Letter | Published:

Common variants at 12q14 and 12q24 are associated with hippocampal volume

Nature Genetics volume 44, pages 545551 (2012) | Download Citation

Abstract

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10−7. In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10−11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10−11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10−7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10−7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

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Acknowledgements

The authors thank the ENIGMA Consortium, which is represented by J.L.S., S.E.M., A.A.V., D.P.H., M.J.W., B.F., N.G.M. and P.M.T.

Aging Gene-Environment Susceptibility–Reykjavik Study (AGES): Research was funded by the US National Institute on Aging (NIA; N01-AG-12100), with contributions from the National Eye Institute (NEI), the National Institute on Deafness and Other Communication Disorders (NIDCD), the US National Heart, Lung, and Blood Institute (NHLBI), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament).

The Atherosclerosis Risk in Communities Study (ARIC): The authors thank the staff and participants of the ARIC study for their important contributions. Research was carried out as a collaborative study supported by the US NHLBI (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, HL087641, HL59367, HL086694 and HL7825); the National Human Genome Research Institute (U01HG004402) and the NIH (HHSN268200625226C). Infrastructure was partly supported by a component of the NIH and the NIH Roadmap for Medical Research (UL1RR025005). This project was also supported by NHLBI grant HL093029.

The Cardiovascular Health Study (CHS): Coauthors were supported in part by US NHLBI grants (HL087652 and HL105756), as well as by NIA grants (AG20098 and AG05133).

The Austrian Stroke Prevention Study (ASPS): The authors thank the staff and the participants of ASPS for their valuable contributions. We thank B. Reinhart for her long-term administrative commitment and I.J. Semmler for technical assistance in creating the DNA bank. The research reported here was funded by the Austrian Science Fond (FWF; P20545-P05 and P13180). The Medical University of Graz supports the databank of ASPS.

Erasmus Rucphen Family Study (ERF): We thank the participants from the Genetic Research in Isolated Populations in the Erasmus Rucphen Family Study who made this work possible. This study is financially supported by the Netherlands Organisation for Scientific Research (NWO), the Internationale Stichting Alzheimer Onderzoek (ISAO), the Hersenstichting Nederland (HSN) and the Centre for Medical Systems Biology (CMSB1 and CMSB2) in the framework of the Netherlands Genomics Initiative (NGI).

Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and its contract with Affymetrix, Inc, for genotyping services (contract N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at the Boston University School of Medicine and Boston Medical Center. Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This study was also supported by grants from the NINDS (NS17950) and the NIA (AG08122, AG16495, AG033193, AG013846 and AG031287).

The Religious Order Study and the Rush Memory and Aging Project: ROS and R-MAP data used in this study were obtained with support from the US NIA (grants P30AG10161, AG17917 and AG15819), the Illinois Department of Public Health and the Rush Clinical Translational Science Consortium and a gift from M. Dowd.

The Rotterdam Study (RS): The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors also thank P. Arp, M. Jhamai, M. Verkerk, L. Herrera and M. Peters for their help in creating the GWAS database and K. Estrada and M.V. Struchalin for their support in the creation and analysis of imputed data. The generation and management of GWAS genotype data for the Rotterdam Study are supported by NWO Investments (nr. 175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (RIDE2; 014-93-015) and the NGI-NWO project (nr. 050-060-810). The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organisation for Health Research and Development (ZonMw), RIDE2, the Dutch Ministry of Education, Culture and Science, the Dutch Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The Rotterdam Scan Study is supported by the NWO (project nrs. 918-46-615, 904-61-096, 904-61-133 and 948-00-010), Nederlandse Hartstichting (2009B102) and Internationaal Parkinson Fonds.

The Tasmanian Study of Gait and Cognition (TASCOG): This study is supported by project grants from the National Health and Medical Research Council of Australia (NHMRC; 403000, 491109 and 606543) and a grant from the Wicking Dementia Education and Research Centre, Hobart. V.S. is supported by an NHMRC–National Heart Foundation Career Development Fellowship (606544). M.A.B. is supported by an NHMRC Senior Principal Research Fellowship (APP1024879).

Three City Study (3C): We thank the staff and participants of the 3C Study for their important contributions. We also thank A. Boland for her technical help in preparing the DNA samples for analyses. The 3C Study is conducted under a partnership agreement between INSERM, Victor Segalen–Bordeaux II University and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l'Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux de Aquitaine et Bourgogne, Fondation de France and the French Ministry of Research–INSERM Programme Cohortes et Collections de Données Biologiques. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille and the Centre National de Génotypage.

