Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Dina Vojinovic; Hieab H Adams; Xueqiu Jian; Qiong Yang; Albert Vernon Smith; Joshua C Bis; Alexander Teumer; Markus Scholz; Nicola J Armstrong; Edith Hofer; Yasaman Saba; Michelle Luciano; Manon Bernard; Stella Trompet; Jingyun Yang; Nathan A Gillespie; Sven J van der Lee; Alexander Neumann; Shahzad Ahmad; Ole A Andreassen; David Ames; Najaf Amin; Konstantinos Arfanakis; Mark E Bastin; Diane M Becker; Alexa S Beiser; Frauke Beyer; Henry Brodaty; R Nick Bryan; Robin Bülow; Anders M Dale; Philip L De Jager; Ian J Deary; Charles DeCarli; Debra A Fleischman; Rebecca F Gottesman; Jeroen van der Grond; Vilmundur Gudnason; Tamara B Harris; Georg Homuth; David S Knopman; John B Kwok; Cora E Lewis; Shuo Li; Markus Loeffler; Oscar L Lopez; Pauline Maillard; Hanan El Marroun; Karen A Mather; Thomas H Mosley; Ryan L Muetzel; Matthias Nauck; Paul A Nyquist; Matthew S Panizzon; Zdenka Pausova; Bruce M Psaty; Ken Rice; Jerome I Rotter; Natalie Royle; Claudia L Satizabal; Reinhold Schmidt; Peter R Schofield; Pamela J Schreiner; Stephen Sidney; David J Stott; Anbupalam Thalamuthu; Andre G Uitterlinden; Maria C Valdés Hernández; Meike W Vernooij; Wei Wen; Tonya White; A Veronica Witte; Katharina Wittfeld; Margaret J Wright; Lisa R Yanek; Henning Tiemeier; William S Kremen; David A Bennett; J Wouter Jukema; Tomas Paus; Joanna M Wardlaw; Helena Schmidt; Perminder S Sachdev; Arno Villringer; Hans Jörgen Grabe; W T Longstreth; Cornelia M van Duijn; Lenore J Launer; Sudha Seshadri; M Arfan Ikram; Myriam Fornage

doi:10.1038/s41467-018-06234-w

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Nat Commun. 2018 Sep 26;9(1):3945. doi: 10.1038/s41467-018-06234-w.

Authors

Dina Vojinovic¹, Hieab H Adams^{2

3}, Xueqiu Jian⁴, Qiong Yang⁵, Albert Vernon Smith^{6

7}, Joshua C Bis⁸, Alexander Teumer⁹, Markus Scholz^{10

11}, Nicola J Armstrong^{12

13}, Edith Hofer^{14

15}, Yasaman Saba¹⁶, Michelle Luciano¹⁷, Manon Bernard¹⁸, Stella Trompet^{19

20}, Jingyun Yang^{21

22}, Nathan A Gillespie²³, Sven J van der Lee², Alexander Neumann²⁴, Shahzad Ahmad², Ole A Andreassen²⁵, David Ames^{26

27}, Najaf Amin², Konstantinos Arfanakis^{21

28

29}, Mark E Bastin^{17

30

31}, Diane M Becker³², Alexa S Beiser⁵, Frauke Beyer³³, Henry Brodaty^{13

34}, R Nick Bryan³⁵, Robin Bülow³⁶, Anders M Dale³⁷, Philip L De Jager^{38

39}, Ian J Deary¹⁷, Charles DeCarli⁴⁰, Debra A Fleischman^{21

22

41}, Rebecca F Gottesman⁴², Jeroen van der Grond⁴³, Vilmundur Gudnason^{6

7}, Tamara B Harris⁴⁴, Georg Homuth⁴⁵, David S Knopman⁴⁶, John B Kwok^{47

48}, Cora E Lewis⁴⁹, Shuo Li⁵, Markus Loeffler^{10

11}, Oscar L Lopez⁵⁰, Pauline Maillard⁴⁰, Hanan El Marroun^{24

51}, Karen A Mather^{13

52}, Thomas H Mosley⁵³, Ryan L Muetzel^{2

24}, Matthias Nauck⁵⁴, Paul A Nyquist⁴², Matthew S Panizzon⁵⁵, Zdenka Pausova^{18

56}, Bruce M Psaty^{8

57

58

59}, Ken Rice⁶⁰, Jerome I Rotter^{61

62}, Natalie Royle^{17

30

31}, Claudia L Satizabal^{63

64}, Reinhold Schmidt¹⁴, Peter R Schofield^{47

52}, Pamela J Schreiner⁶⁵, Stephen Sidney⁶⁶, David J Stott⁶⁷, Anbupalam Thalamuthu¹³, Andre G Uitterlinden⁶⁸, Maria C Valdés Hernández^{17

30

31}, Meike W Vernooij^{2

3}, Wei Wen¹³, Tonya White^{3

24}, A Veronica Witte^{33

69}, Katharina Wittfeld⁷⁰, Margaret J Wright⁷¹, Lisa R Yanek³², Henning Tiemeier^{24

