脑白质高信号的多民族全基因组关联磁共振成像研究
Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.
作者信息
Verhaaren Benjamin F J, Debette Stéphanie, Bis Joshua C, Smith Jennifer A, Ikram M Kamran, Adams Hieab H, Beecham Ashley H, Rajan Kumar B, Lopez Lorna M, Barral Sandra, van Buchem Mark A, van der Grond Jeroen, Smith Albert V, Hegenscheid Katrin, Aggarwal Neelum T, de Andrade Mariza, Atkinson Elizabeth J, Beekman Marian, Beiser Alexa S, Blanton Susan H, Boerwinkle Eric, Brickman Adam M, Bryan R Nick, Chauhan Ganesh, Chen Christopher P L H, Chouraki Vincent, de Craen Anton J M, Crivello Fabrice, Deary Ian J, Deelen Joris, De Jager Philip L, Dufouil Carole, Elkind Mitchell S V, Evans Denis A, Freudenberger Paul, Gottesman Rebecca F, Guðnason Vilmundur, Habes Mohamad, Heckbert Susan R, Heiss Gerardo, Hilal Saima, Hofer Edith, Hofman Albert, Ibrahim-Verbaas Carla A, Knopman David S, Lewis Cora E, Liao Jiemin, Liewald David C M, Luciano Michelle, van der Lugt Aad, Martinez Oliver O, Mayeux Richard, Mazoyer Bernard, Nalls Mike, Nauck Matthias, Niessen Wiro J, Oostra Ben A, Psaty Bruce M, Rice Kenneth M, Rotter Jerome I, von Sarnowski Bettina, Schmidt Helena, Schreiner Pamela J, Schuur Maaike, Sidney Stephen S, Sigurdsson Sigurdur, Slagboom P Eline, Stott David J M, van Swieten John C, Teumer Alexander, Töglhofer Anna Maria, Traylor Matthew, Trompet Stella, Turner Stephen T, Tzourio Christophe, Uh Hae-Won, Uitterlinden André G, Vernooij Meike W, Wang Jing J, Wong Tien Y, Wardlaw Joanna M, Windham B Gwen, Wittfeld Katharina, Wolf Christiane, Wright Clinton B, Yang Qiong, Zhao Wei, Zijdenbos Alex, Jukema J Wouter, Sacco Ralph L, Kardia Sharon L R, Amouyel Philippe, Mosley Thomas H, Longstreth W T, DeCarli Charles C, van Duijn Cornelia M, Schmidt Reinhold, Launer Lenore J, Grabe Hans J, Seshadri Sudha S, Ikram M Arfan, Fornage Myriam
出版信息
Circ Cardiovasc Genet. 2015 Apr;8(2):398-409. doi: 10.1161/CIRCGENETICS.114.000858. Epub 2015 Feb 7.
BACKGROUND
The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.
METHODS AND RESULTS
We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7×10(-19)) and identified novel loci on chr10q24 (P=1.6×10(-9)) and chr2p21 (P=4.4×10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0×10(-8)) and chr2p16 (P=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).
CONCLUSIONS
We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
背景
脑白质高信号（WMH）负担与中风、痴呆和死亡风险增加相关。WMH具有高度遗传性，但其遗传基础尚未完全明确。为了识别影响WMH负担的新型基因变异，我们对多民族全基因组关联研究进行了荟萃分析。
方法与结果
我们纳入了来自29个基于人群队列的21079名中老年人，他们无痴呆和中风，分别为欧洲裔（n = 17936）、非洲裔（n = 1943）、西班牙裔（n = 795）和亚裔（n = 405）。通过经过验证的自动分割方法或经过验证的视觉分级量表在MRI上对WMH负担进行量化。每个研究中的基因型数据被推算至千人基因组参考数据。在每个种族群体中，我们使用针对年龄、性别、颅内体积和祖先主成分进行调整的线性回归模型，研究每个单核苷酸多态性与WMH负担之间的关系。分别对每个种族以及合并样本进行荟萃分析。在欧洲裔样本中，我们证实了17号染色体长臂25区（chr17q25）上一个先前已知的基因座（P = 2.7×10⁻¹⁹），并在10号染色体长臂24区（chr10q24）和2号染色体短臂21区（chr2p21）上识别出新型基因座（P分别为1.6×10⁻⁹和4.4×10⁻⁸）。在多民族荟萃分析中，我们在1号染色体长臂22区（chr1q22）和2号染色体短臂16区（chr2p16）上又识别出2个基因座（P分别为2.0×10⁻⁸和1.5×10⁻⁸）。这些新型基因座包含的基因与阿尔茨海默病（2号染色体短臂21区和10号染色体长臂24区）、脑出血（1号染色体长臂22区）、神经炎症性疾病（2号染色体短臂21区）和神经胶质瘤（10号染色体长臂24区和2号染色体短臂16区）有关。
结论
我们识别出4个新型基因座，它们除了先前提出的缺血机制外，还表明炎症和胶质细胞增殖途径在WMH发生发展中起作用。
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