Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities-Reference-Cited by-同舟云学术

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

Published:2020-07 Issue:7 Volume:51 Page:2111-2121
ISSN:0039-2499
Container-title:Stroke
language:en
Short-container-title:Stroke

Author:

Armstrong Nicola J.¹,Mather Karen A.²³,Sargurupremraj Muralidharan⁴,Knol Maria J.⁵,Malik Rainer⁶,Satizabal Claudia L.⁷⁸⁹,Yanek Lisa R.¹⁰,Wen Wei²,Gudnason Vilmundur G.¹¹¹²,Dueker Nicole D.¹³,Elliott Lloyd T.¹⁴¹⁵,Hofer Edith¹⁶¹⁷,Bis Joshua¹⁸,Jahanshad Neda¹⁹,Li Shuo²⁰,Logue Mark A.²¹²⁰²²,Luciano Michelle²³,Scholz Markus²⁴,Smith Albert V.¹²,Trompet Stella²⁵²⁶,Vojinovic Dina⁵,Xia Rui²⁷,Alfaro-Almagro Fidel¹⁵,Ames David²⁸²⁹,Amin Najaf⁵,Amouyel Philippe³⁰³¹,Beiser Alexa S.⁸⁹²⁰,Brodaty Henry²³²,Deary Ian J.²³,Fennema-Notestine Christine³³³⁴,Gampawar Piyush G.³⁵,Gottesman Rebecca³⁶,Griffanti Ludovica¹⁵,Jack Clifford R.³⁷,Jenkinson Mark¹⁵,Jiang Jiyang²,Kral Brian G.¹⁰,Kwok John B.³⁸³⁹,Lampe Leonie⁴⁰,C.M. Liewald David²³,Maillard Pauline⁴¹,Marchini Jonathan⁴²,Bastin Mark E.²³⁴³,Mazoyer Bernard⁴⁴,Pirpamer Lukas⁴⁵,Rafael Romero José⁸⁹,Roshchupkin Gennady V.⁵⁴⁶,Schofield Peter R.³⁸³,Schroeter Matthias L.⁴⁷⁴⁸⁴⁹,Stott David J.⁵⁰,Thalamuthu Anbupalam²³,Trollor Julian²⁵¹,Tzourio Christophe⁴⁵²,van der Grond Jeroen⁵³,Vernooij Meike W.⁵⁴⁶,Witte Veronica A.⁵⁴⁴⁰,Wright Margaret J.⁵⁵⁵⁶,Yang Qiong²⁰,Morris Zoe⁵⁷,Siggurdsson Siggi⁷⁸⁹,Psaty Bruce¹⁸,Villringer Arno⁴⁸⁴⁹,Schmidt Helena³⁵,Haberg Asta K.⁵⁸⁵⁹,van Duijn Cornelia M.⁵⁶⁰,Jukema J. Wouter⁶¹⁶²,Dichgans Martin⁶⁶³⁶⁴,Sacco Ralph L.⁶⁵⁶⁶⁶⁷,Wright Clinton B.⁶⁸,Kremen William S.⁶⁹⁷⁰,Becker Lewis C.¹⁰,Thompson Paul M.¹⁹,Mosley Thomas H.⁷¹,Wardlaw Joanna M.²³⁴³,Ikram M. Arfan⁵,Adams Hieab H.H.⁵⁴⁶⁷²,Seshadri Sudha¹¹,Sachdev Perminder S.²⁷³,Smith Stephen M.¹⁵,Launer Lenore⁷⁴,Longstreth William¹⁸,DeCarli Charles⁷⁵,Schmidt Reinhold¹⁶,Fornage Myriam²⁷⁷⁶,Debette Stephanie⁴⁷⁷,Nyquist Paul A.¹⁰⁷⁸⁷⁹^ORCID

Affiliation:

1. Mathematics and Statistics, Murdoch University, Perth, Australia (N.J.A.).

2. 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.

3. Neuroscience Research Australia, Sydney, Australia (K.A.M., P.R.S., A.T.).

4. University Bordeaux, Inserm, Bordeaux Population Health Research Center, France (M.S., C.T., S.D.).

5. 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.).

6. Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-Universität LMU Munich, Germany (R.M., M.D.).

7. Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX (C.L.S., S.S.).

8. The Framingham Heart Study, MA (C.L.S., A.S.B., J.R.R., S.S.).

9. Department of Neurology (C.L.S., A.S.B., J.R.R., S.S.), Boston University School of Medicine, MA.

10. GeneSTAR Research Program (L.R.Y., B.G.K., L.C.B., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.

11. Icelandic Heart Association, Kopavogur (V.G.G., S.S.).

12. University of Iceland, Reykjavik, Iceland (V.G.G., A.V.S.).

13. Dr. John T. Macdonald Foundation Department of Human Genetics (R.L.S.), University of Miami, FL.

14. Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, BC, Canada (L.T.E.).

15. 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.

16. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (E.H., R.S.).

17. Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria (E.H.).

18. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA (J.B., B.P., W.L.).

19. 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.).

20. Department of Biostatistics, Boston University School of Public Health, Boston, MA (S.L., M.A.L., A.S.B., Q.Y.).

21. Department of Psychiatry and Biomedical Genetics Section (M.A.L.), Boston University School of Medicine, MA.

22. National Center for PTSD: Behavioral Science Division, VA Boston Healthcare System, Boston, MA (M.A.L.).

23. 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.).