72}, William S Kremen⁵⁵, David A Bennett^{21

22}, J Wouter Jukema^{20

73}, Tomas Paus^{74

75}, Joanna M Wardlaw^{17

30

31}, Helena Schmidt¹⁶, Perminder S Sachdev^{13

76}, Arno Villringer^{33

69}, Hans Jörgen Grabe^{70

77}, W T Longstreth^{57

78}, Cornelia M van Duijn^{2

79}, Lenore J Launer⁴⁴, Sudha Seshadri^{63

64}, M Arfan Ikram^{2

3

80}, Myriam Fornage⁸¹

Affiliations

¹ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam 3015 CN, The Netherlands. [email protected].
² Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam 3015 CN, The Netherlands.
³ Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam 3015 CN, The Netherlands.
⁴ The University of Texas Health Science Center at Houston Institute of Molecular Medicine, Houston, TX 77030, USA.
⁵ Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
⁶ Icelandic Heart Association, Kopavogur 201, Iceland.
⁷ Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
⁹ Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
¹⁰ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany.
¹¹ LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany.
¹² Mathematics and Statistics, Murdoch University, Perth, WA 6150, Australia.
¹³ Centre for Healthy Brain Ageing, School of Psychiatry, UNSW, Sydney, NSW 2052, Australia.
¹⁴ Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz 8036, Austria.
¹⁵ Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz 8036, Austria.
¹⁶ Gottfried Schatz research center, Institute for Molecular biology and biochemistry, Graz 8010, Austria.
¹⁷ Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
¹⁸ Research Institute of the Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
¹⁹ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
²⁰ Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
²¹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL 60612, USA.
²² Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
²³ Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
²⁴ Department of Child and Adolescent Psychiatry/ Psychology, Erasmus University Medical Center Rotterdam, Rotterdam 3000 CB, The Netherlands.
²⁵ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo 0372, Norway.
²⁶ National Ageing Research Institute, Melbourne, VIC 3052, Australia.
²⁷ Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, VIC 3101, Australia.
²⁸ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616, USA.
²⁹ Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, IL 60612, USA.
³⁰ Centre for Clinical Brain Sciences, University of Edinburgh & Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH16 4SB, UK.
³¹ Division of Neuroimaging Sciences, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH16 4SB, UK.
³² Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
³³ Department of Neurology, Max Planck Institute of Cognitive and Brain Sciences, Leipzig 04103, Germany.
³⁴ Dementia Collaborative Research Centre - Assessment and Better Care, University of New South Wales, Sydney, NSW 2031, Australia.
³⁵ The University of Texas at Austin Dell Medical School, Austin, TX 78705, USA.
³⁶ Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany.
³⁷ Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92093, USA.
³⁸ Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
³⁹ Cell Circuits Program, Broad Institute, Cambridge, MA 02142, USA.
⁴⁰ Department of Neurology and Center for Neuroscience, University of California, Davis, CA 95817, USA.
⁴¹ Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
⁴² Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
⁴³ Department of Radiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
⁴⁴ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA.
⁴⁵ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17475, Germany.
⁴⁶ Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
⁴⁷ School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
⁴⁸ Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
⁴⁹ The University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
⁵⁰ Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁵¹ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, 3062 PA, The Netherlands.
⁵² Neuroscience Research Australia Randwick, Sydney, NSW 2031, Australia.
⁵³ The University of Mississippi Medical Center, Jackson, MS 39216, USA.
⁵⁴ Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
⁵⁵ Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
⁵⁶ Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 3E2, Canada.
⁵⁷ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
⁵⁸ Department of Health Services, University of Washington, Seattle, WA 98195-7660, USA.
⁵⁹ Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA.
⁶⁰ Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
⁶¹ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
⁶² Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, 90509 CA, USA.
⁶³ Framingham Heart Study, Framingham, MA 01702, USA.
⁶⁴ Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
⁶⁵ University of Minnesota School of Public Health, Minneapolis, MN 55454, USA.
⁶⁶ Kaiser Permanente Northern California Division of Research, Oakland, CA 94612, USA.
⁶⁷ Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
⁶⁸ Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam 3015, The Netherlands.
⁶⁹ Faculty of Medicine, CRC 1052 Obesity Mechanisms, University of Leipzig, Leipzig 04103, Germany.
⁷⁰ German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald 17475, Germany.
⁷¹ Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia.
⁷² Department of Psychiatry, Erasmus MC University Medical Center, Rotterdam 3015 GD, The Netherlands.
⁷³ Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden 2300 RC, The Netherlands.
⁷⁴ Rotman Research Institute, Baycrest, Toronto, Ontario M6A 2E1, Canada.
⁷⁵ Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada.
⁷⁶ Neuropsychiatric Institute, Prince of Wales Hospital, Randwick Sydney, NSW 2031, Australia.
⁷⁷ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald 17475, Germany.
⁷⁸ Department of Neurology, University of Washington, Seattle, WA 98195-6465, USA.
⁷⁹ Nuffield Department of Population Health, University of Oxford, Oxford, OX37LF, UK.
⁸⁰ Department of Neurology, Erasmus MC University Medical Center, Rotterdam 3015 GD, The Netherlands.
⁸¹ The University of Texas Health Science Center at Houston Institute of Molecular Medicine, Houston, TX 77030, USA. [email protected].

Abstract

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ_genetic = -0.59, p-value = 3.14 × 10^-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Publication types

Meta-Analysis

MeSH terms

Aged
Genome, Human*
Genome-Wide Association Study
Humans
Lateral Ventricles / anatomy & histology*
Middle Aged
Organ Size / genetics

Abstract

Publication types

MeSH terms

Grants and funding