title: Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.
abstract: OBJECTIVE
  We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.
  
  
  METHODS
  We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).
  
  
  RESULTS
  Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.
  
  
  CONCLUSIONS
  Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
authors: Authors' affiliations are listed at the end of the article.
authors: Kristiina
authors: K
authors: Rannikmäe
authors: Authors' affiliations are listed at the end of the article.
authors: Gail
authors: G
authors: Davies
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authors: Pippa A
authors: PA
authors: Thomson
authors: Authors' affiliations are listed at the end of the article.
authors: Steve
authors: S
authors: Bevan
authors: Authors' affiliations are listed at the end of the article.
authors: William J
authors: WJ
authors: Devan
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authors: Guido J
authors: GJ
authors: Falcone
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authors: Matthew
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authors: Traylor
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authors: Christopher D
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authors: Thomas W K
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authors: Farid
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authors: Ranjan
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authors: Jessica G
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authors: Lisa J
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authors: Jordi
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authors: Magdy
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authors: Devin L
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authors: Scott L
authors: SL
authors: Silliman
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authors: Chelsea S
authors: CS
authors: Kidwell
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authors: Joan
authors: J
authors: Montaner
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authors: Carl D
authors: CD
authors: Langefeld
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authors: Agnieszka
authors: A
authors: Slowik
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authors: Björn M
authors: BM
authors: Hansen
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authors: Arne G
authors: AG
authors: Lindgren
authors: Authors' affiliations are listed at the end of the article.
authors: James F
authors: JF
authors: Meschia
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authors: Myriam
authors: M
authors: Fornage
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authors: Joshua C
authors: JC
authors: Bis
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authors: Stéphanie
authors: S
authors: Debette
authors: Authors' affiliations are listed at the end of the article.
authors: Mohammad A
authors: MA
authors: Ikram
authors: Authors' affiliations are listed at the end of the article.
authors: Will T
authors: WT
authors: Longstreth
authors: Authors' affiliations are listed at the end of the article.
authors: Reinhold
authors: R
authors: Schmidt
authors: Authors' affiliations are listed at the end of the article.
authors: Cathy R
authors: CR
authors: Zhang
authors: Authors' affiliations are listed at the end of the article.
authors: Qiong
authors: Q
authors: Yang
authors: Authors' affiliations are listed at the end of the article.
authors: Pankaj
authors: P
authors: Sharma
authors: Authors' affiliations are listed at the end of the article.
authors: Steven J
authors: SJ
authors: Kittner
authors: Authors' affiliations are listed at the end of the article.
authors: Braxton D
authors: BD
authors: Mitchell
authors: Authors' affiliations are listed at the end of the article.
authors: Elizabeth G
authors: EG
authors: Holliday
authors: Authors' affiliations are listed at the end of the article.
authors: Christopher R
authors: CR
authors: Levi
authors: Authors' affiliations are listed at the end of the article.
authors: John
authors: J
authors: Attia
authors: Authors' affiliations are listed at the end of the article.
authors: Peter M
authors: PM
authors: Rothwell
authors: Authors' affiliations are listed at the end of the article.
authors: Deborah L
authors: DL
authors: Poole
authors: Authors' affiliations are listed at the end of the article.
authors: Giorgio B
authors: GB
authors: Boncoraglio
authors: Authors' affiliations are listed at the end of the article.
authors: Bruce M
authors: BM
authors: Psaty
authors: Authors' affiliations are listed at the end of the article.
authors: Rainer
authors: R
authors: Malik
authors: Authors' affiliations are listed at the end of the article.
authors: Natalia
authors: N
authors: Rost
authors: Authors' affiliations are listed at the end of the article.
authors: Bradford B
authors: BB
authors: Worrall
authors: Authors' affiliations are listed at the end of the article.
authors: Martin
authors: M
authors: Dichgans
authors: Authors' affiliations are listed at the end of the article.
authors: Tom
authors: T
authors: Van Agtmael
authors: Authors' affiliations are listed at the end of the article.
authors: Daniel
authors: D
authors: Woo
authors: Authors' affiliations are listed at the end of the article.
authors: Hugh S
authors: HS
authors: Markus
authors: Authors' affiliations are listed at the end of the article.
authors: Sudha
authors: S
authors: Seshadri
authors: Authors' affiliations are listed at the end of the article.
authors: Jonathan
authors: J
authors: Rosand
authors: Authors' affiliations are listed at the end of the article. cathie.sudlow@e.ac.uk.
authors: Cathie L M
authors: CL
authors: Sudlow
mesh_terms: D059345:Cerebral Small Vessel Diseases / Q000175:diagnosis* / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C547475:COL4A1 protein, human; C502625:COL4A2 protein, human; D024141:Collagen Type IV
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