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

Aniket Mishra 1, * Ganesh Chauhan 1, 2 Marie-Helene Violleau 1 Dina Vojinovic 3 Xueqiu Jian 4 Joshua C Bis 5 Shuo Li 6 Yasaman Saba 7 Benjamin Grenier-Boley 8 Qiong Yang 6, 9 Traci M Bartz 5 Edith Hofer 7 Aïcha Soumaré 1 Fen Peng 4 Marie-Gabrielle Duperron 1 Mario Foglio 10 Thomas H Mosley 11 Reinhold Schmidt 7 Bruce M Psaty 5, 12 Lenore J Launer 13 Eric Boerwinkle 4 Yicheng Zhu 14 Bernard Mazoyer 15 Mark Lathrop 10 Celine Bellenguez 8 Cornelia M van Duijn 3, 16 M Arfan Ikram 3 Helena Schmidt 7 W T Longstreth 5 Myriam Fornage 4 Sudha Seshadri 17, 9 Anne Joutel 18 Christophe Tzourio 1, 19 Stephanie Debette 1, 9, 19, *
Abstract : 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, nWESextremes = 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 (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 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 (Pdiscovery = 8.21 × 10-5, Preplication = 5.25 × 10-3, Pcombined = 4.72 × 10-5) and of NOTCH3 using gene-based tests (Pdiscovery = 1.61 × 10-2, Preplication = 3.99 × 10-2, Pcombined = 5.31 × 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.
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Aniket Mishra, Ganesh Chauhan, Marie-Helene Violleau, Dina Vojinovic, Xueqiu Jian, et al.. Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. Brain - A Journal of Neurology , Oxford University Press (OUP), 2019, 142 (4), pp.1009-1023. ⟨10.1093/brain/awz024⟩. ⟨hal-03162406⟩

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