, Jennifer A Ikram, M Kamran Adams, Hieab H Beecham, Ashley H Rajan, Kumar B Lopez, Lorna M Barral, Sandra van Buchem, Mark A van der Grond, Jeroen Smith, Albert V Hegenscheid, Katrin Aggarwal, Neelum T de Andrade, Mariza Atkinson, Elizabeth J Beekman, Marian Beiser, Alexa S Blanton, Susan H Boerwinkle, Eric Brickman, Adam M Bryan, R Nick Chauhan, Ganesh Chen, Christopher P.L.H Chouraki, Vincent de Craen, Anton J.M Crivello, Fabrice Deary, Ian J Deelen, Joris De Jager, Philip L Dufouil, Carole Elkind, Mitchell S.V Evans, Denis A Freudenberger, Paul Gottesman, Rebecca F Gunason, Vilmundur Habes, Mohamad Heckbert, Susan R Heiss, Gerardo Hilal, Saima Hofer, Edith Hofman, Albert Knopman, David S Lewis, Cora E Liao, Jiemin Liewald, David C.M Luciano, Michelle van der Lugt, Aad Martinez, Oliver O Mayeux, Richard Mazoyer, Bernard Nalls, Mike Nauck, Matthias Niessen, Wiro J Oostra, Ben A Psaty, Bruce M Rice, Kenneth M Rotter, Jerome I von Sarnowski, Bettina Schmidt, Helena Schreiner, Pamela J Schuur, Maaike Sidney, Stephen S Sigurdsson, Sigurdur Slagboom, P Eline Stott, David J.M van Swieten, John C Teumer, Alexander Töglhofer, Anna Maria Traylor, Matthew Trompet, Stella Turner, Stephen T Tzourio, Christophe Uh, Hae-Won Uitterlinden, André G Vernooij, Meike W Wang, Jing J Wong, Tien Y Wardlaw, Joanna M Windham, B Gwen Wittfeld, Katharina Wolf, Christiane Wright, Clinton B Yang, Qiong Zhao, Wei Zijdenbos, Alex Jukema, J Wouter Sacco, Ralph L Kardia, Sharon L.R Mosley, Thomas H Longstreth, W T DeCarli, Charles C van Duijn, Cornelia M Schmidt, Reinhold Launer, Lenore J Grabe, Hans J Seshadri, Sudha S Ikram, M Arfan Fornage, Myriam |
| description | BACKGROUND—The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS—We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10) and identified novel loci on chr10q24 (P=1.6×10) and chr2p21 (P=4.4×10). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10) and chr2p16 (P=1.5×10). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS—We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms. |
| doi_str_mv | 10.1161/CIRCGENETICS.114.000858 |
| format | Article |
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Debette, Stéphanie ; Bis, Joshua C ; Smith, Jennifer A ; Ikram, M Kamran ; Adams, Hieab H ; Beecham, Ashley H ; Rajan, Kumar B ; Lopez, Lorna M ; Barral, Sandra ; van Buchem, Mark A ; van der Grond, Jeroen ; Smith, Albert V ; Hegenscheid, Katrin ; Aggarwal, Neelum T ; de Andrade, Mariza ; Atkinson, Elizabeth J ; Beekman, Marian ; Beiser, Alexa S ; Blanton, Susan H ; Boerwinkle, Eric ; Brickman, Adam M ; Bryan, R Nick ; Chauhan, Ganesh ; Chen, Christopher P.L.H ; Chouraki, Vincent ; de Craen, Anton J.M ; Crivello, Fabrice ; Deary, Ian J ; Deelen, Joris ; De Jager, Philip L ; Dufouil, Carole ; Elkind, Mitchell S.V ; Evans, Denis A ; Freudenberger, Paul ; Gottesman, Rebecca F ; Gunason, Vilmundur ; Habes, Mohamad ; Heckbert, Susan R ; Heiss, Gerardo ; Hilal, Saima ; Hofer, Edith ; Hofman, Albert ; Knopman, David S ; Lewis, Cora E ; Liao, Jiemin ; Liewald, David C.M ; Luciano, Michelle ; van der Lugt, Aad ; Martinez, Oliver O ; Mayeux, Richard ; Mazoyer, Bernard ; Nalls, Mike ; Nauck, Matthias ; Niessen, Wiro J ; Oostra, Ben A ; Psaty, Bruce M ; Rice, Kenneth M ; Rotter, Jerome I ; von Sarnowski, Bettina ; Schmidt, Helena ; Schreiner, Pamela J ; Schuur, Maaike ; Sidney, Stephen S ; Sigurdsson, Sigurdur ; Slagboom, P Eline ; Stott, David J.M ; van Swieten, John C ; Teumer, Alexander ; Töglhofer, Anna Maria ; Traylor, Matthew ; Trompet, Stella ; Turner, Stephen T ; Tzourio, Christophe ; Uh, Hae-Won ; Uitterlinden, André G ; Vernooij, Meike W ; Wang, Jing J ; Wong, Tien Y ; Wardlaw, Joanna M ; Windham, B Gwen ; Wittfeld, Katharina ; Wolf, Christiane ; Wright, Clinton B ; Yang, Qiong ; Zhao, Wei ; Zijdenbos, Alex ; Jukema, J Wouter ; Sacco, Ralph L ; Kardia, Sharon L.R ; Mosley, Thomas H ; Longstreth, W T ; DeCarli, Charles C ; van Duijn, Cornelia M ; Schmidt, Reinhold ; Launer, Lenore J ; Grabe, Hans J ; Seshadri, Sudha S ; Ikram, M Arfan ; Fornage, Myriam</creator><creatorcontrib>Verhaaren, Benjamin F.J ; Debette, Stéphanie ; Bis, Joshua C ; Smith, Jennifer A ; Ikram, M Kamran ; Adams, Hieab H ; Beecham, Ashley H ; Rajan, Kumar B ; Lopez, Lorna M ; Barral, Sandra ; van Buchem, Mark A ; van der Grond, Jeroen ; Smith, Albert V ; Hegenscheid, Katrin ; Aggarwal, Neelum T ; de Andrade, Mariza ; Atkinson, Elizabeth J ; Beekman, Marian ; Beiser, Alexa S ; Blanton, Susan H ; Boerwinkle, Eric ; Brickman, Adam M ; Bryan, R Nick ; Chauhan, Ganesh ; Chen, Christopher P.L.H ; Chouraki, Vincent ; de Craen, Anton J.M ; Crivello, Fabrice ; Deary, Ian J ; Deelen, Joris ; De Jager, Philip L ; Dufouil, Carole ; Elkind, Mitchell S.V ; Evans, Denis A ; Freudenberger, Paul ; Gottesman, Rebecca F ; Gunason, Vilmundur ; Habes, Mohamad ; Heckbert, Susan R ; Heiss, Gerardo ; Hilal, Saima ; Hofer, Edith ; Hofman, Albert ; Knopman, David S ; Lewis, Cora E ; Liao, Jiemin ; Liewald, David C.M ; Luciano, Michelle ; van der Lugt, Aad ; Martinez, Oliver O ; Mayeux, Richard ; Mazoyer, Bernard ; Nalls, Mike ; Nauck, Matthias ; Niessen, Wiro J ; Oostra, Ben A ; Psaty, Bruce M ; Rice, Kenneth M ; Rotter, Jerome I ; von Sarnowski, Bettina ; Schmidt, Helena ; Schreiner, Pamela J ; Schuur, Maaike ; Sidney, Stephen S ; Sigurdsson, Sigurdur ; Slagboom, P Eline ; Stott, David J.M ; van Swieten, John C ; Teumer, Alexander ; Töglhofer, Anna Maria ; Traylor, Matthew ; Trompet, Stella ; Turner, Stephen T ; Tzourio, Christophe ; Uh, Hae-Won ; Uitterlinden, André G ; Vernooij, Meike W ; Wang, Jing J ; Wong, Tien Y ; Wardlaw, Joanna M ; Windham, B Gwen ; Wittfeld, Katharina ; Wolf, Christiane ; Wright, Clinton B ; Yang, Qiong ; Zhao, Wei ; Zijdenbos, Alex ; Jukema, J Wouter ; Sacco, Ralph L ; Kardia, Sharon L.R ; Mosley, Thomas H ; Longstreth, W T ; DeCarli, Charles C ; van Duijn, Cornelia M ; Schmidt, Reinhold ; Launer, Lenore J ; Grabe, Hans J ; Seshadri, Sudha S ; Ikram, M Arfan ; Fornage, Myriam</creatorcontrib><description>BACKGROUND—The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS—We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10) and identified novel loci on chr10q24 (P=1.6×10) and chr2p21 (P=4.4×10). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10) and chr2p16 (P=1.5×10). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS—We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.</description><identifier>ISSN: 1942-325X</identifier><identifier>EISSN: 1942-3268</identifier><identifier>DOI: 10.1161/CIRCGENETICS.114.000858</identifier><identifier>PMID: 25663218</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Aged ; Aged, 80 and over ; Chromosomes, Human - genetics ; Cognitive science ; Female ; Genetic Loci ; Genome-Wide Association Study ; Humans ; Male ; Meta-Analysis as Topic ; Middle Aged ; Models, Genetic ; Neuroscience ; Racial Groups ; Stroke - ethnology ; Stroke - genetics ; Stroke - pathology ; White Matter</subject><ispartof>Circulation. Cardiovascular genetics, 2015-04, Vol.8 (2), p.398-409</ispartof><rights>2015 American Heart Association, Inc.