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

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Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.
Stroke ( IF 8.3 ) Pub Date : 2020-06-10 , DOI: 10.1161/strokeaha.119.027544
Nicola J Armstrong ₁ , Karen A Mather _{2,

3} , Muralidharan Sargurupremraj ₄ , Maria J Knol ₅ , Rainer Malik ₆ , Claudia L Satizabal _{7,

8,

9} , Lisa R Yanek ₁₀ , Wei Wen ₂ , Vilmundur G Gudnason _{11,

12} , Nicole D Dueker ₁₃ , Lloyd T Elliott _{14,

15} , Edith Hofer _{16,

17} , Joshua Bis ₁₈ , Neda Jahanshad ₁₉ , Shuo Li ₂₀ , Mark A Logue _{20,

21,

22} , Michelle Luciano ₂₃ , Markus Scholz ₂₄ , Albert V Smith ₁₂ , Stella Trompet _{25,

26} , Dina Vojinovic ₅ , Rui Xia ₂₇ , Fidel Alfaro-Almagro ₁₅ , David Ames _{28,

29} , Najaf Amin ₅ , Philippe Amouyel _{30,

31} , Alexa S Beiser _{8,

9,

20} , Henry Brodaty _{2,

32} , Ian J Deary ₂₃ , Christine Fennema-Notestine _{33,

34} , Piyush G Gampawar ₃₅ , Rebecca Gottesman ₃₆ , Ludovica Griffanti ₁₅ , Clifford R Jack ₃₇ , Mark Jenkinson ₁₅ , Jiyang Jiang ₂ , Brian G Kral ₁₀ , John B Kwok _{38,

39} , Leonie Lampe ₄₀ , David C M Liewald ₂₃ , Pauline Maillard ₄₁ , Jonathan Marchini ₄₂ , Mark E Bastin _{23,

43} , Bernard Mazoyer ₄₄ , Lukas Pirpamer ₄₅ , José Rafael Romero _{8,

9} , Gennady V Roshchupkin _{5,

46} , Peter R Schofield _{3,

38} , Matthias L Schroeter _{47,

48,

49} , David J Stott ₅₀ , Anbupalam Thalamuthu _{2,

3} , Julian Trollor _{2,

51} , Christophe Tzourio _{4,

52} , Jeroen van der Grond ₅₃ , Meike W Vernooij _{5,

46} , Veronica A Witte _{40,

54} , Margaret J Wright _{55,

56} , Qiong Yang ₂₀ , Zoe Morris ₅₇ , Siggi Siggurdsson _{7,

8,

9} , Bruce Psaty ₁₈ , Arno Villringer _{48,

49} , Helena Schmidt ₃₅ , Asta K Haberg _{58,

59} , Cornelia M van Duijn _{5,

60} , J Wouter Jukema _{61,

62} , Martin Dichgans _{6,

63,

64} , Ralph L Sacco _{65,

66,

67} , Clinton B Wright ₆₈ , William S Kremen _{69,

70} , Lewis C Becker ₁₀ , Paul M Thompson ₁₉ , Thomas H Mosley ₇₁ , Joanna M Wardlaw _{23,

43} , M Arfan Ikram ₅ , Hieab H H Adams _{5,

46,

72} , Sudha Seshadri ₁₁ , Perminder S Sachdev _{2,

73} , Stephen M Smith ₁₅ , Lenore Launer ₇₄ , William Longstreth ₁₈ , Charles DeCarli ₇₅ , Reinhold Schmidt ₁₆ , Myriam Fornage _{27,

