Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Summary Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.

Authors 100

1. Rachel M. Brouwer

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

2. Marieke Klein

   Radboud University Nijmegen · Utrecht University · Radboud University Medical Center · University Medical Center Utrecht · University of California San Diego · Donders Institute for Brain, Cognition and Behaviour

   Affiliation as printed

   Department of Human Genetics, Radboud University Medical Center

   Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

   Department of Psychiatry, University of California San Diego

   Donders Institute for Brain, Cognition and Behaviour, Radboud University

3. Katrina L. Grasby

   QIMR Berghofer Medical Research Institute

   Affiliation as printed

   Psychiatric Genetics, QIMR Berghofer Medical Research Institute

4. Hugo Gerard Schnack

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

5. Neda Jahanshad

   University of Southern California

   Affiliation as printed

   Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California

6. Jalmar Teeuw

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

7. Sophia I. Thomopoulos

   University of Southern California

   Affiliation as printed

   Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California

8. Emma Sprooten

   Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

   Affiliation as printed

   Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center

9. Carol E. Franz

   University of California San Diego

   Affiliation as printed

   Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego

10. Nitin Gogtay

    American Psychiatric Association

    Affiliation as printed

    American Psychiatric Association

11. William S. Kremen

    University of California San Diego · VA San Diego Healthcare System · Center of Excellence for Stress and Mental Health

    Affiliation as printed

    Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego

    VA San Diego Center of Excellence for Stress and Mental Health

12. Matthew S. Panizzon

    University of California San Diego

    Affiliation as printed

    Department of Psychiatry and Center for Behavior Genetics of Aging, University of California San Diego

13. Loes M. Olde Loohuis

    University of California System

    Affiliation as printed

    Center for Neurobehavioral Genetics, University of California

14. Christopher D. Whelan
    Affiliation as printed

    Biogen Research and Development

15. Moji Aghajani

    Amsterdam Neuroscience · Amsterdam Public Health · Amsterdam University Medical Centers

    Affiliation as printed

    Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit & GGZinGeest

16. Clara Alloza

    Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Salud Mental

    Affiliation as printed

    Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense

17. Dag Alnæs

    Oslo University Hospital · University of Oslo

    Affiliation as printed

    Division of Mental Health and Addiction, Oslo University Hospital

    NORMENT Centre, University of Oslo

18. Éric Artiges

    École Normale Supérieure Paris-Saclay · Inserm · Université Paris-Saclay · Trajectoires développementales & psychiatrie

    Affiliation as printed

    INSERM U A10 1000 Trajectoires Développementales en Psychiatrie, Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay

19. Rosa Ayesa‐Arriola

    Universidad de Cantabria · Marqués de Valdecilla University Hospital · Instituto de Investigación Marqués de Valdecilla

    Affiliation as printed

    Valdecilla Biomedical Research Institute (IDIVAL), Marqués de Valdecilla University Hospital (HUMV), School of Medicine, University of Cantabria

20. Gareth J. Barker

    King's College London

    Affiliation as printed

    Department of Neuroimaging, King’s College London

    Department of Neuroimaging, King's College London

21. Mark E. Bastin
22. Elisabet Blok

    Erasmus MC · Erasmus MC - Sophia Children’s Hospital

    Affiliation as printed

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children’s Hospital, Erasmus University Medical Centre Rotterdam

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children's Hospital, Erasmus University Medical Centre Rotterdam

23. Erlend Bøen

    Oslo University Hospital

    Affiliation as printed

    Psychosomatic and CL Psychiatry, Oslo University Hospital

24. Isabella A. Breukelaar

    The University of Sydney · Westmead Institute for Medical Research

    Affiliation as printed

    Brain Dynamics Centre, Westmead Institute for Medical Research, The University of Sydney

