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

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

Research output: Contribution to journalArticle

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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 (US)
Pages (from-to)383-394
Number of pages12
JournalAnnals of Neurology
Volume81
Issue number3
DOIs
StatePublished - Mar 1 2017

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Stroke
Genome-Wide Association Study
DNA Methylation
Confidence Intervals
Age of Onset
Cerebral Small Vessel Diseases
Messenger RNA
Cerebral Hemorrhage
Fetal Blood
Single Nucleotide Polymorphism
Blood Vessels
Meta-Analysis
Chromosomes
Odds Ratio
Phenotype
Gene Expression
Brain
Population

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

on behalf of the International Stroke Genetics Consortium, & METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium (2017). Genetic variation at 16q24.2 is associated with small vessel stroke. Annals of Neurology, 81(3), 383-394. https://doi.org/10.1002/ana.24840

Genetic variation at 16q24.2 is associated with small vessel stroke. / on behalf of the International Stroke Genetics Consortium; METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium.

In: Annals of Neurology, Vol. 81, No. 3, 01.03.2017, p. 383-394.

Research output: Contribution to journalArticle

on behalf of the International Stroke Genetics Consortium & METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium 2017, 'Genetic variation at 16q24.2 is associated with small vessel stroke', Annals of Neurology, vol. 81, no. 3, pp. 383-394. https://doi.org/10.1002/ana.24840
on behalf of the International Stroke Genetics Consortium, METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium. Genetic variation at 16q24.2 is associated with small vessel stroke. Annals of Neurology. 2017 Mar 1;81(3):383-394. https://doi.org/10.1002/ana.24840
on behalf of the International Stroke Genetics Consortium ; METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium. / Genetic variation at 16q24.2 is associated with small vessel stroke. In: Annals of Neurology. 2017 ; Vol. 81, No. 3. pp. 383-394.
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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.",
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TY - JOUR

T1 - Genetic variation at 16q24.2 is associated with small vessel stroke

AU - on behalf of the International Stroke Genetics Consortium

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

AU - Traylor, Matthew

AU - Malik, Rainer

AU - Nalls, Mike A.

AU - Cotlarciuc, Ioana

AU - Radmanesh, Farid

AU - Thorleifsson, Gudmar

AU - Hanscombe, Ken B.

AU - Langefeld, Carl

AU - Saleheen, Danish

AU - Rost, Natalia S.

AU - Yet, Idil

AU - Spector, Tim D.

AU - Bell, Jordana T.

AU - Hannon, Eilis

AU - Mill, Jonathan

AU - Chauhan, Ganesh

AU - Debette, Stephanie

AU - Bis, Joshua C.

AU - Longstreth, W. T.

AU - Ikram, M. Arfan

AU - Launer, Lenore J.

AU - Seshadri, Sudha

AU - Hamilton-Bruce, Monica Anne

AU - Jimenez-Conde, Jordi

AU - Cole, John W.

AU - Schmidt, Reinhold

AU - Słowik, Agnieszka

AU - Lemmens, Robin

AU - Lindgren, Arne

AU - Melander, Olle

AU - Grewal, Raji P.

AU - Sacco, Ralph L.

AU - Sacco, Ralph L

AU - Rundek, Tatjana

AU - Arnett, Donna K.

AU - Johnson, Julie A.

AU - Benavente, Oscar R.

AU - Wasssertheil-Smoller, Sylvia

AU - Lee, Jin Moo

AU - Pulit, Sara L.

AU - Wong, Quenna

AU - Rich, Stephen S.

AU - de Bakker, Paul I.W.

AU - McArdle, Patrick F.

AU - Woo, Daniel

AU - Anderson, Christopher D.

AU - Xu, Huichun

AU - Heitsch, Laura

AU - Fornage, Myriam

AU - Jern, Christina

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

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