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5148-c295e4108083ffdf44a681e2d0118b7600a12d68a10f8c9bf0955f5c7ee331223</citedby><cites>FETCH-LOGICAL-c5148-c295e4108083ffdf44a681e2d0118b7600a12d68a10f8c9bf0955f5c7ee331223</cites><orcidid>0000-0003-0970-2837 ; 0000-0001-6950-984X ; 0000-0001-9088-234X ; 0000-0002-4698-1794 ; 0000-0002-6517-2984 ; 0000-0001-8675-7968 ; 0000-0003-2442-4476</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3674,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25663218$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-01198723$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Verhaaren, Benjamin F.J</creatorcontrib><creatorcontrib>Debette, Stéphanie</creatorcontrib><creatorcontrib>Bis, Joshua C</creatorcontrib><creatorcontrib>Smith, Jennifer A</creatorcontrib><creatorcontrib>Ikram, M Kamran</creatorcontrib><creatorcontrib>Adams, Hieab H</creatorcontrib><creatorcontrib>Beecham, Ashley H</creatorcontrib><creatorcontrib>Rajan, Kumar B</creatorcontrib><creatorcontrib>Lopez, Lorna M</creatorcontrib><creatorcontrib>Barral, Sandra</creatorcontrib><creatorcontrib>van Buchem, Mark A</creatorcontrib><creatorcontrib>van der Grond, Jeroen</creatorcontrib><creatorcontrib>Smith, Albert V</creatorcontrib><creatorcontrib>Hegenscheid, Katrin</creatorcontrib><creatorcontrib>Aggarwal, Neelum T</creatorcontrib><creatorcontrib>de Andrade, Mariza</creatorcontrib><creatorcontrib>Atkinson, Elizabeth J</creatorcontrib><creatorcontrib>Beekman, Marian</creatorcontrib><creatorcontrib>Beiser, Alexa S</creatorcontrib><creatorcontrib>Blanton, Susan H</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Brickman, Adam M</creatorcontrib><creatorcontrib>Bryan, R Nick</creatorcontrib><creatorcontrib>Chauhan, Ganesh</creatorcontrib><creatorcontrib>Chen, Christopher P.L.H</creatorcontrib><creatorcontrib>Chouraki, Vincent</creatorcontrib><creatorcontrib>de Craen, Anton J.M</creatorcontrib><creatorcontrib>Crivello, Fabrice</creatorcontrib><creatorcontrib>Deary, Ian J</creatorcontrib><creatorcontrib>Deelen, Joris</creatorcontrib><creatorcontrib>De Jager, Philip L</creatorcontrib><creatorcontrib>Dufouil, Carole</creatorcontrib><creatorcontrib>Elkind, Mitchell S.V</creatorcontrib><creatorcontrib>Evans, Denis A</creatorcontrib><creatorcontrib>Freudenberger, Paul</creatorcontrib><creatorcontrib>Gottesman, Rebecca F</creatorcontrib><creatorcontrib>Gunason, Vilmundur</creatorcontrib><creatorcontrib>Habes, Mohamad</creatorcontrib><creatorcontrib>Heckbert, Susan R</creatorcontrib><creatorcontrib>Heiss, Gerardo</creatorcontrib><creatorcontrib>Hilal, Saima</creatorcontrib><creatorcontrib>Hofer, Edith</creatorcontrib><creatorcontrib>Hofman, Albert</creatorcontrib><creatorcontrib>Knopman, David S</creatorcontrib><creatorcontrib>Lewis, Cora E</creatorcontrib><creatorcontrib>Liao, Jiemin</creatorcontrib><creatorcontrib>Liewald, David C.M</creatorcontrib><creatorcontrib>Luciano, Michelle</creatorcontrib><creatorcontrib>van der Lugt, Aad</creatorcontrib><creatorcontrib>Martinez, Oliver O</creatorcontrib><creatorcontrib>Mayeux, Richard</creatorcontrib><creatorcontrib>Mazoyer, Bernard</creatorcontrib><creatorcontrib>Nalls, Mike</creatorcontrib><creatorcontrib>Nauck, Matthias</creatorcontrib><creatorcontrib>Niessen, Wiro