Pulse lineResearch With Heart Logo

Genetic variation at 16q24.2 is associated with small vessel stroke.

TitleGenetic variation at 16q24.2 is associated with small vessel stroke.
Publication TypeJournal Article
Year of Publication2017
AuthorsTraylor M, Malik R, Nalls MA, Cotlarciuc I, Radmanesh F, Thorleifsson G, Hanscombe KB, Langefeld C, Saleheen D, Rost NS, Yet I, Spector TD, Bell JT, Hannon E, Mill J, Chauhan G, Debette S, Bis JC, Longstreth WT, M Ikram A, Launer LJ, Seshadri S, Hamilton-Bruce MAnne, Jimenez-Conde J, Cole JW, Schmidt R, Słowik A, Lemmens R, Lindgren A, Melander O, Grewal RP, Sacco RL, Rundek T, Rexrode K, Arnett DK, Johnson JA, Benavente OR, Wasssertheil-Smoller S, Lee J-M, Pulit SL, Wong Q, Rich SS, de Bakker PIW, McArdle PF, Woo D, Anderson CD, Xu H, Heitsch L, Fornage M, Jern C, Stefansson K, Thorsteinsdottir U, Gretarsdottir S, Lewis CM, Sharma P, Sudlow CLM, Rothwell PM, Boncoraglio GB, Thijs V, Levi C, Meschia JF, Rosand J, Kittner SJ, Mitchell BD, Dichgans M, Worrall BB
Secondary AuthorsMarkus HS
Corporate AuthorsMETASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium, International Stroke Genetics Consortium
JournalAnn Neurol
Volume81
Issue3
Pagination383-394
Date Published2017 Mar
ISSN1531-8249
KeywordsAdult, Aged, Aged, 80 and over, Cerebral Small Vessel Diseases, Chromosomes, Human, Pair 16, Female, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Stroke, Stroke, Lacunar, Zinc Fingers
Abstract

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke.

METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.

RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10 ).

INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.

DOI10.1002/ana.24840
Alternate JournalAnn Neurol
PubMed ID27997041
PubMed Central IDPMC5366092
Grant ListMR/K013807/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS085419 / NS / NINDS NIH HHS / United States
U01 HL096902 / HL / NHLBI NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
250157 / ERC_ / European Research Council / International
R01 AG008122 / AG / NIA NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
R01 NS059727 / NS / NINDS NIH HHS / United States
U01 HL096814 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States
U01 HL096812 / HL / NHLBI NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
095626 / WT_ / Wellcome Trust / United Kingdom
R01 NS082285 / NS / NINDS NIH HHS / United States
Z01 AG007270-08 / ImNIH / Intramural NIH HHS / United States
U01 HL096917 / HL / NHLBI NIH HHS / United States
U01 HL096899 / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 HL088521 / HL / NHLBI NIH HHS / United States