Genetic Variation at 16q24.2 is associated with small vessel stroke. / Traylor, Matthew; Malik, Rainer ; Nalls, Mike; Cotlarciuc, Ioana; Radmanesh, Farid ; Thorleifsson, Gudmar ; Hanscombe, Ken; Langefeld, Carl ; Saleheen, Danish ; Rost, Natalia ; Yet, Idil ; Spector, Tim ; Bell, Jordana; Hannon, Eilis ; Mill, Jonathan ; Chauhan, Ganesh ; Debette, Stephanie ; Bis, Joshua ; Longstreth , WT ; Ikram, Arfan ; Launer, Lenore ; Seshadri, Sudha ; Hamilton Bruce, Monica Anne ; Jimenez-Conde, Jordi ; Cole, John ; Schmidt, Reinhold ; Słowik, Agnieszka; Lemmens, Robin ; Lindgren, Arne; Melander, Olle ; Grewal, Raji ; Sacco, Ralph; Rundek, Tatjana ; Rexrode, Kathryn ; Arnett, Donna; Johnson, Julie ; Benavente, Oscar; Wasssertheil-Smoller, Sylvia ; Lee, Jin-Moo ; Pulit, Sara ; Wong, Quenna ; Rich, Stephen; de Bakker, Paul ; McArdle, Patrick ; Woo, Daniel ; Anderson, Christopher; Xu, Huichun; Heitsch, Laura ; Fornage, Myriam ; Jern, Christina; Stefansson, Kari; Thorsteinsdottir, Unnur; Gretarsdottir, Solveig; Lewis, Cathryn ; Sharma, Pankaj; Sudlow, Cathie ; Rothwell, Peter ; Boncoraglio, Giorgio; Thijs, Vincent; Levi, Chris; Meschia, James ; Rosand, Jonathan; Kittner, Steven ; Mitchell, Braxton ; Dichgans, Martin ; Worrall, Bradford; Markus, Hugh.

In: Annals of Neurology, Vol. 81, No. 3, 25.03.2017, p. 383–394.

Research output: Contribution to journalArticle

Published

Documents

  • Matthew Traylor
  • Rainer Malik
  • Mike Nalls
  • Farid Radmanesh
  • Gudmar Thorleifsson
  • Ken Hanscombe
  • Carl Langefeld
  • Danish Saleheen
  • Natalia Rost
  • Idil Yet
  • Tim Spector
  • Jordana Bell
  • Eilis Hannon
  • Jonathan Mill
  • Ganesh Chauhan
  • Stephanie Debette
  • Joshua Bis
  • WT Longstreth
  • Arfan Ikram
  • Lenore Launer
  • Sudha Seshadri
  • Monica Anne Hamilton Bruce
  • Jordi Jimenez-Conde
  • John Cole
  • Reinhold Schmidt
  • Agnieszka Słowik
  • Robin Lemmens
  • Arne Lindgren
  • Olle Melander
  • Raji Grewal
  • Ralph Sacco
  • Tatjana Rundek
  • Kathryn Rexrode
  • Donna Arnett
  • Julie Johnson
  • Oscar Benavente
  • Sylvia Wasssertheil-Smoller
  • Jin-Moo Lee
  • Sara Pulit
  • Quenna Wong
  • Stephen Rich
  • Paul de Bakker
  • Patrick McArdle
  • Daniel Woo
  • Christopher Anderson
  • Huichun Xu
  • Laura Heitsch
  • Myriam Fornage
  • Christina Jern
  • Kari Stefansson
  • Unnur Thorsteinsdottir
  • Solveig Gretarsdottir
  • Cathryn Lewis
  • Cathie Sudlow
  • Peter Rothwell
  • Giorgio Boncoraglio
  • Vincent Thijs
  • Chris Levi
  • James Meschia
  • Jonathan Rosand
  • Steven Kittner
  • Braxton Mitchell
  • Martin Dichgans
  • Bradford Worrall
  • Hugh Markus

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 × 10−9). 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 × 10−5; 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 × 10−7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10−6).
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
Original languageEnglish
Pages (from-to)383–394
Number of pages12
JournalAnnals of Neurology
Volume81
Issue number3
DOIs
Publication statusPublished - 25 Mar 2017
This open access research output is licenced under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

ID: 27475163