24. Institute for Medical Informatics, Statistics and Epidemiology (M.S.)

25. Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Leiden University Medical Center, the Netherlands.

26. Department of Cardiology (S.T.), Leiden University Medical Center, the Netherlands.

27. Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, TX (R.X., M.F.).

28. National Ageing Research Institute, Parkville, Victoria, Australia (D.A.).

29. Academic Unit for Psychiatry of Old Age, University of Melbourne, St George’s Hospital, Kew, Australia (D.A.).

30. Lille University, Inserm, Institut Pasteur de Lille, RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases and Labex Distalz, France (P.A.).

31. Lille University, Inserm, CHU Lille, Institut Pasteur de Lille, RID-AGE (P.A.)

32. Dementia Centre for Research Collaboration (H.B.), University of New South Wales, Sydney, Australia.

33. Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

34. Center for Behavior Genetics of Aging (C.F.-N.), University of California, San Diego, La Jolla, CA.

35. Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Medical University of Graz, Austria (P.G.G., H.S.).

36. Department of Neurology, Cerebrovascular and stroke Division (R.G.), Johns Hopkins University School of Medicine, Baltimore, MD.

37. Department of Radiology, Mayo Clinic, Rochester, MN (C.R.J.J.).

38. School of Medical Sciences (J.B.K., P.R.S.), University of New South Wales, Sydney, Australia.

39. Brain and Mind Centre - The University of Sydney, Camperdown, NSW, Australia (J.B.K.).

40. Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (L.L., V.A.W.).

41. Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology, University of California-Davis, Davis, CA (P.M.).

42. Statistical Genetics and Methods at Regeneron Pharmaceuticals, Inc, New York, NY (J.M.).

43. Centre for Clinical Brain Sciences, Edinburgh Imaging, Centre for Cognitive Ageing, University of Edinburgh, United Kingdom (M.E.B., J.M.W.).

44. Institut des Maladies Neurodégénératives, University of Bordeaux, France (B.M.).

45. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Austria (L.P.).

46. Department of Radiology and Nuclear Medicine (G.V.R., M.W.V., H.H.H.A.)

47. LIFE Research Center for Civilization Disease, Leipzig, Germany (M.S.).

48. Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany (M.L.S., A.V.).

49. Day Clinic for Cognitive Neurology, University Hospital Leipzig, Germany (M.L.S., A.V.).

50. Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (D.J.S.).

51. Department of Developmental Disability Neuropsychiatry, School of Psychiatry (J.T.), University of New South Wales, Sydney, Australia.

52. CHU de Bordeaux, Public Health Department, Medical information Department, Bordeaux, France (C.T.).

53. Department of Radiology (J.v.d.G.), Leiden University Medical Center, the Netherlands.

54. Collaborative Research Center 1052 Obesity Mechanisms, Faculty of Medicine, University of Leipzig, Germany (V.A.W).

55. Queensland Brain Institute (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.

56. Centre for Advanced Imaging (M.J.W.), The University of Queensland, St Lucia, QLD, Australia.

57. Neuroradiology Department, Department of Clinical Neurosciences, Western General Hospital, Edinburgh, United Kingdom (Z.M.).

58. Department of Neuromedicine and Movement Science (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.

59. Department of Radiology and Nuclear Medicine (A.K.H.), Norwegian University of Science and Technology, Trondheim, Norway.

60. Nuffield Department of Population Health (C.M.v.D.), University of Oxford, United Kingdom.

61. Department of Cardiology (J.W.J.), Leiden University Medical Center, the Netherlands.

62. Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, the Netherlands (J.W.J.).

63. German Center for Neurodegenerative Diseases, Munich, Germany (M.D.).

64. Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).

65. Department of Public Health Sciences, Miller School of Medicine (R.L.S.), University of Miami, FL.

66. Department of Neurology, Miller School of Medicine (R.L.S.), University of Miami, FL.

67. Evelyn F. McKnight Brain Institute, Department of Neurology (R.L.S.), University of Miami, FL.

68. National Institute of Neurological Disorders and Stroke (C.B.W.), National Institutes of Health, Bethesda, MD.

69. Center for Behavior Genetics of Aging (W.S.K.), University of California, San Diego, La Jolla, CA.

70. Department of Psychiatry (W.S.K.), University of California, San Diego, La Jolla, CA.

71. Department of Geriatric Medicine, Memory Impairment and Neurodegenerative Dementia (MIND) Center, University of Mississippi Medical Center, Jackson (T.H.M.).

72. Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands (H.H.H.A.).

73. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia (P.S.S.).

74. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program (L.L.), National Institutes of Health, Bethesda, MD.

75. 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.).

76. Human Genetics Center, School of Public Health UT, Houston, TX (M.F.).

77. Department of Neurology, CHU de Bordeaux (University Hospital), Bordeaux, France (S.D.).

78. Departments of Neurology, Critical Care Medicine, Neurosurgery (P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.

79. Critical Care Medicine Department (P.A.N.), National Institutes of Health, Bethesda, MD.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Advanced and Specialised Nursing,Cardiology and Cardiovascular Medicine,Clinical Neurology

Reference50 articles.

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