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Ann Neurol. 2017 Mar;81(3):383-394. doi: 10.1002/ana.24840.

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

Author information

1
Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
2
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany.
3
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD.
4
Institute of Cardiovascular Research Royal Holloway University of London (ICR2UL), London, United Kingdom.
5
Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA.
6
J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Boston, MA.
7
Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.
8
deCODE genetics/AMGEN, Reykjavik, Iceland.
9
Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
10
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
11
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
12
University of Exeter Medical School, University of Exeter, Exeter, United Kingdom.
13
Social, Genetic and Developmental Psychiatry Center, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
14
Inserm Research Center for Epidemiology and Biostatistics (U897)-Team Neuroepidemiology, Bordeaux, France.
15
University of Bordeaux, Bordeaux, France.
16
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
17
Departments of Neurology and Epidemiology, University of Washington, Seattle, WA.
18
Department of Neurology, Epidemiology and Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
19
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD.
20
Boston University School of Medicine, Boston, MA.
21
Framingham Heart Study, Framingham, MA.
22
Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
23
Neurovascular Research Group (NEUVAS), Neurology Department, Institut Hospital del Mar d'Investigació Mèdica, Barcelona, Spain.
24
Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD.
25
Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria.
26
Department of Neurology, Jagiellonian University, Krakow, Poland.
27
KU Leuven-University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
28
VIB, Vesalius Research Center, Laboratory of Neurobiology, Department of Neurology, Leuven, Belgium.
29
University Hospitals Leuven, Department of Neurology, Leuven, Belgium.
30
Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden.
31
Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.
32
Department of Clinical Sciences, Lund University, Malmö, Sweden.
33
Neuroscience Institute, Saint Francis Medical Center, School of Health and Medical Sciences, Seton Hall University, South Orange, NJ.
34
Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL.
35
Harvard Medical School, Boston, MA, Center for Faculty Development and Diversity, Brigham and Women's Hospital, Boston, MA.
36
College of Public Health, University of Kentucky, Lexington, KY.
37
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, College of Pharmacy, Gainesville, FL.
38
Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville, FL.
39
Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
40
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY.
41
Stroke Center, Department of Neurology, Washington University School of Medicine, Seattle, WA.
42
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
43
Department of Biostatistics, University of Washington, Seattle, WA.
44
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA.
45
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
46
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
47
Department of Medicine, University of Maryland School of Medicine, MD.
48
University of Cincinnati College of Medicine, Cincinnati, OH.
49
Program in Medical and Population Genetics, Broad Institute, Boston, MA.
50
Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD.
51
Division of Emergency Medicine, Washington University School of Medicine, St Louis, MO.
52
The University of Texas Health Science Center at Houston, Houston, TX.
53
Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
54
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
55
Center for Clinical Brain Sciences & Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
56
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
57
Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy.
58
Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia.
59
John Hunter Hospital, Hunter Medical Research Institute and University of Newcastle, Newcastle, NSW, Australia.
60
Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL.
61
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
62
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.
63
Munich Cluster of Systems Neurology, SyNergy, Munich, Germany.
64
Departments of Neurology and Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA.
65
Stroke Research Group, Division of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.

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.

PMID:
27997041
PMCID:
PMC5366092
DOI:
10.1002/ana.24840
[Indexed for MEDLINE]
Free PMC Article

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