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Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects

Mishra, Aniket and Chauhan, Ganesh and Violleau, Marie-Helene and Vojinovic, Dina and Jian, Xueqiu and Bis, Joshua C and Li, Shuo and Saba, Yasaman and Grenier-Boley, Benjamin and Yang, Qiong and Bartz, Traci M and Hofer, Edith and Soumare, Aicha and Peng, Fen and Duperron, Marie-Gabrielle and Foglio, Mario and Mosley, Thomas H and Schmidt, Reinhold and Psaty, Bruce M and Launer, Lenore J and Boerwinkle, Eric and Zhu, Yicheng and Mazoyer, Bernard and Lathrop, Mark and Bellenguez, Celine and Van Duijn, Cornelia M and Ikram, M. Arfan and Schmidt, Helena and Longstreth, W T and Fornage, Myriam and Seshadri, Sudha and Joutel, Anne and Tzourio, Christophe and Debette, Stephanie (2019) Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. In: BRAIN, 142 (4). pp. 1009-1023.

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Official URL: https://dx.doi.org/10.1093/brain/awz024


We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, n(WESextremes) = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (n(WES) = 2,868, n(WESextremes) = 956) and genome-wide genotypes (n(GW) = 9924, n(GWextremes) = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (P-discovery = 8.21 x 10(-5), P-replication = 5.25 x 10(-3), P-combined = 4.72 x 10(-5)) and of NOTCH3 using gene-based tests (P-discovery = 1.61 x 10(-2), P-replication = 3.99 x 10(-2), P-combined = 5.31 x 10(-3)). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

Item Type: Journal Article
Publication: BRAIN
Additional Information: copyright for this article belongs to OXFORD UNIV PRESS
Keywords: cerebral small vessel disease; white matter hyperintensity; lacunes of presumed vascular origin; extreme phenotype; exome sequencing study
Department/Centre: Autonomous Societies / Centres > Centre for Brain Research
Date Deposited: 22 Aug 2019 05:56
Last Modified: 22 Aug 2019 05:56
URI: http://eprints.iisc.ac.in/id/eprint/63246

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