Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting
OBJECTIVETo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODSWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-def...
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| Veröffentlicht in: | Neurology 2019-01, Vol.92 (5), p.e486-e503 |
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| creator | Bis, Joshua C Smith, Albert Vernon Saba, Yasaman Luciano, Michelle Bastin, Mark E Lemmens, Robin Ames, David Chong, Elizabeth van der Lugt, Aad Jimenez-Conde, Jordi Rundek, Tatjana Arnett, Donna K Jern, Christina Johnson, Julie A Benavente, Oscar R Geerlings, Mirjam I Tzourio, Christophe Sachdev, Perminder S Markus, Hugh S Seshadri, Sudha Anderson, Christopher D de Bakker, Paul IW Engström, Gunnar Kissela, Brett M Pera, Joanna Soriano-Tárraga, Carolina Stanne, Tara Nyquist, Paul Drazyk, Anna Markus, Hugh Chasman, Daniel Elkind, Mitchell Bijlenga, Philippe Yue, Suo Mateen, Farrah Meschia, James Pare, Guillaume Klijn, Karin Kamatani, Yoichiro Tregouet, David Carrera, Caty Ruigrok, Ynte Sargurupremraj, Murali Liebeskind, David Tan, Rhea Broderick, Joseph Sale, Michele Konrad, Jan Nordestgaard, Børge G Psaty, Bruce M Benn, Marianne Farrall, Martin Nalls, Mike Oliveira, Sofia A Becker, James T Carlsson, Cynthia M Carney, Regina M Crocco, Elizabeth A Faber, Kelley M Farlow, Martin R Farrer, Lindsay A Gearing, Marla Gilbert, John R Hamilton-Nelson, Kara L Haroutunian, Vahram Huebinger, Ryan M Kukull, Walter A Lah, James J Li, Ge Lunetta, Kathryn L Mack, Wendy J Manly, Jennifer J Masliah, Eliezer Miller, Carol A Pierce, Aimee Potter, Huntington Raj, Ashok Sano, Mary Spina, Salvatore Tanzi, Rudolph E Vinters, Harry V Yu, Chang-En Yu, Lei Liu, Yongmei Johnson, Andrew D deStefano, Anita L van Buchem, Mark A Boerwinkle, Eric de Craen, Anton J.M Ibrahim-Verbaas, Carla A Oostra, Ben A Cupples, L Adrienne Meisinger, Christa Nambi, Vijay Halperin, Eran Orru, Marco Ernst, Florian Chilukoti, Ravi Kumar Wilson, James F Gudnason, Vilmundur |
| description | OBJECTIVETo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.
METHODSWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.
RESULTSThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BIFBN2, p = 1.77 × 10; and LINC00539/ZDHHC20, p = 5.82 × 10. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10; p[SSBI] = 5.23 × 10 for hypertension), smoking (p[BI] = 4.4 × 10; p[SSBI] = 1.2 × 10), diabetes (p[BI] = 1.7 × 10; p[SSBI] = 2.8 × 10), previous cardiovascular disease (p[BI] = 1.0 × 10; p[SSBI] = 2.3 × 10), stroke (p[BI] = 3.9 × 10; p[SSBI] = 3.2 × 10), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10; p[SSBI] = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.
CONCLUSIONIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. |
| doi_str_mv | 10.1212/WNL.0000000000006851 |
| format | Article |
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Smith, Albert Vernon ; Saba, Yasaman ; Luciano, Michelle ; Bastin, Mark E ; Lemmens, Robin ; Ames, David ; Chong, Elizabeth ; van der Lugt, Aad ; Jimenez-Conde, Jordi ; Rundek, Tatjana ; Arnett, Donna K ; Jern, Christina ; Johnson, Julie A ; Benavente, Oscar R ; Geerlings, Mirjam I ; Tzourio, Christophe ; Sachdev, Perminder S ; Markus, Hugh S ; Seshadri, Sudha ; Anderson, Christopher D ; de Bakker, Paul IW ; Engström, Gunnar ; Kissela, Brett M ; Pera, Joanna ; Soriano-Tárraga, Carolina ; Stanne, Tara ; Nyquist, Paul ; Drazyk, Anna ; Markus, Hugh ; Chasman, Daniel ; Elkind, Mitchell ; Bijlenga, Philippe ; Yue, Suo ; Mateen, Farrah ; Meschia, James ; Pare, Guillaume ; Klijn, Karin ; Kamatani, Yoichiro ; Tregouet, David ; Carrera, Caty ; Ruigrok, Ynte ; Sargurupremraj, Murali ; Liebeskind, David ; Tan, Rhea ; Broderick, Joseph ; Sale, Michele ; Konrad, Jan ; Nordestgaard, Børge G ; Psaty, Bruce M ; Benn, Marianne ; Farrall, Martin ; Nalls, Mike ; Oliveira, Sofia A ; Becker, James T ; Carlsson, Cynthia M ; Carney, Regina M ; Crocco, Elizabeth A ; Faber, Kelley M ; Farlow, Martin R ; Farrer, Lindsay A ; Gearing, Marla ; Gilbert, John R ; Hamilton-Nelson, Kara L ; Haroutunian, Vahram ; Huebinger, Ryan M ; Kukull, Walter A ; Lah, James J ; Li, Ge ; Lunetta, Kathryn L ; Mack, Wendy J ; Manly, Jennifer J ; Masliah, Eliezer ; Miller, Carol A ; Pierce, Aimee ; Potter, Huntington ; Raj, Ashok ; Sano, Mary ; Spina, Salvatore ; Tanzi, Rudolph E ; Vinters, Harry V ; Yu, Chang-En ; Yu, Lei ; Liu, Yongmei ; Johnson, Andrew D ; deStefano, Anita L ; van Buchem, Mark A ; Boerwinkle, Eric ; de Craen, Anton J.M ; Ibrahim-Verbaas, Carla A ; Oostra, Ben A ; Cupples, L Adrienne ; Meisinger, Christa ; Nambi, Vijay ; Halperin, Eran ; Orru, Marco ; Ernst, Florian ; Chilukoti, Ravi Kumar ; Wilson, James F ; Gudnason, Vilmundur</creator><creatorcontrib>Bis, Joshua C ; Smith, Albert Vernon ; Saba, Yasaman ; Luciano, Michelle ; Bastin, Mark E ; Lemmens, Robin ; Ames, David ; Chong, Elizabeth ; van der Lugt, Aad ; Jimenez-Conde, Jordi ; Rundek, Tatjana ; Arnett, Donna K ; Jern, Christina ; Johnson, Julie A ; Benavente, Oscar R ; Geerlings, Mirjam I ; Tzourio, Christophe ; Sachdev, Perminder S ; Markus, Hugh S ; Seshadri, Sudha ; Anderson, Christopher D ; de Bakker, Paul IW ; Engström, Gunnar ; Kissela, Brett M ; Pera, Joanna ; Soriano-Tárraga, Carolina ; Stanne, Tara ; Nyquist, Paul ; Drazyk, Anna ; Markus, Hugh ; Chasman, Daniel ; Elkind, Mitchell ; Bijlenga, Philippe ; Yue, Suo ; Mateen, Farrah ; Meschia, James ; Pare, Guillaume ; Klijn, Karin ; Kamatani, Yoichiro ; Tregouet, David ; Carrera, Caty ; Ruigrok, Ynte ; Sargurupremraj, Murali ; Liebeskind, David ; Tan, Rhea ; Broderick, Joseph ; Sale, Michele ; Konrad, Jan ; Nordestgaard, Børge G ; Psaty, Bruce M ; Benn, Marianne ; Farrall, Martin ; Nalls, Mike ; Oliveira, Sofia A ; Becker, James T ; Carlsson, Cynthia M ; Carney, Regina M ; Crocco, Elizabeth A ; Faber, Kelley M ; Farlow, Martin R ; Farrer, Lindsay A ; Gearing, Marla ; Gilbert, John R ; Hamilton-Nelson, Kara L ; Haroutunian, Vahram ; Huebinger, Ryan M ; Kukull, Walter A ; Lah, James J ; Li, Ge ; Lunetta, Kathryn L ; Mack, Wendy J ; Manly, Jennifer J ; Masliah, Eliezer ; Miller, Carol A ; Pierce, Aimee ; Potter, Huntington ; Raj, Ashok ; Sano, Mary ; Spina, Salvatore ; Tanzi, Rudolph E ; Vinters, Harry V ; Yu, Chang-En ; Yu, Lei ; Liu, Yongmei ; Johnson, Andrew D ; deStefano, Anita L ; van Buchem, Mark A ; Boerwinkle, Eric ; de Craen, Anton J.M ; Ibrahim-Verbaas, Carla A ; Oostra, Ben A ; Cupples, L Adrienne ; Meisinger, Christa ; Nambi, Vijay ; Halperin, Eran ; Orru, Marco ; Ernst, Florian ; Chilukoti, Ravi Kumar ; Wilson, James F ; Gudnason, Vilmundur ; Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ; et al</creatorcontrib><description>OBJECTIVETo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.
METHODSWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.
RESULTSThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BIFBN2, p = 1.77 × 10; and LINC00539/ZDHHC20, p = 5.82 × 10. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10; p[SSBI] = 5.23 × 10 for hypertension), smoking (p[BI] = 4.4 × 10; p[SSBI] = 1.2 × 10), diabetes (p[BI] = 1.7 × 10; p[SSBI] = 2.8 × 10), previous cardiovascular disease (p[BI] = 1.0 × 10; p[SSBI] = 2.3 × 10), stroke (p[BI] = 3.9 × 10; p[SSBI] = 3.2 × 10), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10; p[SSBI] = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.
CONCLUSIONIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.</description><identifier>ISSN: 0028-3878</identifier><identifier>ISSN: 1526-632X</identifier><identifier>EISSN: 1526-632X</identifier><identifier>DOI: 10.1212/WNL.0000000000006851</identifier><identifier>PMID: 30651383</identifier><language>eng</language><publisher>United States: American Academy of Neurology</publisher><subject>Basic Medicine ; blood-pressure ; disease ; Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ; genome-wide association ; Health Sciences ; Hälsovetenskap ; insights ; ischemic-stroke ; Life Sciences ; matter hyperintensity volume ; Medical and Health Sciences ; Medical Genetics ; Medicin och hälsovetenskap ; Medicinsk genetik ; Medicinska och farmaceutiska grundvetenskaper ; mendelian randomization ; metaanalysis ; Neurosciences ; Neurosciences & Neurology ; Neurovetenskaper ; polymorphisms ; Public Health, Global Health, Social Medicine and Epidemiology ; Santé publique et épidémiologie ; silent ; small vessel</subject><ispartof>Neurology, 2019-01, Vol.92 (5), p.e486-e503</ispartof><rights>2019 American Academy of Neurology</rights><rights>Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 2019 American Academy of Neurology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c7771-a7416ae7190988d6afd139b0c47c33af14bb3eb3f4a6e7f2548b12f0d302931c3</citedby><cites>FETCH-LOGICAL-c7771-a7416ae7190988d6afd139b0c47c33af14bb3eb3f4a6e7f2548b12f0d302931c3</cites><orcidid>0000-0002-8309-094X ; 0000-0002-2502-3669 ; 0000-0001-5185-6384 ; 0000-0001-9574-6195 ; 0000-0003-0585-6206 ; 0000-0003-2967-9662 ; 0000-0003-3684-4208 ; 0000-0002-9595-3220 ; 0000-0003-0970-2837 ; 0000-0001-9088-234X ; 0000-0002-8057-2505</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,550,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30651383$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-02457571$$DView record in HAL$$Hfree_for_read</backlink><backlink>$$Uhttps://gup.ub.gu.se/publication/279500$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/8e729b7e-2a77-47b8-ac26-34b031890ed6$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:140618910$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Bis, Joshua C</creatorcontrib><creatorcontrib>Smith, Albert Vernon</creatorcontrib><creatorcontrib>Saba, Yasaman</creatorcontrib><creatorcontrib>Luciano, Michelle</creatorcontrib><creatorcontrib>Bastin, Mark E</creatorcontrib><creatorcontrib>Lemmens, Robin</creatorcontrib><creatorcontrib>Ames, David</creatorcontrib><creatorcontrib>Chong, Elizabeth</creatorcontrib><creatorcontrib>van der Lugt, Aad</creatorcontrib><creatorcontrib>Jimenez-Conde, Jordi</creatorcontrib><creatorcontrib>Rundek, Tatjana</creatorcontrib><creatorcontrib>Arnett, Donna K</creatorcontrib><creatorcontrib>Jern, Christina</creatorcontrib><creatorcontrib>Johnson, Julie A</creatorcontrib><creatorcontrib>Benavente, Oscar R</creatorcontrib><creatorcontrib>Geerlings, Mirjam I</creatorcontrib><creatorcontrib>Tzourio, Christophe</creatorcontrib><creatorcontrib>Sachdev, Perminder S</creatorcontrib><creatorcontrib>Markus, Hugh S</creatorcontrib><creatorcontrib>Seshadri, Sudha</creatorcontrib><creatorcontrib>Anderson, Christopher D</creatorcontrib><creatorcontrib>de Bakker, Paul IW</creatorcontrib><creatorcontrib>Engström, Gunnar</creatorcontrib><creatorcontrib>Kissela, Brett