PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome A Genome-Wide Meta-Analysis
PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome A Genome-Wide Meta-Analysis
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DOI：
10.1161/circresaha.118.313533
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发表时间：
2019-01-04
影响因子：
20.1
通讯作者：
Jimenez-Conde, Jordi
中科院分区：
文献类型：
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作者：
Mola-Caminal, Marina;Carrera, Caty;Jimenez-Conde, Jordi
理由：缺血性中风是导致成人残疾的主要原因之一。中风后功能结果的部分可变性归因于遗传因素，但没有基因位点与中风结果一致相关。目的：我们的目的是确定影响恢复过程的遗传位点，使用准确的表型来产生迄今为止缺血性卒中恢复中最大的GWAS（全基因组关联研究）。方法和结果：对GWAS进行了一项12个队列、2期（发现-复制和联合）荟萃分析，包括前领土和先前独立的缺血性脑卒中病例。采用3个月改良Rankin量表记录功能结局。对分析进行了校正，如出院美国国立卫生研究院卒中量表。进行基因负荷试验。发现阶段（n=1225）之后是开放（n=2482）和严格的联合分析（n=1791）。那些在3个月以外的时间点记录改良Rankin量表或先前功能状态数据不完整的队列被排除在严格的分析之外。卒中后3个月，PATJ （pals1相关紧密连接）基因的新变异与较差的功能预后相关。最高变异为rs76221407 （G等位基因，β =0.40， P=1.70 × 10-9）。结论：我们的研究结果确定了一组与3个月功能预后相关的PATJ基因常见变异，具有全基因组显著性水平。未来的研究应该检查PATJ在卒中恢复中的作用，并考虑严格的表型分析，以丰富捕获的信息，揭示其他卒中结局位点。
Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome.Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date.Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, beta=0.40, P=1.70x10-9).Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.