J</creatorcontrib><creatorcontrib>Oostra, Ben A</creatorcontrib><creatorcontrib>Psaty, Bruce M</creatorcontrib><creatorcontrib>Rice, Kenneth M</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>von Sarnowski, Bettina</creatorcontrib><creatorcontrib>Schmidt, Helena</creatorcontrib><creatorcontrib>Schreiner, Pamela J</creatorcontrib><creatorcontrib>Schuur, Maaike</creatorcontrib><creatorcontrib>Sidney, Stephen S</creatorcontrib><creatorcontrib>Sigurdsson, Sigurdur</creatorcontrib><creatorcontrib>Slagboom, P Eline</creatorcontrib><creatorcontrib>Stott, David J.M</creatorcontrib><creatorcontrib>van Swieten, John C</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Töglhofer, Anna Maria</creatorcontrib><creatorcontrib>Traylor, Matthew</creatorcontrib><creatorcontrib>Trompet, Stella</creatorcontrib><creatorcontrib>Turner, Stephen T</creatorcontrib><creatorcontrib>Tzourio, Christophe</creatorcontrib><creatorcontrib>Uh, Hae-Won</creatorcontrib><creatorcontrib>Uitterlinden, André G</creatorcontrib><creatorcontrib>Vernooij, Meike W</creatorcontrib><creatorcontrib>Wang, Jing J</creatorcontrib><creatorcontrib>Wong, Tien Y</creatorcontrib><creatorcontrib>Wardlaw, Joanna M</creatorcontrib><creatorcontrib>Windham, B Gwen</creatorcontrib><creatorcontrib>Wittfeld, Katharina</creatorcontrib><creatorcontrib>Wolf, Christiane</creatorcontrib><creatorcontrib>Wright, Clinton B</creatorcontrib><creatorcontrib>Yang, Qiong</creatorcontrib><creatorcontrib>Zhao, Wei</creatorcontrib><creatorcontrib>Zijdenbos, Alex</creatorcontrib><creatorcontrib>Jukema, J Wouter</creatorcontrib><creatorcontrib>Sacco, Ralph L</creatorcontrib><creatorcontrib>Kardia, Sharon L.R</creatorcontrib><creatorcontrib>Mosley, Thomas H</creatorcontrib><creatorcontrib>Longstreth, W T</creatorcontrib><creatorcontrib>DeCarli, Charles C</creatorcontrib><creatorcontrib>van Duijn, Cornelia M</creatorcontrib><creatorcontrib>Schmidt, Reinhold</creatorcontrib><creatorcontrib>Launer, Lenore J</creatorcontrib><creatorcontrib>Grabe, Hans J</creatorcontrib><creatorcontrib>Seshadri, Sudha S</creatorcontrib><creatorcontrib>Ikram, M Arfan</creatorcontrib><creatorcontrib>Fornage, Myriam</creatorcontrib><title>Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI</title><title>Circulation. Cardiovascular genetics</title><addtitle>Circ Cardiovasc Genet</addtitle><description>BACKGROUND—The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS—We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10) and identified novel loci on chr10q24 (P=1.6×10) and chr2p21 (P=4.4×10). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10) and chr2p16 (P=1.5×10). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS—We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Chromosomes, Human - genetics</subject><subject>Cognitive science</subject><subject>Female</subject><subject>Genetic Loci</subject><subject>Genome-Wide Association Study</subject><subject>Humans</subject><subject>Male</subject><subject>Meta-Analysis as Topic</subject><subject>Middle Aged</subject><subject>Models, Genetic</subject><subject>Neuroscience</subject><subject>Racial Groups</subject><subject>Stroke - ethnology</subject><subject>Stroke - genetics</subject><subject>Stroke - pathology</subject><subject>White 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Stephen S</creator><creator>Sigurdsson, Sigurdur</creator><creator>Slagboom, P Eline</creator><creator>Stott, David J.M</creator><creator>van Swieten, John