Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here:

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

Olle Melander

Principal investigator

Default user image.

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


  • 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

Summary, in English

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.


  • Department Office of Clinical Sciences, Lund
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year







Annals of Neurology





Document type

Journal article


John Wiley and Sons


  • Medical Genetics


  • genetic variation
  • small vessel stroke
  • 16q24.2




  • ISSN: 0364-5134