title: Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium.
abstract: BACKGROUND
  Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.
  
  
  RESULTS
  We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).
  
  
  CONCLUSIONS
  Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors: Anita
authors: A
authors: DeStefano
authors: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors: Xiaoming
authors: X
authors: Liu
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Jennifer A
authors: JA
authors: Brody
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors: Seung Hoan
authors: SH
authors: Choi
authors: Department of Radiology, Erasmus MC, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Benjamin F J
authors: BF
authors: Verhaaren
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France; Department of Epidemiology, University of Versailles Saint-Quentin-en-Yvelines, Paris, France.
authors: Stéphanie
authors: S
authors: Debette
authors: Department of Radiology, Erasmus MC, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands; Department of Neurology, Erasmus MC, Rotterdam, The Netherlands (M.A.I.); Netherlands; Consortium for Healthy Aging, Leiden, The Netherlands.
authors: M Arfan
authors: MA
authors: Ikram
authors: Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, United States of America.
authors: Eyal
authors: E
authors: Shahar
authors: Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors: Kenneth R
authors: KR
authors: Butler
authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors: Rebecca F
authors: RF
authors: Gottesman
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Donna
authors: D
authors: Muzny
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Christie L
authors: CL
authors: Kovar
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health, Seattle, Washington, United States of America.
authors: Bruce M
authors: BM
authors: Psaty
authors: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Department of Statistics, University of Auckland, Auckland, New Zealand.
authors: Thomas
authors: T
authors: Lumley
authors: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors: Mayetri
authors: M
authors: Gupta
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Philip A
authors: PA
authors: Wolf
authors: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors: Cornelia
authors: C
authors: van Duijn
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Richard A
authors: RA
authors: Gibbs
authors: Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors: Thomas H
authors: TH
authors: Mosley
authors: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Department of Neurology, University of Washington, Seattle, Washington, United States of America.
authors: W T
authors: WT
authors: Longstreth
authors: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Texas, United States of America.
authors: Eric
authors: E
authors: Boerwinkle
authors: Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Sudha
authors: S
authors: Seshadri
authors: Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Texas, United States of America.
authors: Myriam
authors: M
authors: Fornage
mesh_terms: D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D018740:Genetic Heterogeneity; D006801:Humans; D007438:Introns; D007511:Ischemia / Q000235:genetics*; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C504206:NINJ2 protein, human