TY - JOUR
T1 - Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects
AU - Mishra, Aniket
AU - Chauhan, Ganesh
AU - Violleau, Marie Helene
AU - Vojinovic, Dina
AU - Jian, Xueqiu
AU - Bis, Joshua C.
AU - Li, Shuo
AU - Saba, Yasaman
AU - Grenier-Boley, Benjamin
AU - Yang, Qiong
AU - Bartz, Traci M.
AU - Hofer, Edith
AU - Soumaré, Aïcha
AU - Peng, Fen
AU - Duperron, Marie Gabrielle
AU - Foglio, Mario
AU - Mosley, Thomas H.
AU - Schmidt, Reinhold
AU - Psaty, Bruce M.
AU - Launer, Lenore J.
AU - Boerwinkle, Eric
AU - Zhu, Yicheng
AU - Mazoyer, Bernard
AU - Lathrop, Mark
AU - Bellenguez, Celine
AU - Van Duijn, Cornelia M.
AU - Arfan Ikram, M.
AU - Schmidt, Helena
AU - Longstreth, W. T.
AU - Fornage, Myriam
AU - Seshadri, Sudha
AU - Joutel, Anne
AU - Tzourio, Christophe
AU - Debette, Stephanie
PY - 2019
Y1 - 2019
N2 - 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 genebased 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.
AB - 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 genebased 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.
KW - Cerebral small vessel disease
KW - Exome sequencing study
KW - Extreme phenotype
KW - Lacunes of presumed vascular origin
KW - White matter hyperintensity
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U2 - 10.1093/brain/awz024
DO - 10.1093/brain/awz024
M3 - Article
C2 - 30859180
AN - SCOPUS:85064239977
VL - 142
SP - 1009
EP - 1023
JO - Brain
JF - Brain
SN - 0006-8950
IS - 4
ER -