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

TitleAssociation of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects.
Publication TypeJournal Article
Year of Publication2019
AuthorsMishra A, Chauhan G, Violleau M-H, Vojinovic D, Jian X, Bis JC, Li S, Saba Y, Grenier-Boley B, Yang Q, Bartz TM, Hofer E, Soumaré A, Peng F, Duperron M-G, Foglio M, Mosley TH, Schmidt R, Psaty BM, Launer LJ, Boerwinkle E, Zhu Y, Mazoyer B, Lathrop M, Bellenguez C, van Duijn CM, M Ikram A, Schmidt H, Longstreth WT, Fornage M, Seshadri S, Joutel A, Tzourio C
Secondary AuthorsDebette S
JournalBrain
Volume142
Issue4
Pagination1009-1023
Date Published2019 04 01
ISSN1460-2156
KeywordsAged, Aged, 80 and over, Brain Ischemia, Cerebral Small Vessel Diseases, Cohort Studies, Female, Heterozygote, High-Temperature Requirement A Serine Peptidase 1, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Receptor, Notch3, Stroke, White Matter, Whole Exome Sequencing
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.

DOI10.1093/brain/awz024
Alternate JournalBrain
PubMed ID30859180
PubMed Central IDPMC6439324
Grant ListHHSN268201100008C / HL / NHLBI NIH HHS / United States
UH3 NS100605 / NS / NINDS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 NS087541 / NS / NINDS NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
5RC2HL102419 / RA / ARRA NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268200900009C / WH / WHI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01 AG052409 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States