C</creator><creator>Teumer, Alexander</creator><creator>Töglhofer, Anna Maria</creator><creator>Traylor, Matthew</creator><creator>Trompet, Stella</creator><creator>Turner, Stephen T</creator><creator>Tzourio, Christophe</creator><creator>Uh, Hae-Won</creator><creator>Uitterlinden, André G</creator><creator>Vernooij, Meike W</creator><creator>Wang, Jing J</creator><creator>Wong, Tien Y</creator><creator>Wardlaw, Joanna M</creator><creator>Windham, B Gwen</creator><creator>Wittfeld, Katharina</creator><creator>Wolf, Christiane</creator><creator>Wright, Clinton B</creator><creator>Yang, Qiong</creator><creator>Zhao, Wei</creator><creator>Zijdenbos, Alex</creator><creator>Jukema, J Wouter</creator><creator>Sacco, Ralph L</creator><creator>Kardia, Sharon L.R</creator><creator>Mosley, Thomas H</creator><creator>Longstreth, W T</creator><creator>DeCarli, Charles C</creator><creator>van Duijn, Cornelia M</creator><creator>Schmidt, Reinhold</creator><creator>Launer, Lenore J</creator><creator>Grabe, Hans J</creator><creator>Seshadri, Sudha S</creator><creator>Ikram, M Arfan</creator><creator>Fornage, Myriam</creator><general>American Heart Association, Inc</general><general>American Heart Association</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>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0003-0970-2837</orcidid><orcidid>https://orcid.org/0000-0001-6950-984X</orcidid><orcidid>https://orcid.org/0000-0001-9088-234X</orcidid><orcidid>https://orcid.org/0000-0002-4698-1794</orcidid><orcidid>https://orcid.org/0000-0002-6517-2984</orcidid><orcidid>https://orcid.org/0000-0001-8675-7968</orcidid><orcidid>https://orcid.org/0000-0003-2442-4476</orcidid></search><sort><creationdate>201504</creationdate><title>Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI</title><author>Verhaaren, Benjamin F.J ; Debette, Stéphanie ; Bis, Joshua C ; Smith, Jennifer A ; Ikram, M Kamran ; Adams, Hieab H ; Beecham, Ashley H ; Rajan, Kumar B ; Lopez, Lorna M ; Barral, Sandra ; van Buchem, Mark A ; van der Grond, Jeroen ; Smith, Albert V ; Hegenscheid, Katrin ; Aggarwal, Neelum T ; de Andrade, Mariza ; Atkinson, Elizabeth J ; Beekman, Marian ; Beiser, Alexa S ; Blanton, Susan H ; Boerwinkle, Eric ; Brickman, Adam M ; Bryan, R Nick ; Chauhan, Ganesh ; Chen, Christopher P.L.H ; Chouraki, Vincent ; de Craen, Anton J.M ; Crivello, Fabrice ; Deary, Ian J ; Deelen, Joris ; De Jager, Philip L ; Dufouil, Carole ; Elkind, Mitchell S.V ; Evans, Denis A ; Freudenberger, Paul ; Gottesman, Rebecca F ; Gunason, Vilmundur ; Habes, Mohamad ; Heckbert, Susan R ; Heiss, Gerardo ; Hilal, Saima ; Hofer, Edith ; Hofman, Albert ; Knopman, David S ; Lewis, Cora E ; Liao, Jiemin ; Liewald, David C.M ; Luciano, Michelle ; van der Lugt, Aad ; Martinez, Oliver O ; Mayeux, Richard ; Mazoyer, Bernard ; Nalls, Mike ; Nauck, Matthias ; Niessen, Wiro J ; Oostra, Ben A ; Psaty, Bruce M ; Rice, Kenneth M ; Rotter, Jerome I ; von Sarnowski, Bettina ; Schmidt, Helena ; Schreiner, Pamela J ; Schuur, Maaike ; Sidney, Stephen S ; Sigurdsson, Sigurdur ; Slagboom, P Eline ; Stott, David J.M ; van Swieten, John C ; Teumer, Alexander ; Töglhofer, Anna Maria ; Traylor, Matthew ; Trompet, Stella ; Turner, Stephen T ; Tzourio, Christophe ; Uh, Hae-Won ; Uitterlinden, André G ; Vernooij, Meike W ; Wang, Jing J ; Wong, Tien Y ; Wardlaw, Joanna M ; Windham, B Gwen ; Wittfeld, Katharina ; Wolf, Christiane ; Wright, Clinton B ; Yang, Qiong ; Zhao, Wei ; Zijdenbos, Alex ; Jukema, J Wouter ; Sacco, Ralph L ; Kardia, Sharon L.R ; Mosley, Thomas H ; Longstreth, W T ; DeCarli, Charles C ; van Duijn, Cornelia M ; Schmidt, Reinhold ; Launer, Lenore J ; Grabe, Hans J ; Seshadri, Sudha S ; Ikram, M Arfan ; Fornage, Myriam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5148-c295e4108083ffdf44a681e2d0118b7600a12d68a10f8c9bf0955f5c7ee331223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Chromosomes, Human - genetics</topic><topic>Cognitive science</topic><topic>Female</topic><topic>Genetic Loci</topic><topic>Genome-Wide Association Study</topic><topic>Humans</topic><topic>Male</topic><topic>Meta-Analysis as Topic</topic><topic>Middle Aged</topic><topic>Models, Genetic</topic><topic>Neuroscience</topic><topic>Racial Groups</topic><topic>Stroke - ethnology</topic><topic>Stroke - genetics</topic><topic>Stroke - pathology</topic><topic>White Matter</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Verhaaren, Benjamin F.J</creatorcontrib><creatorcontrib>Debette, Stéphanie</creatorcontrib><creatorcontrib>Bis, Joshua C</creatorcontrib><creatorcontrib>Smith, Jennifer A</creatorcontrib><creatorcontrib>Ikram, M Kamran</creatorcontrib><creatorcontrib>Adams, Hieab H</creatorcontrib><creatorcontrib>Beecham, Ashley H</creatorcontrib><creatorcontrib>Rajan, Kumar B</creatorcontrib><creatorcontrib>Lopez, Lorna M</creatorcontrib><creatorcontrib>Barral, Sandra</creatorcontrib><creatorcontrib>van Buchem, Mark A</creatorcontrib><creatorcontrib>van der Grond, Jeroen</creatorcontrib><creatorcontrib>Smith, Albert V</creatorcontrib><creatorcontrib>Hegenscheid, Katrin</creatorcontrib><creatorcontrib>Aggarwal, Neelum T</creatorcontrib><creatorcontrib>de Andrade, Mariza</creatorcontrib><creatorcontrib>Atkinson, Elizabeth J</creatorcontrib><creatorcontrib>Beekman, Marian</creatorcontrib><creatorcontrib>Beiser, Alexa S</creatorcontrib><creatorcontrib>Blanton, Susan H</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Brickman, Adam M</creatorcontrib><creatorcontrib>Bryan, R Nick</creatorcontrib><creatorcontrib>Chauhan, Ganesh</creatorcontrib><creatorcontrib>Chen, Christopher P.L.H</creatorcontrib><creatorcontrib>Chouraki, Vincent</creatorcontrib><creatorcontrib>de Craen, Anton J.M</creatorcontrib><creatorcontrib>Crivello, Fabrice</creatorcontrib><creatorcontrib>Deary, Ian J</creatorcontrib><creatorcontrib>Deelen, Joris</creatorcontrib><creatorcontrib>De Jager, Philip L</creatorcontrib><creatorcontrib>Dufouil, Carole</creatorcontrib><creatorcontrib>Elkind, Mitchell S.V</creatorcontrib><creatorcontrib>Evans, Denis A</creatorcontrib><creatorcontrib>Freudenberger, Paul</creatorcontrib><creatorcontrib>Gottesman, Rebecca F</creatorcontrib><creatorcontrib>Gunason, Vilmundur</creatorcontrib><creatorcontrib>Habes, Mohamad</creatorcontrib><creatorcontrib>Heckbert, Susan R</creatorcontrib><creatorcontrib>Heiss, Gerardo</creatorcontrib><creatorcontrib>Hilal, Saima</creatorcontrib><creatorcontrib>Hofer, Edith</creatorcontrib><creatorcontrib>Hofman, Albert</creatorcontrib><creatorcontrib>Knopman, David S</creatorcontrib><creatorcontrib>Lewis, Cora E</creatorcontrib><creatorcontrib>Liao, Jiemin</creatorcontrib><creatorcontrib>Liewald, David C.M</creatorcontrib><creatorcontrib>Luciano, Michelle</creatorcontrib><creatorcontrib>van der Lugt, Aad</creatorcontrib><creatorcontrib>Martinez, Oliver O</creatorcontrib><creatorcontrib>Mayeux, Richard</creatorcontrib><creatorcontrib>Mazoyer, Bernard</creatorcontrib><creatorcontrib>Nalls, Mike</creatorcontrib><creatorcontrib>Nauck, Matthias</creatorcontrib><creatorcontrib>Niessen, Wiro