基于人群的MRI定义脑梗死的遗传和生活方式风险因素。
Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.
作者信息
Chauhan Ganesh, Adams Hieab H H, 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, Guðnason 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, Hernández Maria Del C Valdés, Luciano Michelle, Liewald David, Deary Ian J, Starr John M, Bastin Mark E, Muñoz Maniega Susana, 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 André G, van der Lugt Aad, Wittfeld Katharina, Grabe Hans J, Hosten Norbert, von Sarnowski Bettina, Völker Uwe, Levi Christopher, Jimenez-Conde Jordi, Sharma Pankaj, Sudlow Cathie L M, 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 I W, Asselbergs Folkert W, Srikanth Velandai, Thomson Russell, McWhirter Rebekah, Moran Chris, Callisaya Michele, Phan Thanh, Rutten-Jacobs Loes C A, 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 W T, Debette Stéphanie
出版信息
Neurology. 2019 Jan 28;92(5):e486-e503. doi: 10.1212/WNL.0000000000006851.
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, = 1.77 × 10; and LINC00539/ZDHHC20, = 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 ( value for BI, = 9.38 × 10; = 5.23 × 10 for hypertension), smoking ( = 4.4 × 10; = 1.2 × 10), diabetes ( = 1.7 × 10; = 2.8 × 10), previous cardiovascular disease ( = 1.0 × 10; = 2.3 × 10), stroke ( = 3.9 × 10; = 3.2 × 10), and MRI-defined white matter hyperintensity burden ( = 1.43 × 10; = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( ≤ 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.
目的
在基于人群的大型队列中探索磁共振成像（MRI）定义的脑梗死（BI）的遗传和生活方式风险因素。
方法
我们对全基因组关联研究（GWAS）进行了荟萃分析，并在来自5个种族的18个基于人群的队列（n = 20949）中，研究了血管危险因素及其遗传风险评分（GRS）与MRI定义的BI以及BI的一个子集，即小皮质下BI（SSBI）之间的关联（3726例BI患者，2021例SSBI患者）。在7个基于人群的队列（n = 6862；1483例BI患者，630例SBBI患者）中对顶级基因座进行了随访，并且我们测试了与包括缺血性卒中和病理定义的BI在内的相关表型的关联。
结果
BI的平均患病率为17.7%，SSBI为10.5%，在65岁以后急剧上升。两个基因座显示出与BI存在全基因组显著关联：FBN2，P = 1.77×10⁻⁸；以及LINC00539/ZDHHC20，P = 5.82×10⁻⁸。两者均与血压（BP）相关表型有关，但在较小的随访样本中未得到重复验证，也未显示与相关表型的关联。观察到BP特征与BI和SSBI存在年龄和性别调整后的关联（BI的P值，高血压为P = 9.38×10⁻⁶；P = 5.23×10⁻⁵）、吸烟（P = 4.4×10⁻⁵；P = 1.2×10⁻⁴）、糖尿病（P = 1.7×10⁻⁴；P = 2.8×10⁻⁴）、既往心血管疾病（P = 1.0×10⁻³；P = 2.3×10⁻³）、卒中（P = 3.9×10⁻³；P = 3.2×10⁻³）以及MRI定义的白质高信号负荷（P = 1.43×10⁻³；P = 3.16×10⁻³），但与体重指数或胆固醇无关。BP特征的GRS与BI和SSBI相关（P≤0.0022），未显示出定向多效性迹象。
结论
在这项包括超过20000名基于人群参与者的多民族GWAS荟萃分析中，我们确定了BI的遗传风险基因座，一旦有更多大型数据集，这些基因座需要进一步验证。高血压，包括遗传决定的高血压，是BI最显著的可改变的因果风险因素。
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