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Cerebral small vessel disease genomics and its implications across the lifespan.

TitleCerebral small vessel disease genomics and its implications across the lifespan.
Publication TypeJournal Article
Year of Publication2020
AuthorsSargurupremraj M, Suzuki H, Jian X, et al.
Corporate AuthorsInternational Network against Thrombosis(INVENT) Consortium, International Headache Genomics Consortium(IHGC)
JournalNat Commun
Volume11
Issue1
Pagination6285
Date Published2020 12 08
ISSN2041-1723
KeywordsAdult, Aged, Aged, 80 and over, Alzheimer Disease, Cerebral Small Vessel Diseases, Diffusion Tensor Imaging, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Medical History Taking, Mendelian Randomization Analysis, Middle Aged, Risk Assessment, Risk Factors, Stroke, White Matter, Young Adult
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

DOI10.1038/s41467-020-19111-2
Alternate JournalNat Commun
PubMed ID33293549
PubMed Central IDPMC7722866
Grant ListN01HC85080 / HL / NHLBI NIH HHS / United States
HHSN268201800006I / HL / NHLBI NIH HHS / United States
/ DH_ / Department of Health / United Kingdom
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
G0701120 / MRC_ / Medical Research Council / United Kingdom
MR/M013111/1 / MRC_ / Medical Research Council / United Kingdom
HHSN268201800003I / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 AG023629 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
U01 HG004729 / HG / NHGRI NIH HHS / United States
75N92019D00031 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
N01HC65226 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 NS087541 / NS / NINDS NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
R01 AG049607 / AG / NIA NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
R01 NS062059 / NS / NINDS NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
G1001245 / MRC_ / Medical Research Council / United Kingdom
N01HC85082 / HL / NHLBI NIH HHS / United States
U01 AG058589 / AG / NIA NIH HHS / United States
MR/R024065/1 / MRC_ / Medical Research Council / United Kingdom
HHSN268201800005I / HL / NHLBI NIH HHS / United States
N02 HL64278 / HL / NHLBI 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
HHSN268201800007I / HL / NHLBI NIH HHS / United States
MR/N027558/1 / MRC_ / Medical Research Council / United Kingdom
N01AG12100 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
MR/S015132/1 / MRC_ / Medical Research Council / United Kingdom
/ / CIHR / Canada
N01HC85083 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
Z01 HL004607 / ImNIH / Intramural NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
M01 RR000052 / RR / NCRR NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
UH2 NS100605 / NS / NINDS NIH HHS / United States
G0700704 / MRC_ / Medical Research Council / United Kingdom
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
HHSN268201800004I / HL / NHLBI NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States