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

Traylor, Matthew; Malik, Rainer; Nalls, Mike A.; Cotlarciuc, Ioana; Radmanesh, Farid; Thorleifsson, Gudmar; Hanscombe, Ken B.; Langefeld, Carl D.; Saleheen, Danish and Rost, Natalia S., et al. (2017) In Annals of Neurology 81(3). p.383-394
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... (More)

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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published
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keywords
genetic variation, small vessel stroke, 16q24.2
in
Annals of Neurology
volume
81
issue
3
pages
12 pages
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:85016118346
  • pmid:27997041
  • wos:000397280100008
ISSN
0364-5134
DOI
10.1002/ana.24840
language
English
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yes
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ad82f8ae-3860-453e-9326-5c2cd7d74ba4
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2017-04-24 13:14:17
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2018-05-13 04:30:44
@article{ad82f8ae-3860-453e-9326-5c2cd7d74ba4,
  abstract     = {<p>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<sup>−9</sup>). 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<sup>−5</sup>; 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<sup>−7</sup>) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10<sup>−6</sup>). 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.</p>},
  author       = {Traylor, Matthew and Malik, Rainer and Nalls, Mike A. and Cotlarciuc, Ioana and Radmanesh, Farid and Thorleifsson, Gudmar and Hanscombe, Ken B. and Langefeld, Carl D. and Saleheen, Danish and Rost, Natalia S. and Yet, Idil and Spector, Tim D. and Bell, Jordana T. and Hannon, Eilis and Mill, Jonathan and Chauhan, Ganesh and Debette, Stephanie and Bis, Joshua C. and Longstreth, W. T. and Ikram, M. Arfan and Launer, Lenore J. and Seshadri, Sudha and Hamilton-Bruce, Monica Anne and Jimenez-Conde, Jordi and Cole, John W. and Schmidt, Reinhold and Słowik, Agnieszka and Lemmens, Robin and Lindgren, Arne and Melander, Olle and Grewal, Raji P. and Sacco, Ralph L. and Rundek, Tatjana and Rexrode, Kathryn and Arnett, Donna K. and Johnson, Julie A. and Benavente, Oscar R and Wasssertheil-Smoller, Sylvia and Lee, Jin-Moo and Pulit, Sara L and Wong, Quenna and Rich, Stephen and De Bakker, Paul I.W. and McArdle, Patrick F. and Woo, Daniel and Anderson, Christopher D. and Xu, Huichun and Heitsch, Laura and Fornage, Myriam and Jern, Christina and Stefansson, Kari and Thorsteinsdottir, Unnur and Gretarsdottir, Solveig and Lewis, Cathryn M. and Sharma, Pankaj and Sudlow, Cathie L M and Rothwell, Peter M. and Boncoraglio, Giorgio B. and Thijs, Vincent and Levi, Chris and Meschia, James F. and Rosand, Jonathan and Kittner, Steven J and Mitchell, Braxton D and Dichgans, Martin and Worrall, Bradford and Markus, Hugh S. and ,  and , },
  issn         = {0364-5134},
  keyword      = {genetic variation,small vessel stroke,16q24.2},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {383--394},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Genetic variation at 16q24.2 is associated with small vessel stroke},
  url          = {http://dx.doi.org/10.1002/ana.24840},
  volume       = {81},
  year         = {2017},
}