J</creatorcontrib><creatorcontrib>Oostra, Ben A</creatorcontrib><creatorcontrib>Psaty, Bruce M</creatorcontrib><creatorcontrib>Rice, Kenneth M</creatorcontrib><creatorcontrib>Rotter, Jerome I</creatorcontrib><creatorcontrib>von Sarnowski, Bettina</creatorcontrib><creatorcontrib>Schmidt, Helena</creatorcontrib><creatorcontrib>Schreiner, Pamela J</creatorcontrib><creatorcontrib>Schuur, Maaike</creatorcontrib><creatorcontrib>Sidney, Stephen S</creatorcontrib><creatorcontrib>Sigurdsson, Sigurdur</creatorcontrib><creatorcontrib>Slagboom, P Eline</creatorcontrib><creatorcontrib>Stott, David J.M</creatorcontrib><creatorcontrib>van Swieten, John C</creatorcontrib><creatorcontrib>Teumer, Alexander</creatorcontrib><creatorcontrib>Töglhofer, Anna Maria</creatorcontrib><creatorcontrib>Traylor, Matthew</creatorcontrib><creatorcontrib>Trompet, Stella</creatorcontrib><creatorcontrib>Turner, Stephen T</creatorcontrib><creatorcontrib>Tzourio, Christophe</creatorcontrib><creatorcontrib>Uh, Hae-Won</creatorcontrib><creatorcontrib>Uitterlinden, André G</creatorcontrib><creatorcontrib>Vernooij, Meike W</creatorcontrib><creatorcontrib>Wang, Jing J</creatorcontrib><creatorcontrib>Wong, Tien Y</creatorcontrib><creatorcontrib>Wardlaw, Joanna M</creatorcontrib><creatorcontrib>Windham, B Gwen</creatorcontrib><creatorcontrib>Wittfeld, Katharina</creatorcontrib><creatorcontrib>Wolf, Christiane</creatorcontrib><creatorcontrib>Wright, Clinton B</creatorcontrib><creatorcontrib>Yang, Qiong</creatorcontrib><creatorcontrib>Zhao, Wei</creatorcontrib><creatorcontrib>Zijdenbos, Alex</creatorcontrib><creatorcontrib>Jukema, J Wouter</creatorcontrib><creatorcontrib>Sacco, Ralph L</creatorcontrib><creatorcontrib>Kardia, Sharon L.R</creatorcontrib><creatorcontrib>Mosley, Thomas H</creatorcontrib><creatorcontrib>Longstreth, W T</creatorcontrib><creatorcontrib>DeCarli, Charles C</creatorcontrib><creatorcontrib>van Duijn, Cornelia M</creatorcontrib><creatorcontrib>Schmidt, Reinhold</creatorcontrib><creatorcontrib>Launer, Lenore J</creatorcontrib><creatorcontrib>Grabe, Hans J</creatorcontrib><creatorcontrib>Seshadri, Sudha S</creatorcontrib><creatorcontrib>Ikram, M Arfan</creatorcontrib><creatorcontrib>Fornage, Myriam</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>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Circulation. Cardiovascular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Verhaaren, Benjamin F.J</au><au>Debette, Stéphanie</au><au>Bis, Joshua C</au><au>Smith, Jennifer A</au><au>Ikram, M Kamran</au><au>Adams, Hieab H</au><au>Beecham, Ashley H</au><au>Rajan, Kumar B</au><au>Lopez, Lorna M</au><au>Barral, Sandra</au><au>van Buchem, Mark A</au><au>van der Grond, Jeroen</au><au>Smith, Albert V</au><au>Hegenscheid, Katrin</au><au>Aggarwal, Neelum T</au><au>de Andrade, Mariza</au><au>Atkinson, Elizabeth J</au><au>Beekman, Marian</au><au>Beiser, Alexa S</au><au>Blanton, Susan H</au><au>Boerwinkle, Eric</au><au>Brickman, Adam M</au><au>Bryan, R Nick</au><au>Chauhan, Ganesh</au><au>Chen, Christopher P.L.H</au><au>Chouraki, Vincent</au><au>de Craen, Anton J.M</au><au>Crivello, Fabrice</au><au>Deary, Ian J</au><au>Deelen, Joris</au><au>De Jager, Philip L</au><au>Dufouil, Carole</au><au>Elkind, Mitchell S.V</au><au>Evans, Denis A</au><au>Freudenberger, Paul</au><au>Gottesman, Rebecca