76} , Stephanie Debette _{4,

77} , Paul A Nyquist _{10,

78,

79}

Affiliation

Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.).
Centre for Healthy Brain Ageing, School of Psychiatry (K.A.M., W.W., H.B., J.J., A.T., J.T., P.S.S.), University of New South Wales, Sydney, Australia.
Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.).
University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.).
Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (M.J.K., D.V., N.A., G.V.R., M.W.V., C.M.v.D., M.A.I., H.H.H.A.).
Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.).
Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.).
The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).
Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA.
GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
Icelandic Heart Association, Kopavogur (V.G.G., S.S.).
University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.).
Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL.
Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.).
Wellcome Centre for Integrative Neuroimaging (WIN FMRIB) (L.T.E., F.A.-A., L.G., M.J., S.M.S.), University of Oxford, United Kingdom.
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.).
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.).
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.).
Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey (N.J., P.M.T.).
Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.).
Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA.
National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.).
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, United Kingdom (M.L., I.J.D., D.C.M.L., M.E.B., J.M.W.).
Institute for Medical Informatics, Statistics and Epidemiology (M.S.).
Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands.
Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands.
Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.).
National Ageing Research Institute, Parkville, Victoria, Australia (D.A.).
Academic Unit for Psychiatry of Old Age, University of Melbourne, St George's Hospital, Kew, Australia (D.A.).
Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.).
Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.).
Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia.
Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.
Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA.
Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.).
Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.).
School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia.
Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.).
Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.).
Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.).
Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.).
Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.).
Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.).
Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.).
Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.).
LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.).
Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.).
Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.).
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.).
Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia.
CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.).
Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands.
Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W).
Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.
Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.
Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.).
Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.
Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.
Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom.
Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.).
German Center for Neurodegenerative Diseases, Munich, Germany (M.D.).
Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).
Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL.
Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL.
Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL.
National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD.
Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA.
Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA.
Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.).
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.).
Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.).
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD.
Alzheimer's Disease Center and Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience University of California at Davis (C.D.).
Human Genetics Center, School of Public Health UT, Houston, TX (M.F.).
Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.).
Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD.

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), and POLR2F (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.

中文翻译：

常见的遗传变异表明脑室周围和深部白质高信号的不同原因。

背景和目的：脑室周围白质高信号 (WMH; PVWMH) 和深部 WMH (DWMH) 是 WMH 的区域分类，反映了所提出的病因差异。迄今为止，在第一项研究中，我们对 DWMH 和 PVWMH 进行了全基因组关联分析，以表明这些表型具有不同的遗传基础。方法：参与者年龄在 45 岁及以上，没有中风和痴呆症。我们对来自 CHARGE（基因组流行病学心脏和衰老研究队列）、ENIGMA（通过元分析增强神经成像遗传学）和 UKB（英国生物库）的 26,654 名参与者进行了 PVWMH 和 DWMH 的全基因组关联分析。使用全基因组关联分析成对方法研究区域相关性。PVWMH、DWMH、中风、NBEAL )、10q23.1 ( TSPAN14/FAM231A ) 和 10q24.33 ( SH3PXD2A)。在对所有队列进行的更大范围的综合荟萃分析中，我们确定了 PVWMH 的 10 个重要区域：染色体 2（3 个区域）、6、7、10（2 个区域）、13、16 和 17q23.1。新的感兴趣位点包括 7q36.1 ( NOS3 ) 和 16q24.2。在发现/复制和组合分析中，我们发现 DWMH 和 PVWMH 的 17q25.1 基因座的全基因组显着关联。使用基于基因的关联分析，仅针对 PVWMH 确定了所有地区的 19 个基因，包括新基因：CALCRL (2q32.1)、KLHL24 (3q27.1)、VCAN (5q27.1) 和POLR2F（22q13.1）。17q25.1 基因座中的 13 个基因对两种表型都很重要。观察到 PVWMH 与小血管缺血性卒中存在更广泛的遗传相关性。两种表型都与痴呆症没有关联。结论：我们的研究证实这些表型具有独特且共享的遗传结构。遗传分析表明 PVWMH 与缺血性卒中更相关，而 DWMH 基因座与血管、星形胶质细胞和神经元功能有关。我们的研究证实这些表型是不同的神经影像学分类，并确定了仅与 PVWMH 相关的新候选基因。

更新日期：2020-06-23

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