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

• Published in: Brain (London, England : 1878) Vol. 142; no. 4; pp. 1009 - 1023
• Main Authors: Mishra, Aniket, Chauhan, Ganesh, Violleau, Marie-Helene, Vojinovic, Dina, Jian, Xueqiu, Bis, Joshua C, Li, Shuo, Saba, Yasaman, Grenier-Boley, Benjamin, Yang, Qiong, Bartz, Traci M, Hofer, Edith, Soumaré, Aïcha, Peng, Fen, Duperron, Marie-Gabrielle, Foglio, Mario, Mosley, Thomas H, Schmidt, Reinhold, Psaty, Bruce M, Launer, Lenore J, Boerwinkle, Eric, Zhu, Yicheng, Mazoyer, Bernard, Lathrop, Mark, Bellenguez, Celine, Van Duijn, Cornelia M, Ikram, M Arfan, Schmidt, Helena, Longstreth, W T, Fornage, Myriam, Seshadri, Sudha, Joutel, Anne, Tzourio, Christophe, Debette, Stephanie
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.04.2019
• Subjects: Aged; Aged, 80 and over; Brain Ischemia - genetics; Cerebral Small Vessel Diseases - diagnostic imaging; Cerebral Small Vessel Diseases - genetics; Cerebral Small Vessel Diseases - metabolism; Cohort Studies; Exome Sequencing - methods; Female; Genetics; Geriatry and gerontology; Heterozygote; High-Temperature Requirement A Serine Peptidase 1 - genetics; High-Temperature Requirement A Serine Peptidase 1 - metabolism; Human genetics; Human health and pathology; Humans; Life Sciences; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neurobiology; Neurons and Cognition; Original; Polymorphism, Single Nucleotide; Populations and Evolution; Receptor, Notch3 - genetics; Receptor, Notch3 - metabolism; Receptor, Notch3 - physiology; Stroke - genetics; White Matter - diagnostic imaging; White Matter - metabolism; exome sequencing study; cerebral small vessel disease; lacunes of presumed vascular origin; extreme phenotype; white matter hyperintensity
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awz024

Mishra et al. present a composite extreme-phenotype strategy for gene mapping of cerebral small vessel disease in population cohorts of older persons. They identify associations with variants in HTRA1 and NOTCH3, and describe two participants heterozygous for known pathogenic variants for familial small vessel disease in NOTCH3 and HTRA1. 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.