M</creatorcontrib><creatorcontrib>Pera, Joanna</creatorcontrib><creatorcontrib>Soriano-Tárraga, Carolina</creatorcontrib><creatorcontrib>Stanne, Tara</creatorcontrib><creatorcontrib>Nyquist, Paul</creatorcontrib><creatorcontrib>Drazyk, Anna</creatorcontrib><creatorcontrib>Markus, Hugh</creatorcontrib><creatorcontrib>Chasman, Daniel</creatorcontrib><creatorcontrib>Elkind, Mitchell</creatorcontrib><creatorcontrib>Bijlenga, Philippe</creatorcontrib><creatorcontrib>Yue, Suo</creatorcontrib><creatorcontrib>Mateen, Farrah</creatorcontrib><creatorcontrib>Meschia, James</creatorcontrib><creatorcontrib>Pare, Guillaume</creatorcontrib><creatorcontrib>Klijn, Karin</creatorcontrib><creatorcontrib>Kamatani, Yoichiro</creatorcontrib><creatorcontrib>Tregouet, David</creatorcontrib><creatorcontrib>Carrera, Caty</creatorcontrib><creatorcontrib>Ruigrok, Ynte</creatorcontrib><creatorcontrib>Sargurupremraj, Murali</creatorcontrib><creatorcontrib>Liebeskind, David</creatorcontrib><creatorcontrib>Tan, Rhea</creatorcontrib><creatorcontrib>Broderick, Joseph</creatorcontrib><creatorcontrib>Sale, Michele</creatorcontrib><creatorcontrib>Konrad, Jan</creatorcontrib><creatorcontrib>Nordestgaard, Børge G</creatorcontrib><creatorcontrib>Psaty, Bruce M</creatorcontrib><creatorcontrib>Benn, Marianne</creatorcontrib><creatorcontrib>Farrall, Martin</creatorcontrib><creatorcontrib>Nalls, Mike</creatorcontrib><creatorcontrib>Oliveira, Sofia A</creatorcontrib><creatorcontrib>Becker, James T</creatorcontrib><creatorcontrib>Carlsson, Cynthia M</creatorcontrib><creatorcontrib>Carney, Regina M</creatorcontrib><creatorcontrib>Crocco, Elizabeth A</creatorcontrib><creatorcontrib>Faber, Kelley M</creatorcontrib><creatorcontrib>Farlow, Martin R</creatorcontrib><creatorcontrib>Farrer, Lindsay A</creatorcontrib><creatorcontrib>Gearing, Marla</creatorcontrib><creatorcontrib>Gilbert, John R</creatorcontrib><creatorcontrib>Hamilton-Nelson, Kara L</creatorcontrib><creatorcontrib>Haroutunian, Vahram</creatorcontrib><creatorcontrib>Huebinger, Ryan M</creatorcontrib><creatorcontrib>Kukull, Walter A</creatorcontrib><creatorcontrib>Lah, James J</creatorcontrib><creatorcontrib>Li, Ge</creatorcontrib><creatorcontrib>Lunetta, Kathryn L</creatorcontrib><creatorcontrib>Mack, Wendy J</creatorcontrib><creatorcontrib>Manly, Jennifer J</creatorcontrib><creatorcontrib>Masliah, Eliezer</creatorcontrib><creatorcontrib>Miller, Carol A</creatorcontrib><creatorcontrib>Pierce, Aimee</creatorcontrib><creatorcontrib>Potter, Huntington</creatorcontrib><creatorcontrib>Raj, Ashok</creatorcontrib><creatorcontrib>Sano, Mary</creatorcontrib><creatorcontrib>Spina, Salvatore</creatorcontrib><creatorcontrib>Tanzi, Rudolph E</creatorcontrib><creatorcontrib>Vinters, Harry V</creatorcontrib><creatorcontrib>Yu, Chang-En</creatorcontrib><creatorcontrib>Yu, Lei</creatorcontrib><creatorcontrib>Liu, Yongmei</creatorcontrib><creatorcontrib>Johnson, Andrew D</creatorcontrib><creatorcontrib>deStefano, Anita L</creatorcontrib><creatorcontrib>van Buchem, Mark A</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>de Craen, Anton J.M</creatorcontrib><creatorcontrib>Ibrahim-Verbaas, Carla A</creatorcontrib><creatorcontrib>Oostra, Ben A</creatorcontrib><creatorcontrib>Cupples, L Adrienne</creatorcontrib><creatorcontrib>Meisinger, Christa</creatorcontrib><creatorcontrib>Nambi, Vijay</creatorcontrib><creatorcontrib>Halperin, Eran</creatorcontrib><creatorcontrib>Orru, Marco</creatorcontrib><creatorcontrib>Ernst, Florian</creatorcontrib><creatorcontrib>Chilukoti, Ravi Kumar</creatorcontrib><creatorcontrib>Wilson, James F</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium</creatorcontrib><creatorcontrib>et al</creatorcontrib><title>Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting</title><title>Neurology</title><addtitle>Neurology</addtitle><description>OBJECTIVETo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.
METHODSWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.
RESULTSThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BIFBN2, p = 1.77 × 10; and LINC00539/ZDHHC20, p = 5.82 × 10. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10; p[SSBI] = 5.23 × 10 for hypertension), smoking (p[BI] = 4.4 × 10; p[SSBI] = 1.2 × 10), diabetes (p[BI] = 1.7 × 10; p[SSBI] = 2.8 × 10), previous cardiovascular disease (p[BI] = 1.0 × 10; p[SSBI] = 2.3 × 10), stroke (p[BI] = 3.9 × 10; p[SSBI] = 3.2 × 10), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10; p[SSBI] = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.
CONCLUSIONIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.</description><subject>Basic Medicine</subject><subject>blood-pressure</subject><subject>disease</subject><subject>Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi</subject><subject>genome-wide association</subject><subject>Health Sciences</subject><subject>Hälsovetenskap</subject><subject>insights</subject><subject>ischemic-stroke</subject><subject>Life Sciences</subject><subject>matter hyperintensity volume</subject><subject>Medical and Health Sciences</subject><subject>Medical Genetics</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicinsk genetik</subject><subject>Medicinska och farmaceutiska grundvetenskaper</subject><subject>mendelian randomization</subject><subject>metaanalysis</subject><subject>Neurosciences</subject><subject>Neurosciences & Neurology</subject><subject>Neurovetenskaper</subject><subject>polymorphisms</subject><subject>Public Health, Global Health, Social Medicine and Epidemiology</subject><subject>Santé publique et épidémiologie</subject><subject>silent</subject><subject>small vessel</subject><issn>0028-3878</issn><issn>1526-632X</issn><issn>1526-632X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>D8T</sourceid><recordid>eNp9kl1rFDEUhgdR7Fr9ByJz6YVT8zGTjxuhFG0Lq4IoeheSzMlu3Gxmm8x06b9v2l1LW7CBQw4nz_sekpyqeovRESaYfPz9bX6E7i0mOvysmuGOsIZR8ud5NUOIiIYKLg6qVzn_RagccvmyOqCIdZgKOqvUKUQYva117OvgHeTxKkCdfF7VTttxSLl2Q6q__jhvenA-Ql-bpH2sfXQ62TGXpNb1ZthMQY9-iI3RuUAZxtHHxevqhdMhw5v9flj9-vL558lZM_9-en5yPG8s5xw3mreYaeBYIilEz7TrMZUG2ZZbSrXDrTEUDHWtZsAd6VphMHGop4hIii09rJqdb97CZjJqk_xapys1aK_2pVXJQLWCcCoLP_8vH6ZNCVPiRiCAE2k4KKI5Vy03QmlLmKKtQRQLiaBnT7ZfFLtSWty6lffvECr8px1f4DX0FuKYdHgge3gS_VIthkvFKJMSdcXgw85g-Uh2djxXPmZIa4VI2_GO40tc8Pf7fmm4mMonq7XPFkLQEYYpK4K5pIJ0jBa03aE2DTkncHf2GKmbyVNl8tTjySuyd_dvdCf6N2oFEDtgO4QRUl6FaQtJLUGHcfm09zUwQOZ3</recordid><startdate>20190129</startdate><enddate>20190129</enddate><creator>Bis, Joshua C</creator><creator>Smith, Albert Vernon</creator><creator>Saba, Yasaman</creator><creator>Luciano, Michelle</creator><creator>Bastin, Mark E</creator><creator>Lemmens, Robin</creator><creator>Ames, David</creator><creator>Chong, Elizabeth</creator><creator>van der Lugt, Aad</creator><creator>Jimenez-Conde, Jordi</creator><creator>Rundek, Tatjana</creator><creator>Arnett, Donna K</creator><creator>Jern, Christina</creator><creator>Johnson, Julie A</creator><creator>Benavente, Oscar R</creator><creator>Geerlings, Mirjam I</creator><creator>Tzourio, Christophe</creator><creator>Sachdev, Perminder S</creator><creator>Markus, Hugh S</creator><creator>Seshadri, Sudha</creator><creator>Anderson, Christopher D</creator><creator>de Bakker, Paul IW</creator><creator>Engström, Gunnar</creator><creator>Kissela, Brett M</creator><creator>Pera, Joanna</creator><creator>Soriano-Tárraga, Carolina</creator><creator>Stanne, Tara</creator><creator>Nyquist, Paul</creator><creator>Drazyk, Anna</creator><creator>Markus, Hugh</creator><creator>Chasman, 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MRI-defined brain infarcts in a