Author information

Author notes

    • Joshua C Bis
    • , Charles DeCarli
    • , Albert Vernon Smith
    • , Fedde van der Lijn
    • , Fabrice Crivello
    • , Myriam Fornage
    •  & Stephanie Debette

    These authors contributed equally to this work.

    • Cornelia M van Duijn
    • , Thomas H Mosley
    • , Reinhold Schmidt
    • , Christophe Tzourio
    • , Lenore J Launer
    • , M Arfan Ikram
    •  & Sudha Seshadri

    These authors jointly directed this work.

Affiliations

  1. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.

    • Joshua C Bis
  2. Department of Neurology, University of California, Davis, Sacramento, California, USA.

    • Charles DeCarli
  3. Center of Neuroscience, University of California, Davis, Sacramento, California, USA.

    • Charles DeCarli
  4. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert Vernon Smith
    • , Sigurdur Sigurdsson
    • , Gauti K Gislason
    •  & Vilmundur Gudnason
  5. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert Vernon Smith
    •  & Vilmundur Gudnason
  6. Department of Medical Informatics, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Fedde van der Lijn
    •  & Wiro J Niessen
  7. Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Fedde van der Lijn
    • , Benjamin F J Verhaaren
    • , Wiro J Niessen
    • , Meike W Vernooij
    • , Aad van der Lugt
    •  & M Arfan Ikram
  8. Neurofunctional Imaging Group, University of Bordeaux, Unité Mixte de Recherche (UMR) 5296, Bordeaux, France.

    • Fabrice Crivello
    •  & Bernard Mazoyer
  9. Neurofunctional Imaging Group, Centre National de la Recherche Scientifique (CNRS), UMR 5296, Bordeaux, France.

    • Fabrice Crivello
    •  & Bernard Mazoyer
  10. Neurofunctional Imaging Group, Commissariat à l′Energie Atomique (CEA), UMR 5296, Bordeaux, France.

    • Fabrice Crivello
    •  & Bernard Mazoyer
  11. Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.

    • Myriam Fornage
  12. Human Genetics Center, School of Public Health, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.

    • Myriam Fornage
  13. Institut National de la Santé et de la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France.

    • Stephanie Debette
    • , Carole Dufouil
    •  & Alexis Elbaz
  14. Department of Epidemiology, University of Versailles Saint-Quentin-en-Yvelines, Paris, France.

    • Stephanie Debette
  15. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Stephanie Debette
    • , Anita L DeStefano
    • , Alexa Beiser
    • , Aleksandra Pikula
    • , Rhoda Au
    • , Philip A Wolf
    •  & Sudha Seshadri
  16. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Joshua M Shulman
    • , Lori B Chibnik
    •  & Philip L De Jager
  17. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Joshua M Shulman
    • , Lori B Chibnik
    •  & Philip L De Jager
  18. Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.

    • Helena Schmidt
  19. Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia.

    • Velandai Srikanth
    • , Thanh G Phan
    •  & Richard J Beare
  20. Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.

    • Velandai Srikanth
    • , Jim Stankovich
    •  & Russell Thomson
  21. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Maaike Schuur
    • , Maksim Struchalin
    • , Carla A Ibrahim-Verbaas
    • , Najaf Amin
    • , Ben A Oostra
    •  & Cornelia M van Duijn
  22. Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Maaike Schuur
    • , Carla A Ibrahim-Verbaas
    • , Tom den Heijer
    • , Renée F A G de Bruijn
    •  & John C van Swieten
  23. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

    • Lei Yu
    • , Debra Fleischman
    • , Konstantinos Arfanakis
    •  & David A Bennett
  24. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Seung-Hoan Choi
    • , Anita L DeStefano
    •  & Alexa Beiser
  25. Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Benjamin F J Verhaaren
    • , Tom den Heijer
    • , Renée F A G de Bruijn
    • , Albert Hofman
    • , Meike W Vernooij
    •  & M Arfan Ikram
  26. The National, Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Anita L DeStefano
    • , Alexa Beiser
    • , Rhoda Au
    • , Philip A Wolf
    •  & Sudha Seshadri
  27. INSERM, U744, Lille, France.

