Abstract 148: Exome Sequence Study on Extreme MRI Markers of Cerebral Small Vessel Disease

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We performed an exome sequence association study on extreme MRI-markers of cerebral small vessel disease (extensive-CSVD versus minimal-CSVD) in participants from the 3C-Dijon French population-based cohort study, focusing on genes harbouring causal mutations for Mendelian forms of CSVD (NOTCH3, HTRA1, COL4A1, COL4A2, TREX1 and CTSA). The study population comprised 514 participants aged 73.30±4.24 years (59.24% women). The extensive-CSVD group comprised 261 persons in the upper extreme distribution of WMHV residuals adjusted for age, gender, and intracranial volume, prioritizing participants with lacunar brain infarcts within the top quartile of WMHV residuals. The minimal-CSVD group comprised 253 participants without MRI-defined brain infarct who were in the lower extreme distribution of WMHV residuals. These participants were whole-exome sequenced with average depth coverage of 100X. We screened for the presence of known pathogenic genotypes in our cohort, and performed single variant association tests and gene-based burden tests. We identified one individual with extensive-CSVD carrying a heterozygote genotype in HTRA1 previously described as a CARASIL causing mutation in Asians, and not previously reported in European families with the dominant HTRA1 phenotype. We also identified significant association of a common intronic variant, rs2293871, in HTRA1 with extensive-CSVD (p=8.209 х 10-5) that remained significant after correction for multiple testing and accounting for regional linkage disequilibrium. Furthermore, the burden of rare and low frequency protein-modifying alleles in NOTCH3 was significantly associated with increased risk of extensive-CSVD (p=9.990 х 10-3). In conclusion, we describe a novel strategy to identify genetic determinants of CSVD using population cohorts of elderly based on an extreme composite phenotype. We report one clinically important case carrying a heterozygote genotype at the CARASIL causing mutation. We show significant association of an intronic common variant in HTRA1 gene and the burden of rare and low frequency protein damaging variants in NOTCH3 gene with extensive-CSVD. These associations suggest some shared mechanisms between monogenic and multifactorial CSVD.

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