25. Joanna K. Bright

    University of Southern California

    Affiliation as printed

    Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California

26. Elizabeth E.L. Buimer

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

27. Robin Bülow

    Universitätsmedizin Greifswald · Universität Greifswald

    Affiliation as printed

    Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald

28. Dara M. Cannon

    Ollscoil na Gaillimhe – University of Galway

    Affiliation as printed

    Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway

29. Simone Ciufolini

    King's College London

    Affiliation as printed

    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London

    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London

30. Nicolas Andres Crossley

    Pontificia Universidad Católica de Chile · King's College London

    Affiliation as printed

    Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile

    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London

    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London

31. Christienne G. Damatac

    Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

    Affiliation as printed

    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center

32. Paola Dazzan

    King's College London

    Affiliation as printed

    Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London

    Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London

33. Casper L. de Mol

    Erasmus MC

    Affiliation as printed

    Department of Neurology, Erasmus University Medical Centre Rotterdam

34. Sonja M. C. de Zwarte

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

35. Sylvane Desrivières

    King's College London

    Affiliation as printed

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London

36. Covadonga M. Díaz‐Caneja

    Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Salud Mental

    Affiliation as printed

    Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense

37. Nhat Trung Doan

    University of Oslo

    Affiliation as printed

    NORMENT Centre, University of Oslo

38. Katharina Dohm

    University of Münster

    Affiliation as printed

    Department of Psychiatry, University of Münster

39. Juliane Hilde Fröhner

    Technische Universität Dresden

    Affiliation as printed

    Section of Systems Neuroscience Department of Psychiatry and Psychotherapy, Technische Universität Dresden

40. Janik Goltermann

    University of Münster

    Affiliation as printed

    Department of Psychiatry, University of Münster

41. Antoine Grigis

    Commissariat à l'Énergie Atomique et aux Énergies Alternatives · Université Paris-Saclay · CEA Paris-Saclay - Etablissement de Saclay

    Affiliation as printed

    Université Paris-Saclay, CEA

42. Dominik Grotegerd

    University of Münster

    Affiliation as printed

    Department of Psychiatry, University of Münster

43. Laura K. M. Han

    Amsterdam Neuroscience · Amsterdam Public Health · Amsterdam University Medical Centers

    Affiliation as printed

    Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit & GGZinGeest

44. Mathew A. Harris
45. Catharina Annette Hartman

    University Medical Center Groningen · University of Groningen

    Affiliation as printed

    University of Groningen, University Medical Center Groningen, Department of Psychiatry, Interdisciplinary Center Psychopathology and Emotion regulation (ICPE)

46. Sarah J. Heany

    University of Cape Town

    Affiliation as printed

    Department of Psychiatry and Mental Health, University of Cape Town

47. Walter Leonhard Heindel

    University of Münster · University Hospital Münster

    Affiliation as printed

    Institute of Clinical Radiology, University and University Hospital Münster

48. Dirk J. Heslenfeld

    Vrije Universiteit Amsterdam

    Affiliation as printed

    Departments of Experimental and Clinical Psychology, Vrije Universiteit Amsterdam

49. Sarah Hohmann

    Heidelberg University · Central Institute of Mental Health · Medizinische Fakultät Mannheim

    Affiliation as printed

    Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University

50. Bernd Ittermann

    Physikalisch-Technische Bundesanstalt

    Affiliation as printed

    Physikalisch-Technische Bundesanstalt (PTB)

51. Philip R. Jansen

    Erasmus MC · Erasmus MC - Sophia Children’s Hospital · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children’s Hospital, Erasmus University Medical Centre Rotterdam

    Department of Clinical Genetics, VUmc

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children's Hospital, Erasmus University Medical Centre Rotterdam

52. Joost Janssen

    Hospital General Universitario Gregorio Marañón · Centro de Investigación Biomédica en Red de Salud Mental

    Affiliation as printed

    Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense

53. Tianye Jia

    King's College London · Fudan University

    Affiliation as printed

    Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology and Neuroscience, SGDP Centre, King’s College London

    Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Science and Technology for Brain-Inspired Intelligence and MoE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University

    Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology and Neuroscience, SGDP Centre, King's College London

54. Jiyang Jiang

    UNSW Sydney · Centre for Healthy Brain Ageing

    Affiliation as printed

    Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales

55. Christiane Jockwitz Aachen Department of Psychiatry, Psychotherapy and Psychosomatics

    Forschungszentrum Jülich · RWTH Aachen University

    Affiliation as printed

    Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Medical Faculty

    Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich

56. Temmuz Karali

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Psychiatry and Psychotherapy, University Hospital LMU

    Department of Radiology, University Hospital LMU

57. Daniel Keeser

    LMU Klinikum · Munich Center for Neurosciences – Brain and Mind · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Psychiatry and Psychotherapy, University Hospital LMU

    Department of Radiology, University Hospital LMU

    Munich Center for Neurosciences (MCN) – Brain & Mind

58. Martijn Koevoets

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

59. Rhoshel Lenroot

    University of New Mexico · UNSW Sydney · Neuroscience Research Australia

    Affiliation as printed

    Neuroscience Research Australia

    School of Psychiatry and Behavioral Sciences, School of Medicine, University of New Mexico

    School of Psychiatry, University of New South Wales

60. Berend Malchow

    Universitätsmedizin Göttingen · University of Göttingen

    Affiliation as printed

    Department of Psychiatry and Psychotherapy, University Medical Center Göttingen

61. René C.W. Mandl

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

62. Vicente Medel

    Pontificia Universidad Católica de Chile

    Affiliation as printed

    Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile

63. Susanne L. Meinert

    University of Münster

    Affiliation as printed

    Department of Psychiatry, University of Münster

64. Catherine Morgan

    University of Auckland · Brain Research New Zealand

    Affiliation as printed

    Brain Research New Zealand

    School of Psychology and Centre for Brain Research, The University of Auckland

65. Thomas W. Mühleisen

    Forschungszentrum Jülich · University of Basel · Düsseldorf University Hospital · Heinrich Heine University Düsseldorf

    Affiliation as printed

    Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf

    Department of Biomedicine, University of Basel

    Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich

66. Leila Nabulsi

    Ollscoil na Gaillimhe – University of Galway

    Affiliation as printed

    Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway

67. Nils Opel

    University of Münster

    Affiliation as printed

    Department of Psychiatry, University of Münster

68. Víctor Ortiz‐García de la Foz

    Instituto de Investigación Marqués de Valdecilla

    Affiliation as printed

    Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute IDIVAL

69. Bronwyn J. Overs

    Neuroscience Research Australia

    Affiliation as printed

    Neuroscience Research Australia

70. Jean‐Luc Martinot

    École Normale Supérieure Paris-Saclay · Inserm · Université Paris-Saclay · Sorbonne Université · Pitié-Salpêtrière Hospital · Trajectoires développementales & psychiatrie

    Affiliation as printed

    APHP, Sorbonne Université, Pitie-Salpetriere Hospital, Department of Child and Adolescent Psychiatry

    INSERM U A10 1000 Trajectoires Développementales en Psychiatrie, Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay

71. Erin Burke Quinlan

    King's College London

    Affiliation as printed

    Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology and Neuroscience, SGDP Centre, King’s College London

    Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology and Neuroscience, SGDP Centre, King's College London

72. Ronny Redlich

    University of Münster

    Affiliation as printed

    Department of Mental Health, Institute of Translational Psychiatry, The University of Münster

73. Tiago Reis Marques

    King's College London · MRC London Institute of Medical Sciences · Imperial College London

    Affiliation as printed

    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London

    Psychiatric Imaging Group, MRC London Institute of Medical Sciences (LMS), Imperial College London

    Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London

74. Jonathan Repple

    University of Münster

    Affiliation as printed

    Department of Psychiatry, University of Münster

75. Gloria M.P. Roberts

    UNSW Sydney

    Affiliation as printed

    School of Psychiatry, University of New South Wales

76. Gennady V. Roshchupkin

    Erasmus MC

    Affiliation as printed

    Department of Epidemiology, Erasmus University Medical Centre Rotterdam

    Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam

77. Nikita Setiaman

    Utrecht University · Erasmus MC · University Medical Center Utrecht · Erasmus MC - Sophia Children’s Hospital

    Affiliation as printed

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children’s Hospital, Erasmus University Medical Centre Rotterdam

    Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children's Hospital, Erasmus University Medical Centre Rotterdam

78. Elena Shumskaya

    Radboud University Medical Center · Donders Institute for Brain, Cognition and Behaviour

    Affiliation as printed

    Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center

    Department of Human Genetics, Radboud University Medical Center

79. Frederike Stein

    Philipps University of Marburg

    Affiliation as printed

    Department of Psychiatry and Psychotherapy, Philipps-University Marburg

80. Gustavo P. Sudre

    National Human Genome Research Institute

    Affiliation as printed

    Social and Behavioral Research Branch, National Human Genome Research Institute

81. Shun Takahashi

    Wakayama Medical University · LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Neuropsychiatry, Wakayama Medical University

    Department of Psychiatry and Psychotherapy, University Hospital LMU

82. Anbupalam Thalamuthu

    UNSW Sydney · Centre for Healthy Brain Ageing

    Affiliation as printed

    Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales

83. Diana Tordesillas‐Gutiérrez

    Centro de Investigación Biomédica en Red de Salud Mental · Instituto de Investigación Marqués de Valdecilla

    Affiliation as printed

    CIBERSAM, Biomedical Research Network on Mental Health Area

    Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute IDIVAL

84. Aad van der Lugt

    Erasmus MC

    Affiliation as printed

    Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam

85. Neeltje E.M. van Haren

    Utrecht University · Erasmus MC · University Medical Center Utrecht · Erasmus MC - Sophia Children’s Hospital

    Affiliation as printed

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children’s Hospital, Erasmus University Medical Centre Rotterdam

    Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht University

    Department of Child and Adolescent Psychiatry/Psychology, Sophia Children's Hospital, Erasmus University Medical Centre Rotterdam

86. Joanna Marguerite Wardlaw
87. Wei Xiong Wen

    UNSW Sydney · Centre for Healthy Brain Ageing

    Affiliation as printed

    Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales

88. Henk‐Jan Westeneng

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University

89. Katharina Wittfeld

    Universitätsmedizin Greifswald · German Center for Neurodegenerative Diseases · Universität Greifswald

    Affiliation as printed

    Department of Psychiatry and Psychotherapy, University Medicine Greifswald

    German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald,

90. Alyssa H. Zhu
91. André Zugman

    Universidade Federal de São Paulo

    Affiliation as printed

    Laboratory of Integrative Neuroscience (LiNC), Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP)

92. Nicola J. Armstrong

    Murdoch University

    Affiliation as printed

    Mathematics and Statistics, Murdoch University

93. Gaia Bonfiglio
94. Janita Bralten

    Radboud University Medical Center

    Affiliation as printed

    Department of Human Genetics, Radboud University Medical Center

95. Shareefa Dalvie

    University of Cape Town

    Affiliation as printed

    Department of Psychiatry and Mental Health, University of Cape Town

96. Gail Davies
97. Marta Di Forti

    King's College London

    Affiliation as printed

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London

    Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London

98. Linda Ding

    University of Southern California

    Affiliation as printed

    Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California

99. Gary J Donohoe

    Ollscoil na Gaillimhe – University of Galway

    Affiliation as printed

    Centre for Neuroimaging & Cognitive Genomics (NICOG), School of Psychology and Discipline of Biochemistry, National University of Ireland Galway

100. Andreas J. Forstner

     University of Bonn · Philipps University of Marburg · University Hospital Bonn

     Affiliation as printed

     Centre for Human Genetics, Philipps-University Marburg

     Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn