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Stroke. 2018 Aug;49(8):1812-1819. doi: 10.1161/STROKEAHA.118.020689.

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Author information

1
From the Institute of Molecular Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (M.F., X.J.).
2
Department of Neurology, Boston University School of Medicine, MA (C.L.S., S. Seshadri).
3
Icelandic Heart Association, Kópavogur, Iceland (A.V.S., G.E., S. Sigurdsson, V.G.G.).
4
German Center for Neurodegenerative Diseases, Site Rostock/Greifswald, Germany (K.W.).
5
Cardiovascular Health Research Unit (B.M.P., J.C.B., S.R.H.).
6
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor (J.A.S., S.L.R.K., W.Z.).
7
Division of Public Health Sciences (F.-C.H., J.D.).
8
Center for Neuroimaging, Indiana University School of Medicine, Indianapolis (K.N., S.L.R.).
9
Department of Neurology (E.H., R.S.).
10
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, United Kingdom (I.J.D., J.M.W., J.M.S., M.d.C.V.-H., M.E.B., N.A.R., S.P.H.).
11
Department of Neurology and Neurosurgery (P.A.N., R.F.G.).
12
Bordeaux Population Health Research Centre U1219, Inserm, France (A.M., G.C., S.D.).
13
Department of Epidemiology (C.M.v.D., H.H.H.A.).
14
Department of Biostatistics, Boston University School of Public Health, MA (A.S.B., A.L.D., Q.Y., S.L.).
15
Institute for Community Medicine (A.T.).
16
Department of Internal Medicine (B.I.F.).
17
Institute of Molecular Biology and Biochemistry (H.S., Y.S.), Medical University of Graz, Austria.
18
Department of Medicine (D.M.B., L.R.Y., R.A.M.), Johns Hopkins School of Medicine, Baltimore, MD.
19
Department of Radiology, Leiden University Medical Center, the Netherlands (M.A.v.B.).
20
Department of Medicine, The University of Vermont Larner College of Medicine, Burlington (M.C.).
21
Department of Diagnostic Medicine, Dell Medical School at The University of Texas at Austin (R.N.B.).
22
Departments of Radiology and Medical Informatics (W.J.N.).
23
Department of Medicine, The University of Mississippi School of Medicine, Jackson (W.J.N.).
24
Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia (M.H.).
25
Department of Biochemistry (D.W.B., N.D.P.), Wake Forest School of Medicine, Winston-Salem, NC.
26
Department of Epidemiology, The University of Alabama at Birmingham School of Public Health (C.E.L.).
27
Department of Neurology, UC Davis School of Medicine (C.S.D., P.M.), CA.
28
Institute of Genetics and Functional Genomics, University of Greifswald, Germany (G.H.).
29
Institute for Diagnostic Radiology and Neuroradiology (S.L.).
30
Department of Biostatistics, University of Washington School of Public Health, Seattle (K.M.R.).
31
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas (J.A.M.).
32
Division of Research, Kaiser Permanente Northern California, Oakland (S. Sidney).
33
Departments of Internal Medicine, Epidemiology, and Clinical Chemistry (A.G.U.).
34
Institute for Clinical Chemistry and Laboratory Medicine (M.N.).
35
Institute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, CA (J.I.R.).
36
Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis (P.J.S.).
37
Human Genetics Center, The University of Texas Health Science Center at Houston School of Public Health (E.B.).
38
Neurodegeneratives Diseases Institute-CNRS UMR 5293 (B.M.), University of Bordeaux, France.
39
Department of Neurology (B.v.S.).
40
Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, MD (D.L.).
41
Departments of Radiology and Epidemiology (M.W.V.).
42
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (S.T.T.).
43
Departments of Epidemiology, Radiology and Neurology (M.A.I.), Erasmus University Medical Center, Rotterdam, the Netherlands.
44
Department of Psychiatry and Psychotherapy (H.J.G.), University Medicine Greifswald, Germany.
45
Departments of Neurology and Epidemiology (W.T.L.), University of Washington, Seattle, WA.
46
Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD (L.J.L.).

Abstract

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

KEYWORDS:

cerebral small vessel disease; exome; magnetic resonance imaging; meta-analysis; white matter

PMID:
30002152
PMCID:
PMC6202149
DOI:
10.1161/STROKEAHA.118.020689
[Indexed for MEDLINE]
Free PMC Article

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