population-based setting</title><author>Bis, Joshua C ; Smith, Albert Vernon ; Saba, Yasaman ; Luciano, Michelle ; Bastin, Mark E ; Lemmens, Robin ; Ames, David ; Chong, Elizabeth ; van der Lugt, Aad ; Jimenez-Conde, Jordi ; Rundek, Tatjana ; Arnett, Donna K ; Jern, Christina ; Johnson, Julie A ; Benavente, Oscar R ; Geerlings, Mirjam I ; Tzourio, Christophe ; Sachdev, Perminder S ; Markus, Hugh S ; Seshadri, Sudha ; Anderson, Christopher D ; de Bakker, Paul IW ; Engström, Gunnar ; Kissela, Brett M ; Pera, Joanna ; Soriano-Tárraga, Carolina ; Stanne, Tara ; Nyquist, Paul ; Drazyk, Anna ; Markus, Hugh ; Chasman, Daniel ; Elkind, Mitchell ; Bijlenga, Philippe ; Yue, Suo ; Mateen, Farrah ; Meschia, James ; Pare, Guillaume ; Klijn, Karin ; Kamatani, Yoichiro ; Tregouet, David ; Carrera, Caty ; Ruigrok, Ynte ; Sargurupremraj, Murali ; Liebeskind, David ; Tan, Rhea ; Broderick, Joseph ; Sale, Michele ; Konrad, Jan ; Nordestgaard, Børge G ; Psaty, Bruce M ; Benn, Marianne ; Farrall, Martin ; Nalls, Mike ; Oliveira, Sofia A ; Becker, James T ; Carlsson, Cynthia M ; Carney, Regina M ; Crocco, Elizabeth A ; Faber, Kelley M ; Farlow, Martin R ; Farrer, Lindsay A ; Gearing, Marla ; Gilbert, John R ; Hamilton-Nelson, Kara L ; Haroutunian, Vahram ; Huebinger, Ryan M ; Kukull, Walter A ; Lah, James J ; Li, Ge ; Lunetta, Kathryn L ; Mack, Wendy J ; Manly, Jennifer J ; Masliah, Eliezer ; Miller, Carol A ; Pierce, Aimee ; Potter, Huntington ; Raj, Ashok ; Sano, Mary ; Spina, Salvatore ; Tanzi, Rudolph E ; Vinters, Harry V ; Yu, Chang-En ; Yu, Lei ; Liu, Yongmei ; Johnson, Andrew D ; deStefano, Anita L ; van Buchem, Mark A ; Boerwinkle, Eric ; de Craen, Anton J.M ; Ibrahim-Verbaas, Carla A ; Oostra, Ben A ; Cupples, L Adrienne ; Meisinger, Christa ; Nambi, Vijay ; Halperin, Eran ; Orru, Marco ; Ernst, Florian ; Chilukoti, Ravi Kumar ; Wilson, James F ; Gudnason, Vilmundur</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c7771-a7416ae7190988d6afd139b0c47c33af14bb3eb3f4a6e7f2548b12f0d302931c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Basic Medicine</topic><topic>blood-pressure</topic><topic>disease</topic><topic>Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi</topic><topic>genome-wide association</topic><topic>Health Sciences</topic><topic>Hälsovetenskap</topic><topic>insights</topic><topic>ischemic-stroke</topic><topic>Life Sciences</topic><topic>matter hyperintensity volume</topic><topic>Medical and Health Sciences</topic><topic>Medical Genetics</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicinsk genetik</topic><topic>Medicinska och farmaceutiska grundvetenskaper</topic><topic>mendelian randomization</topic><topic>metaanalysis</topic><topic>Neurosciences</topic><topic>Neurosciences & 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Aimee</creatorcontrib><creatorcontrib>Potter, Huntington</creatorcontrib><creatorcontrib>Raj, Ashok</creatorcontrib><creatorcontrib>Sano, Mary</creatorcontrib><creatorcontrib>Spina, Salvatore</creatorcontrib><creatorcontrib>Tanzi, Rudolph E</creatorcontrib><creatorcontrib>Vinters, Harry V</creatorcontrib><creatorcontrib>Yu, Chang-En</creatorcontrib><creatorcontrib>Yu, Lei</creatorcontrib><creatorcontrib>Liu, Yongmei</creatorcontrib><creatorcontrib>Johnson, Andrew D</creatorcontrib><creatorcontrib>deStefano, Anita L</creatorcontrib><creatorcontrib>van Buchem, Mark A</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>de Craen, Anton J.M</creatorcontrib><creatorcontrib>Ibrahim-Verbaas, Carla A</creatorcontrib><creatorcontrib>Oostra, Ben A</creatorcontrib><creatorcontrib>Cupples, L