F</au><au>Gunason, Vilmundur</au><au>Habes, Mohamad</au><au>Heckbert, Susan R</au><au>Heiss, Gerardo</au><au>Hilal, Saima</au><au>Hofer, Edith</au><au>Hofman, Albert</au><au>Knopman, David S</au><au>Lewis, Cora E</au><au>Liao, Jiemin</au><au>Liewald, David C.M</au><au>Luciano, Michelle</au><au>van der Lugt, Aad</au><au>Martinez, Oliver O</au><au>Mayeux, Richard</au><au>Mazoyer, Bernard</au><au>Nalls, Mike</au><au>Nauck, Matthias</au><au>Niessen, Wiro J</au><au>Oostra, Ben A</au><au>Psaty, Bruce M</au><au>Rice, Kenneth M</au><au>Rotter, Jerome I</au><au>von Sarnowski, Bettina</au><au>Schmidt, Helena</au><au>Schreiner, Pamela J</au><au>Schuur, Maaike</au><au>Sidney, Stephen S</au><au>Sigurdsson, Sigurdur</au><au>Slagboom, P Eline</au><au>Stott, David J.M</au><au>van Swieten, John C</au><au>Teumer, Alexander</au><au>Töglhofer, Anna Maria</au><au>Traylor, Matthew</au><au>Trompet, Stella</au><au>Turner, Stephen T</au><au>Tzourio, Christophe</au><au>Uh, Hae-Won</au><au>Uitterlinden, André G</au><au>Vernooij, Meike W</au><au>Wang, Jing J</au><au>Wong, Tien Y</au><au>Wardlaw, Joanna M</au><au>Windham, B Gwen</au><au>Wittfeld, Katharina</au><au>Wolf, Christiane</au><au>Wright, Clinton B</au><au>Yang, Qiong</au><au>Zhao, Wei</au><au>Zijdenbos, Alex</au><au>Jukema, J Wouter</au><au>Sacco, Ralph L</au><au>Kardia, Sharon L.R</au><au>Mosley, Thomas H</au><au>Longstreth, W T</au><au>DeCarli, Charles C</au><au>van Duijn, Cornelia M</au><au>Schmidt, Reinhold</au><au>Launer, Lenore J</au><au>Grabe, Hans J</au><au>Seshadri, Sudha S</au><au>Ikram, M Arfan</au><au>Fornage, Myriam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI</atitle><jtitle>Circulation. Cardiovascular genetics</jtitle><addtitle>Circ Cardiovasc Genet</addtitle><date>2015-04</date><risdate>2015</risdate><volume>8</volume><issue>2</issue><spage>398</spage><epage>409</epage><pages>398-409</pages><issn>1942-325X</issn><eissn>1942-3268</eissn><abstract>BACKGROUND—The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS—We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10) and identified novel loci on chr10q24 (P=1.6×10) and chr2p21 (P=4.4×10). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10) and chr2p16 (P=1.5×10). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS—We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>25663218</pmid><doi>10.1161/CIRCGENETICS.114.000858</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-0970-2837</orcidid><orcidid>https://orcid.org/0000-0001-6950-984X</orcidid><orcidid>https://orcid.org/0000-0001-9088-234X</orcidid><orcidid>https://orcid.org/0000-0002-4698-1794</orcidid><orcidid>https://orcid.org/0000-0002-6517-2984</orcidid><orcidid>https://orcid.org/0000-0001-8675-7968</orcidid><orcidid>https://orcid.org/0000-0003-2442-4476</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1942-325X |
| ispartof | Circulation. Cardiovascular genetics, 2015-04, Vol.8 (2), p.398-409 |
| issn | 1942-325X 1942-3268 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_01198723v1 |
| source | MEDLINE; American Heart Association Journals |
| subjects | Aged Aged, 80 and over Chromosomes, Human - genetics Cognitive science Female Genetic Loci Genome-Wide Association Study Humans Male Meta-Analysis as Topic Middle Aged Models, Genetic Neuroscience Racial Groups Stroke - ethnology Stroke - genetics Stroke - pathology White Matter |
| title | Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI |
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