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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Matthew Traylor
  • Rainer Malik
  • Mike A. Nalls
  • Ioana Cotlarciuc
  • Farid Radmanesh
  • Gudmar Thorleifsson
  • Ken B. Hanscombe
  • Carl D. Langefeld
  • Danish Saleheen
  • Natalia S. Rost
  • Idil Yet
  • Tim D. Spector
  • Jordana T. Bell
  • Eilis Hannon
  • Jonathan Mill
  • Ganesh Chauhan
  • Stephanie Debette
  • Joshua C. Bis
  • W. T. Longstreth
  • M. Arfan Ikram
  • Lenore J. Launer
  • Sudha Seshadri
  • Monica Anne Hamilton-Bruce
  • Jordi Jimenez-Conde
  • John W. Cole
  • Reinhold Schmidt
  • Agnieszka Słowik
  • Robin Lemmens
  • Arne Lindgren
  • Olle Melander
  • Raji P. Grewal
  • Ralph L. Sacco
  • Tatjana Rundek
  • Kathryn Rexrode
  • Donna K. Arnett
  • Julie A. Johnson
  • Oscar R Benavente
  • Sylvia Wasssertheil-Smoller
  • Jin-Moo Lee
  • Sara L Pulit
  • Quenna Wong
  • Stephen Rich
  • Paul I.W. De Bakker
  • Patrick F. McArdle
  • Daniel Woo
  • Christopher D. Anderson
  • Huichun Xu
  • Laura Heitsch
  • Myriam Fornage
  • Christina Jern
  • METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium
  • on behalf of the International Stroke Genetics Consortium
Enheter & grupper
Externa organisationer
  • National Institute on Aging, United States
  • University of Pennsylvania
  • University of Exeter
  • Institut Gustave Roussy
  • University of Bordeaux
  • University of Washington
  • Erasmus University Medical Center
  • Boston University
  • Hospital del Mar Medical Research Institute
  • Medical University of Graz
  • Jagellonian University
  • Catholic University of Leuven
  • University Hospitals Leuven
  • Skåne University Hospital
  • Seton Hall University
  • University of Miami
  • Brigham and Women's Hospital / Harvard Medical School
  • University of Kentucky
  • Florida Museum Natural History
  • University of British Columbia
  • Yeshiva University
  • Washington University School of Medicine
  • University Medical Center Utrecht
  • Broad Institute
  • Washington University in St. Louis
  • University of Texas
  • Sahlgrenska Academy
  • Slotervaart Hospital
  • King's College London
  • University Hospital Munich
  • Royal Holloway University of London
  • Massachusetts General Hospital
  • deCODE Genetics
  • Wake Forest University
  • Framingham Heart Study
  • Royal Adelaide Hospital
  • University of Virginia School of Medicine
  • University of Cincinnati College of Medicine
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik

Nyckelord

Originalspråkengelska
Sidor (från-till)383-394
Antal sidor12
TidskriftAnnals of Neurology
Volym81
Utgivningsnummer3
StatusPublished - 2017 mar 1
PublikationskategoriForskning
Peer review utfördJa