Imaging Endophenotypes of Stroke as a Target for Genetic Studies.
Imaging Endophenotypes of Stroke as a Target for Genetic Studies.
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DOI：
10.1161/strokeaha.117.017073
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发表时间：
2018-06
期刊：
影响因子：
8.3
通讯作者：
Fornage M
中科院分区：
文献类型：
--
作者：
Jian X;Fornage M
(NBEAL1); rs941898 (EVL); rs962888 (EFTUD2/C1QL1); and rs9515201 (COL4A2). Interestingly, COL4A2 and the adjacent COL4A1 encode α subunits of type IV collagen the major structural component of basement membranes and have been implicated in hereditary cerebral small vessel disease and intracerebral hemorrhage. 19, 20 Because common variants detectable by GWAS have been estimated to account for at most a quarter of the WMH phenotypic variance, 21 genetic studies of WMH are now focusing on rare variants and other omics. 22 An analysis of 250 000 mostly rare to low frequency variants, mapping to coding regions of the genome (exome) and genotyped in 20 719 participants of European and African ancestry, showed that rare nonsynonymous variants in MRPL38, located in the previously identified chr17q25 locus, are associated with WMH independently of the known GWAS signal (manuscript submitted). MRPL38 encodes a mitochondrial ribosomal protein. Gene mutations resulting in impaired mitochondrial translation have been implicated in severe, early onset neurological disease. 23 Future whole-genome sequence analysis will provide a more complete picture of the role of rare variants in WMH susceptibility. 24 MRI-defined brain Infarcts (BI) are common in the elderly and typically occur in the absence of clinically recognized stroke symptoms. Like WMH, they are associated with future incident cognitive decline and stroke. The majority (> 90%) of BI are small subcortical brain infarcts (SSBI) 3 to 15 mm in size, which are also referred to as lacunes. The remaining 10% are larger subcortical infarcts or cortical infarcts. 25 A GWAS of covert MRI infarcts in 9401 participants from 6 community-based cohorts (mean age: 69 years; 19.4% had at least 1 MRI infarct) identified novel associations in the MACROD2/FLRT3 region of chromosome 20p12. 26 A more recent transethnic meta-analysis of GWAS in 20 949 participants from 5 ethnicities has been completed. Both MRI-defined BI (n= 3726) and SSBI (n= 2021) were analyzed. Two loci reached genome-wide significance for association with BI: FBN2 and LINC00539/ZDHHC20. However, associations were not replicated in a smaller independent sample of 3143 participants, including 1134 with BI and 543 with SSBI. The inconsistent findings among studies and the failure of replication efforts may not only be attributable to insufficient power, genetic heterogeneity across ethnic groups, and the use of different definition of BI (eg, diameter threshold may vary across studies) but may also in part explain these observations. These loci did not seem to associate with ischemic stroke and pathologically defined BI, warranting additional studies to validate these findings and further examine the shared pathogenesis between covert and overt brain vascular disease. 22 Recent application of high resolution structural MRI and ongoing development of semiautomated detection techniques have allowed assessment of cortical cerebral microinfarcts (diameter< 1 mm). 27 The cause of these brain abnormalities is likely heterogeneous. Cerebral microinfarcts have been associated with dementia, cognitive decline, and motor function impairment. 28 The genetic basis of cerebral microinfarcts is unknown.Perivascular spaces (also known as Virchow–Robin spaces) are fluid-filled spaces that follow the typical course of penetrating vessels through the brain parenchyma. They seem either linear if imaged parallel to the course of the vessel or round or ovoid (diameter< 3 mm in general) if imaged perpendicular to the course of the vessel, with hyperintense signal on T2 images. 29 Enlarged perivascular …
