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Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

ABSTRACT: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. 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. 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. 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.

SUBMITTER: Chauhan G

PROVIDER: S-EPMC6369905 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Chauhan Ganesh G Adams Hieab H H HHH Satizabal Claudia L CL Bis Joshua C JC Teumer Alexander A Sargurupremraj Muralidharan M Hofer Edith E Trompet Stella S Hilal Saima S Smith Albert Vernon AV Jian Xueqiu X Malik Rainer R Traylor Matthew M Pulit Sara L SL Amouyel Philippe P Mazoyer Bernard B Zhu Yi-Cheng YC Kaffashian Sara S Schilling Sabrina S Beecham Gary W GW Montine Thomas J TJ Schellenberg Gerard D GD Kjartansson Olafur O Guðnason Vilmundur V Knopman David S DS Griswold Michael E ME Windham B Gwen BG Gottesman Rebecca F RF Mosley Thomas H TH Schmidt Reinhold R Saba Yasaman Y Schmidt Helena H Takeuchi Fumihiko F Yamaguchi Shuhei S Nabika Toru T Kato Norihiro N Rajan Kumar B KB Aggarwal Neelum T NT De Jager Philip L PL Evans Denis A DA Psaty Bruce M BM Rotter Jerome I JI Rice Kenneth K Lopez Oscar L OL Liao Jiemin J Chen Christopher C Cheng Ching-Yu CY Wong Tien Y TY Ikram Mohammad K MK van der Lee Sven J SJ Amin Najaf N Chouraki Vincent V DeStefano Anita L AL Aparicio Hugo J HJ Romero Jose R JR Maillard Pauline P DeCarli Charles C Wardlaw Joanna M JM Hernández Maria Del C Valdés MDCV Luciano Michelle M Liewald David D Deary Ian J IJ Starr John M JM Bastin Mark E ME Muñoz Maniega Susana S Slagboom P Eline PE Beekman Marian M Deelen Joris J Uh Hae-Won HW Lemmens Robin R Brodaty Henry H Wright Margaret J MJ Ames David D Boncoraglio Giorgio B GB Hopewell Jemma C JC Beecham Ashley H AH Blanton Susan H SH Wright Clinton B CB Sacco Ralph L RL Wen Wei W Thalamuthu Anbupalam A Armstrong Nicola J NJ Chong Elizabeth E Schofield Peter R PR Kwok John B JB van der Grond Jeroen J Stott David J DJ Ford Ian I Jukema J Wouter JW Vernooij Meike W MW Hofman Albert A Uitterlinden André G AG van der Lugt Aad A Wittfeld Katharina K Grabe Hans J HJ Hosten Norbert N von Sarnowski Bettina B Völker Uwe U Levi Christopher C Jimenez-Conde Jordi J Sharma Pankaj P Sudlow Cathie L M CLM Rosand Jonathan J Woo Daniel D Cole John W JW Meschia James F JF Slowik Agnieszka A Thijs Vincent V Lindgren Arne A Melander Olle O Grewal Raji P RP Rundek Tatjana T Rexrode Kathy K Rothwell Peter M PM Arnett Donna K DK Jern Christina C Johnson Julie A JA Benavente Oscar R OR Wasssertheil-Smoller Sylvia S Lee Jin-Moo JM Wong Quenna Q Mitchell Braxton D BD Rich Stephen S SS McArdle Patrick F PF Geerlings Mirjam I MI van der Graaf Yolanda Y de Bakker Paul I W PIW Asselbergs Folkert W FW Srikanth Velandai V Thomson Russell R McWhirter Rebekah R Moran Chris C Callisaya Michele M Phan Thanh T Rutten-Jacobs Loes C A LCA Bevan Steve S Tzourio Christophe C Mather Karen A KA Sachdev Perminder S PS van Duijn Cornelia M CM Worrall Bradford B BB Dichgans Martin M Kittner Steven J SJ Markus Hugh S HS Ikram Mohammad A MA Fornage Myriam M Launer Lenore J LJ Seshadri Sudha S Longstreth W T WT Debette Stéphanie S

Neurology 20190128 5

<h4>Objective</h4>To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.<h4>Methods</h4>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 followe ...[more]

PMID: 30651383

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Project description:Background and purposePrevious studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsUsing 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).ResultsThe most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.ConclusionsThis first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

Project description:BackgroundStudies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions.MethodsParticipants (n=2662, mean age 74.6±4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression.ResultsThirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1-6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1-1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9-4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0-1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0-1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3-2.5] and IRR, 1.9 [95% CI, 1.3-2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2-2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5-4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2-1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1-2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0-2.0]).ConclusionsThe risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke.

Dataset Information

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Publications

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

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