Title | Genetic variation at 16q24.2 is associated with small vessel stroke. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Traylor 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 Authors | Markus HS |
Corporate Authors | METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium, International Stroke Genetics Consortium |
Journal | Ann Neurol |
Volume | 81 |
Issue | 3 |
Pagination | 383-394 |
Date Published | 2017 Mar |
ISSN | 1531-8249 |
Keywords | Adult, 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. |
DOI | 10.1002/ana.24840 |
Alternate Journal | Ann Neurol |
PubMed ID | 27997041 |
PubMed Central ID | PMC5366092 |
Grant List | MR/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 |