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Neurology

Publication date: 2019-01-29
Volume: 92 Pages: E486 - E503
Publisher: American Academy of Neurology

Author:

Chauhan, Ganesh
Adams, Hieab HH ; Satizabal, Claudia L ; Bis, Joshua C ; Teumer, Alexander ; Sargurupremraj, Muralidharan ; Hofer, Edith ; Trompet, Stella ; Hilal, Saima ; Smith, Albert Vernon ; Jian, Xueqiu ; Malik, Rainer ; Traylor, Matthew ; Pulit, Sara L ; Amouyel, Philippe ; Mazoyer, Bernard ; Zhu, Yi-Cheng ; Kaffashian, Sara ; Schilling, Sabrina ; Beecham, Gary W ; Montine, Thomas J ; Schellenberg, Gerard D ; Kjartansson, Olafur ; Gudnason, Vilmundur ; Knopman, David S ; Griswold, Michael E ; Windham, B Gwen ; Gottesman, Rebecca F ; Mosley, Thomas H ; Schmidt, Reinhold ; Saba, Yasaman ; Schmidt, Helena ; Takeuchi, Fumihiko ; Yamaguchi, Shuhei ; Nabika, Toru ; Kato, Norihiro ; Rajan, Kumar B ; Aggarwal, Neelum T ; De Jager, Philip L ; Evans, Denis A ; Psaty, Bruce M ; Rotter, Jerome I ; Rice, Kenneth ; Lopez, Oscar L ; Liao, Jiemin ; Chen, Christopher ; Cheng, Ching-Yu ; Wong, Tien Y ; Ikram, Mohammad K ; van der Lee, Sven J ; Amin, Najaf ; Chouraki, Vincent ; DeStefano, Anita L ; Aparicio, Hugo J ; Romero, Jose R ; Maillard, Pauline ; DeCarli, Charles ; Wardlaw, Joanna M ; Hernandez, Maria del C Valdes ; Luciano, Michelle ; Liewald, David ; Deary, Ian J ; Starr, John M ; Bastin, Mark E ; Maniega, Susana Munoz ; Slagboom, P Eline ; Beekman, Marian ; Deelen, Joris ; Uh, Hae-Won ; Lemmens, Robin ; Brodaty, Henry ; Wright, Margaret J ; Ames, David ; Boncoraglio, Giorgio B ; Hopewell, Jemma C ; Beecham, Ashley H ; Blanton, Susan H ; Wright, Clinton B ; Sacco, Ralph L ; Wen, Wei ; Thalamuthu, Anbupalam ; Armstrong, Nicola J ; Chong, Elizabeth ; Schofield, Peter R ; Kwok, John B ; van der Grond, Jeroen ; Stott, David J ; Ford, Ian ; Jukema, J Wouter ; Vernooij, Meike W ; Hofman, Albert ; Uitterlinden, Andre G ; van der Lugt, Aad ; Wittfeld, Katharina ; Grabe, Hans J ; Hosten, Norbert ; von Sarnowski, Bettina ; Voelker, Uwe ; Levi, Christopher ; Jimenez-Conde, Jordi ; Sharma, Pankaj ; Sudlow, Cathie LM ; Rosand, Jonathan ; Woo, Daniel ; Cole, John W ; Meschia, James F ; Slowik, Agnieszka ; Thijs, Vincent ; Lindgren, Arne ; Melander, Olle ; Grewal, Raji P ; Rundek, Tatjana ; Rexrode, Kathy ; Rothwell, Peter M ; Arnett, Donna K ; Jern, Christina ; Johnson, Julie A ; Benavente, Oscar R ; Wasssertheil-Smoller, Sylvia ; Lee, Jin-Moo ; Wong, Quenna ; Mitchell, Braxton D ; Rich, Stephen S ; McArdle, Patrick F ; Geerlings, Mirjam I ; van der Graaf, Yolanda ; de Bakker, Paul IW ; Asselbergs, Folkert W ; Srikanth, Velandai ; Thomson, Russell ; McWhirter, Rebekah ; Moran, Chris ; Callisaya, Michele ; Thanh, Phan ; Rutten-Jacobs, Loes CA ; Bevan, Steve ; Tzourio, Christophe ; Mather, Karen A ; Sachdev, Perminder S ; van Duijn, Cornelia M ; Worrall, Bradford B ; Dichgans, Martin ; Kittner, Steven J ; Markus, Hugh S ; Ikram, Mohammad A ; Fornage, Myriam ; Launer, Lenore J ; Seshadri, Sudha ; Longstreth, WT ; Debette, Stephanie

Keywords:

Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, GENOME-WIDE ASSOCIATION, MATTER HYPERINTENSITY VOLUME, SMALL VESSEL DISEASE, MENDELIAN RANDOMIZATION, ISCHEMIC-STROKE, BLOOD-PRESSURE, SILENT, METAANALYSIS, POLYMORPHISMS, INSIGHTS, 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, 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences, Neurology & Neurosurgery, 3202 Clinical sciences, 3209 Neurosciences

Abstract:

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We 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. RESULTS: The 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 BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. 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 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), 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. CONCLUSION: In 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.