Adrienne</creatorcontrib><creatorcontrib>Meisinger, Christa</creatorcontrib><creatorcontrib>Nambi, Vijay</creatorcontrib><creatorcontrib>Halperin, Eran</creatorcontrib><creatorcontrib>Orru, Marco</creatorcontrib><creatorcontrib>Ernst, Florian</creatorcontrib><creatorcontrib>Chilukoti, Ravi Kumar</creatorcontrib><creatorcontrib>Wilson, James F</creatorcontrib><creatorcontrib>Gudnason, Vilmundur</creatorcontrib><creatorcontrib>Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium</creatorcontrib><creatorcontrib>et al</creatorcontrib><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><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Göteborgs universitet</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Lunds universitet</collection><collection>SwePub Articles full text</collection><jtitle>Neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bis, Joshua C</au><au>Smith, Albert Vernon</au><au>Saba, Yasaman</au><au>Luciano, Michelle</au><au>Bastin, Mark E</au><au>Lemmens, Robin</au><au>Ames, David</au><au>Chong, Elizabeth</au><au>van der Lugt, Aad</au><au>Jimenez-Conde, Jordi</au><au>Rundek, Tatjana</au><au>Arnett, Donna K</au><au>Jern, Christina</au><au>Johnson, Julie A</au><au>Benavente, Oscar R</au><au>Geerlings, Mirjam I</au><au>Tzourio, Christophe</au><au>Sachdev, Perminder S</au><au>Markus, Hugh S</au><au>Seshadri, Sudha</au><au>Anderson, Christopher D</au><au>de Bakker, Paul IW</au><au>Engström, Gunnar</au><au>Kissela, Brett M</au><au>Pera, Joanna</au><au>Soriano-Tárraga, Carolina</au><au>Stanne, Tara</au><au>Nyquist, Paul</au><au>Drazyk, Anna</au><au>Markus, Hugh</au><au>Chasman, Daniel</au><au>Elkind, Mitchell</au><au>Bijlenga, Philippe</au><au>Yue, Suo</au><au>Mateen, Farrah</au><au>Meschia, James</au><au>Pare, Guillaume</au><au>Klijn, Karin</au><au>Kamatani, Yoichiro</au><au>Tregouet, David</au><au>Carrera, Caty</au><au>Ruigrok, Ynte</au><au>Sargurupremraj, Murali</au><au>Liebeskind, David</au><au>Tan, Rhea</au><au>Broderick, Joseph</au><au>Sale, Michele</au><au>Konrad, Jan</au><au>Nordestgaard, Børge G</au><au>Psaty, Bruce M</au><au>Benn, Marianne</au><au>Farrall, Martin</au><au>Nalls, Mike</au><au>Oliveira, Sofia A</au><au>Becker, James T</au><au>Carlsson, Cynthia M</au><au>Carney, Regina M</au><au>Crocco, Elizabeth A</au><au>Faber, Kelley M</au><au>Farlow, Martin R</au><au>Farrer, Lindsay A</au><au>Gearing, Marla</au><au>Gilbert, John R</au><au>Hamilton-Nelson, Kara L</au><au>Haroutunian, Vahram</au><au>Huebinger, Ryan M</au><au>Kukull, Walter A</au><au>Lah, James J</au><au>Li, Ge</au><au>Lunetta, Kathryn L</au><au>Mack, Wendy J</au><au>Manly, Jennifer J</au><au>Masliah, Eliezer</au><au>Miller, Carol A</au><au>Pierce, Aimee</au><au>Potter, Huntington</au><au>Raj, Ashok</au><au>Sano, Mary</au><au>Spina, Salvatore</au><au>Tanzi, Rudolph E</au><au>Vinters, Harry V</au><au>Yu, Chang-En</au><au>Yu, Lei</au><au>Liu, Yongmei</au><au>Johnson, Andrew D</au><au>deStefano, Anita L</au><au>van Buchem, Mark A</au><au>Boerwinkle, Eric</au><au>de Craen, Anton J.M</au><au>Ibrahim-Verbaas, Carla A</au><au>Oostra, Ben A</au><au>Cupples, L Adrienne</au><au>Meisinger, Christa</au><au>Nambi, Vijay</au><au>Halperin, Eran</au><au>Orru, Marco</au><au>Ernst, Florian</au><au>Chilukoti, Ravi Kumar</au><au>Wilson, James F</au><au>Gudnason, Vilmundur</au><aucorp>Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium</aucorp><aucorp>et al</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting</atitle><jtitle>Neurology</jtitle><addtitle>Neurology</addtitle><date>2019-01-29</date><risdate>2019</risdate><volume>92</volume><issue>5</issue><spage>e486</spage><epage>e503</epage><pages>e486-e503</pages><issn>0028-3878</issn><issn>1526-632X</issn><eissn>1526-632X</eissn><abstract>OBJECTIVETo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.
METHODSWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.
RESULTSThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BIFBN2, p = 1.77 × 10; and LINC00539/ZDHHC20, p = 5.82 × 10. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10; p[SSBI] = 5.23 × 10 for hypertension), smoking (p[BI] = 4.4 × 10; p[SSBI] = 1.2 × 10), diabetes (p[BI] = 1.7 × 10; p[SSBI] = 2.8 × 10), previous cardiovascular disease (p[BI] = 1.0 × 10; p[SSBI] = 2.3 × 10), stroke (p[BI] = 3.9 × 10; p[SSBI] = 3.2 × 10), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10; p[SSBI] = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.
CONCLUSIONIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.</abstract><cop>United States</cop><pub>American Academy of Neurology</pub><pmid>30651383</pmid><doi>10.1212/WNL.0000000000006851</doi><orcidid>https://orcid.org/0000-0002-8309-094X</orcidid><orcidid>https://orcid.org/0000-0002-2502-3669</orcidid><orcidid>https://orcid.org/0000-0001-5185-6384</orcidid><orcidid>https://orcid.org/0000-0001-9574-6195</orcidid><orcidid>https://orcid.org/0000-0003-0585-6206</orcidid><orcidid>https://orcid.org/0000-0003-2967-9662</orcidid><orcidid>https://orcid.org/0000-0003-3684-4208</orcidid><orcidid>https://orcid.org/0000-0002-9595-3220</orcidid><orcidid>https://orcid.org/0000-0003-0970-2837</orcidid><orcidid>https://orcid.org/0000-0001-9088-234X</orcidid><orcidid>https://orcid.org/0000-0002-8057-2505</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-3878 |
| ispartof | Neurology, 2019-01, Vol.92 (5), p.e486-e503 |
| issn | 0028-3878 1526-632X 1526-632X |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_482739 |
| source | Alma/SFX Local Collection; SWEPUB Freely available online; Journals@Ovid Complete |
| subjects | Basic Medicine blood-pressure disease Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi genome-wide association Health Sciences Hälsovetenskap insights ischemic-stroke Life Sciences matter hyperintensity volume Medical and Health Sciences Medical Genetics Medicin och hälsovetenskap Medicinsk genetik Medicinska och farmaceutiska grundvetenskaper mendelian randomization metaanalysis Neurosciences Neurosciences & Neurology Neurovetenskaper polymorphisms Public Health, Global Health, Social Medicine and Epidemiology Santé publique et épidémiologie silent small vessel |
| title | Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T22%3A18%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20and%20lifestyle%20risk%20factors%20for%20MRI-defined%20brain%20infarcts%20in%20a%20population-based%20setting&rft.jtitle=Neurology&rft.au=Bis,%20Joshua%20C&rft.aucorp=Stroke%20Genetics%20Network%20(SiGN),%20the%20International%20Stroke%20Genetics%20Consortium%20(ISGC),%20METASTROKE,%20Alzheimer's%20Disease%20Genetics%20Consortium%20(ADGC),%20and%20the%20Neurology%20Working%20Group%20of%20the%20Cohorts%20for%20Heart%20and%20Aging%20Research%20in%20Genomic%20Epidemiology%20(CHARGE)%20Consortium&rft.date=2019-01-29&rft.volume=92&rft.issue=5&rft.spage=e486&rft.epage=e503&rft.pages=e486-e503&rft.issn=0028-3878&rft.eissn=1526-632X&rft_id=info:doi/10.1212/WNL.0000000000006851&rft_dat=%3Cproquest_swepu%3E2179382563%3C/proquest_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2179382563&rft_id=info:pmid/30651383&rfr_iscdi=true |