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

2017-03

Traylor, Matthew

Malik, Rainer

Nalls, Mike A

Cotlarciuc, Ioana

Radmanesh, Farid

Thorleifsson, Gudmar

Hanscombe, Ken B

Langefeld, Carl

Saleheen, Danish

Rost, Natalia S

Yet, Idil

Spector, Tim D

Bell, Jordana T

Hannon, Eilis

Mill, Jonathan

Chauhan, Ganesh

Debette, Stephanie

Bis, Joshua C

Longstreth, WT Jr

Ikram, M Arfan

Launer, Lenore J

Seshadri, Sudha

Hamilton-Bruce, Monica Anne

Jimenez-Conde, Jordi

Cole, John W

Schmidt, Reinhold

Słowik, Agnieszka

Lemmens, Robin

Lindgren, Arne

Melander, Olle

Grewal, Raji P

Sacco, Ralph L

Rundek, Tatjana

Rexrode, Kathryn

Arnett, Donna K

Johnson, Julie A

Benavente, Oscar R

Wasssertheil-Smoller, Sylvia

Lee, Jin-Moo

Pulit, Sara L

Wong, Quenna

Rich, Stephen S

de Bakker, Paul IW

McArdle, Patrick F

Woo, Daniel

Anderson, Christopher D

Xu, Huichun

Heitsch, Laura

Fornage, Myriam

Jern, Christina

Stefansson, Kari

Thorsteinsdottir, Unnur

Gretarsdottir, Solveig

Lewis, Cathryn M

Sharma, Pankaj

Sudlow, Cathie LM

Rothwell, Peter M

Boncoraglio, Giorgio B

Thijs, Vincent

Levi, Chris

Meschia, James F

Rosand, Jonathan

Kittner, Steven J

Mitchell, Braxton D

Dichgans, Martin

Worrall, Bradford B

Markus, Hugh S

METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium

International Stroke Genetics Consortium

Journal Article

10.1002/ana.24840

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 a quarter of all ischaemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown 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 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 (OR(95% CI)=1.16(1.10-1.22); p=3.2x10-9 ). The lead SNP (rs12445022) was also associated with cerebral white matter hyperintensities (OR(95% CI)=1.10(1.05-1.16); p=5.3x10-5 ; N=3,670), but not intracerebral haemorrhage (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=9.4x10-7 ), and DNA methylation at probe cg16596957 in whole blood (p=5.3x10-6 ). 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.

link

Annals of Neurology 2016; 81(3): 383-394

Annals of Neurology