Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.
Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.
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DOI：
10.1016/s1474-4422(21)00031-4
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发表时间：
2021-05
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通讯作者：
International Stroke Genetics Consortium
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作者：
Traylor M;Persyn E;Tomppo L;Klasson S;Abedi V;Bakker MK;Torres N;Li L;Bell S;Rutten-Jacobs L;Tozer DJ;Griessenauer CJ;Zhang Y;Pedersen A;Sharma P;Jimenez-Conde J;Rundek T;Grewal RP;Lindgren A;Meschia JF;Salomaa V;Havulinna A;Kourkoulis C;Crawford K;Marini S;Mitchell BD;Kittner SJ;Rosand J;Dichgans M;Jern C;Strbian D;Fernandez-Cadenas I;Zand R;Ruigrok Y;Rost N;Lemmens R;Rothwell PM;Anderson CD;Wardlaw J;Lewis CM;Markus HS;Helsinki Stroke, Study Dutch Parelsnoer Institute-Cerebrovascular Accident (CVA) Study Group;National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network;UK DNA Lacunar Stroke Study Investigators;International Stroke Genetics Consortium
腔隙性脑卒中的遗传基础知之甚少，迄今为止在16 q24上发现了一个单一的基因座。我们试图确定新的关联，并提供对疾病的机制见解。我们对新招募的经MRI确诊的腔隙性卒中患者和现有的全基因组关联研究（GWAS）的数据进行了汇总分析。作为英国DNA腔隙性卒中研究1和2的一部分，患者从英国的医院招募，并从国际卒中遗传学联盟的合作者招募。病例组和对照组按血统分层，并进行了两项荟萃分析：一项是欧洲血统分析，另一项是包括所有血统组的跨种族分析。我们还对GWAS进行了多性状分析，并与大脑白色物质高信号（一种病因相关的放射学性状）的研究进行了联合分析，以发现其他遗传相关性。我们进行了全转录组关联研究（TWAS），以检测表达与腔隙性卒中相关的基因;使用基因组注释的多标记分析确定了显著富集的途径;并使用孟德尔随机化评估了与疾病因果相关的心血管危险因素。我们的荟萃分析包括来自欧洲、美国和澳大利亚的研究，包括7338例病例和254798例对照，其中2987例（与29540例对照匹配）使用MRI证实。在欧洲或跨种族荟萃分析中，发现五个基因座（ICA 1 L-WDR 12-CARF-NBEAL 1、ULK 4、SPI 1-SLC 39 A13-PSMC 3-RAPSN、ZCCHC 14、ZBTB 14-EPB 41 L3）与腔隙性中风相关。在多性状分析中发现另外7个位点（SLC 25 A44-PMF 1-BGln、LOX-ZNF 474-LOC 100505841、FOXF 2-FOXQ 1、VTA 1-GPR 126、SH 3 PXD 2A、HTRA 1-ARMS 2、COL 4A 2）与脑白色物质高信号相关（n=42 310）。其中两个基因座含有参与单基因腔隙性卒中的基因（COL 4A 2和HTRA 1）。TWAS确定了6个基因（SCL 25 A44、ULK 4、CARF、FAM 117 B、ICA 1 L、NBEAL 1）的表达与腔隙性卒中之间的关联。途径分析涉及细胞外基质的破坏、磷脂酰肌醇5磷酸结合和迂回结合（错误发现率<0.05）。孟德尔随机分析确定了血压升高、吸烟史和2型糖尿病与腔隙性卒中的正相关性。腔隙性卒中具有相当大的遗传成分，目前已确定了12个基因座，可能代表未来的治疗目标。这些基因座提供了对腔隙性卒中发病机制的见解，突出了疾病风险中血管细胞外基质（COL 4A 2，LOX，SH 3 PXD 2A，GPR 126，HTRA 1），周细胞分化（FOXF 2，GPR 126），TGF-β信号传导（HTRA 1）和髓鞘形成（ULK 4，GPR 126）的破坏。英国心脏基金会
The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. British Heart Foundation.