Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

被引：82

作者：

Armstrong, Nicola J. ^{[1
]}

Mather, Karen A. ^{[2
,6
]}

Sargurupremraj, Muralidharan ^{[7
]}

Knol, Maria J. ^{[8
]}

Malik, Rainer ^{[9
]}

Satizabal, Claudia L. ^{[10
,11
,12
]}

Yanek, Lisa R. ^{[15
]}

Wen, Wei ^{[2
]}

Gudnason, Vilmundur G. ^{[20
,21
]}

Dueker, Nicole D. ^{[22
,23
,24
,25
,26
]}

Elliott, Lloyd T. ^{[27
,28
]}

Hofer, Edith ^{[30
,31
]}

Bis, Joshua ^{[32
]}

Jahanshad, Neda ^{[33
]}

Li, Shuo ^{[34
]}

Logue, Mark A. ^{[8
,13
,14
,34
,35
]}

Luciano, Michelle ^{[36
]}

Scholz, Markus ^{[7
,37
,39
]}

Smith, Albert V. ^{[21
]}

Trompet, Stella ^{[40
,41
]}

Vojinovic, Dina ^{[8
]}

Xia, Rui ^{[44
]}

Alfaro-Almagro, Fidel ^{[28
]}

Ames, David ^{[45
,46
]}

Amin, Najaf ^{[8
]}

Amouyel, Philippe ^{[47
,48
]}

Beiser, Alexa S. ^{[11
,12
,34
]}

Brodaty, Henry ^{[2
,4
]}

Deary, Ian J. ^{[36
]}

Fennema-Notestine, Christine ^{[49
,50
]}

Gampawar, Piyush G. ^{[53
]}

Gottesman, Rebecca ^{[16
]}

Griffanti, Ludovica ^{[28
]}

Jack, Clifford R., Jr. ^{[54
]}

Jenkinson, Mark ^{[28
]}

Jiang, Jiyang ^{[2
]}

Kral, Brian G. ^{[15
]}

Kwok, John B. ^{[3
,55
]}

Lampe, Leonie ^{[77
]}

Liewald, David C. M. ^{[36
]}

Maillard, Pauline ^{[57
]}

Marchini, Jonathan ^{[58
]}

Bastin, Mark E. ^{[36
,59
]}

Mazoyer, Bernard ^{[60
]}

Pirpamer, Lukas ^{[61
]}

Rafael Romero, Jose ^{[11
,12
]}

Roshchupkin, Gennady V. ^{[8
,62
]}

Schofield, Peter R. ^{[3
,6
]}

Schroeter, Matthias L. ^{[64
,65
]}

Stott, David J. ^{[66
]}

机构：

[1] Murdoch Univ, Math & Stat, Perth, WA, Australia

[2] Univ New South Wales, Ctr Hlth Brain Ageing, Sch Psychiat, Sydney, NSW, Australia

[3] Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia

[4] Univ New South Wales, Dementia Ctr Res Collaborat, Sydney, NSW, Australia

[5] Univ New South Wales, Dept Dev Disabil Neuropsychiat, Sch Psychiat, Sydney, NSW, Australia

[6] Neurosci Res Australia, Sydney, NSW, Australia

[7] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, Bordeaux, France

[8] Erasmus MC, Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[9] Ludwig Maximilians Univ LMU Munich, Inst Stroke & Dementia Res ISD, Univ Hosp, Munich, Germany

[10] UT Hlth San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA

[11] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[12] Boston Univ, Dept Neurol, Sch Med, Boston, MA 02215 USA

[13] Boston Univ, Dept Psychiat, Sch Med, Boston, MA 02215 USA

[14] Boston Univ, Biomed Genet Sect, Sch Med, Boston, MA 02215 USA

[15] Johns Hopkins Univ, Sch Med, GeneSTAR Res Program, Baltimore, MD USA

[16] Johns Hopkins Univ, Sch Med, Dept Neurol, Cerebrovasc & Stroke Div, Baltimore, MD 21205 USA

[17] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[18] Johns Hopkins Univ, Sch Med, Dept Crit Care Med, Baltimore, MD USA

[19] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA

[20] Iceland Heart Assoc, Kopavogur, Iceland

[21] Univ Iceland, Reykjavik, Iceland

[22] Univ Miami, John P Hussman Inst Human Genom, Coral Gables, FL 33124 USA

[23] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Coral Gables, FL 33124 USA

[24] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Coral Gables, FL 33124 USA

[25] Univ Miami, Miller Sch Med, Dept Neurol, Coral Gables, FL 33124 USA

[26] Univ Miami, Evelyn F McKnight Brain Inst, Dept Neurol, Coral Gables, FL 33124 USA

[27] Simon Fraser Univ, Dept Stat & Actuarial Sci, Burnaby, BC, Canada

[28] Univ Oxford, Wellcome Ctr Integrat Neuroimaging WIN FMRIB, Oxford, England

[29] Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England

[30] Med Univ Graz, Dept Neurol, Clin Div Neurogeriatr, Graz, Austria

[31] Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria

[32] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[33] Univ Southern Calif, Keck Sch Med USC, Mark & Mary Stevens Neuroimaging & Informat Inst, Marina Del Rey, CA USA

[34] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[35] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA

[36] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland

[37] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[38] Univ Leipzig, Collaborat Res Ctr 1052 Obes Mech, Fac Med, Leipzig, Germany

[39] LIFE Res Ctr Civilizat Dis, Leipzig, Germany

[40] Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands

[41] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands

[42] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands

[43] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands

[44] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, McGovern Med Sch, Houston, TX 77030 USA

[45] Natl Ageing Res Inst, Parkville, Vic, Australia

[46] Univ Melbourne, St Georges Hosp, Acad Unit Psychiat Old Age, Kew, Australia

[47] Lille Univ, Inst Pasteur Lille, RID AGE Risk Factors & Mol Determinants Aging Rel, INSERM, Lille, France

[48] Lille Univ, Inst Pasteur Lille, RID AGE, INSERM,CHU Lille, Lille, France

[49] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[50] Univ Calif San Diego, Ctr Behav Genet Aging, La Jolla, CA 92093 USA

来源：

STROKE | 2020年 / 51卷 / 07期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 奥地利科学基金会; 英国生物技术与生命科学研究理事会; 美国国家卫生研究院; 俄罗斯基础研究基金会;

关键词：

brain; genome-wide association study; neuroimaging; risk factors; white matter; SMALL VESSEL DISEASE; SILENT BRAIN INFARCTS; COL4A2; MUTATION; ASSOCIATION; LESIONS; PATHOGENESIS; METAANALYSIS; EXPRESSION; PATHOLOGY; INSIGHTS;

D O I：

10.1161/STROKEAHA.119.027544

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A).In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes:CALCRL(2q32.1),KLHL24(3q27.1),VCAN(5q27.1), andPOLR2F(22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

引用

页码：2111 / 2121

页数：11

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