    • Jean-Charles Lambert
    • , Philippe Amouyel
    •  & Vincent Chouraki
  28. Institut Pasteur de Lille, Lille, France.

    • Jean-Charles Lambert
    • , Philippe Amouyel
    •  & Vincent Chouraki
  29. Université Lille Nord de France, Lille, France.

    • Jean-Charles Lambert
    • , Philippe Amouyel
    •  & Vincent Chouraki
  30. Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.

    • Clifford R Jack Jr
  31. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.

    • Debra Fleischman
  32. Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois, USA.

    • Debra Fleischman
  33. Biospective, Inc., Montreal, Quebec, Canada.

    • Alex Zijdenbos
  34. Department of Neurology, Sint Franciscus Gasthuis, Rotterdam, The Netherlands.

    • Tom den Heijer
  35. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Laura H Coker
  36. Department of Neurology, Medical University Graz, Graz, Austria.

    • Christian Enzinger
    • , Margherita Cavalieri
    • , Franz Fazekas
    •  & Reinhold Schmidt
  37. University of Queensland, Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.

    • Patrick Danoy
  38. Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.

    • Konstantinos Arfanakis
  39. Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

    • Mark A van Buchem
  40. Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Juebin Huang
    •  & Thomas H Mosley
  41. Faculty of Applied Sciences, Delft University of Technology, Delft, The Netherlands.

    • Wiro J Niessen
  42. Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.

    • Albert Hofman
    • , Andre G Uitterlinden
    • , Cornelia M van Duijn
    •  & M Arfan Ikram
  43. Centre Hospitalier Régional Universitaire de Lille, Lille, France.

    • Philippe Amouyel
  44. Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Kevin B Freeman
  45. Department of Clinical Genetics, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Ben A Oostra
  46. Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Jason L Stein
    • , Derrek P Hibar
    •  & Paul M Thompson
  47. Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Sarah E Medland
    • , Margaret J Wright
    •  & Nicholas G Martin
  48. Quantitative Genetics, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • Sarah E Medland
  49. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Sarah E Medland
  50. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Alejandro Arias Vasquez
    •  & Barbara Franke
  51. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Alejandro Arias Vasquez
    • , Barbara Franke
    •  & Lenore J Launer
  52. Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Michael A Nalls
  53. Department of Internal Medicine, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands.

    • Andre G Uitterlinden
  54. Pierre and Marie Curie University (UPMC), University of Paris 6, UMR S708, Neuroepidemiology, Paris, France.

    • Alexis Elbaz
  55. Developmental Imaging Group, Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.

    • Richard J Beare
  56. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Oscar L Lopez
    •  & James T Becker
  57. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Oscar L Lopez
    •  & James T Becker
  58. Department of Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Oscar L Lopez
    •  & James T Becker
  59. Laboratory of Epidemiology, Demography, and Biometry, NIH, Bethesda, Maryland, USA.

    • Tamara B Harris
  60. Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

    • Monique M B Breteler
  61. Population Health Sciences, University of Bonn, Bonn, Germany.

    • Monique M B Breteler
  62. Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, Massachusetts, USA.

    • Monique M B Breteler
  63. Harvard Medical School, Boston, Massachusetts, USA.

    • Philip L De Jager
  64. Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

    • David Knopman
  65. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
  66. Department of Epidemiology, University of Washington, Seattle, Washington, USA.

    • W T Longstreth Jr
  67. Human Genetics Group, University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia.

    • Matthew A Brown
  68. Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands.

    • Cornelia M van Duijn
  69. Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, Mississippi, USA.

    • Thomas H Mosley
  70. University of Bordeaux, U708, Bordeaux, France.

    • Christophe Tzourio
  71. INSERM, Neuroepidemiology U708, Bordeaux, France.

    • Christophe Tzourio

Consortia

  1. Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium

  2. the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Authors

    Contributions

    Study concept and design were performed by J.C.B., C. DeCarli, M.A.v.B., C. Dufouil, P.A., A.G.U., M.M.B.B., F.F., M.A.B., C.M.v.D., T.H.M., C.T., L.J.L., M.A.I. and S. Seshadri. Acquisition of data was carried out by F.v.d.L., F.C., H.S., V.S., M. Schuur, S. Sigurdsson, B.F.J.V., J.-C.L., C.R.J., J.S., D.F., T.d.H., B.M., L.H.C., C.E., P.D., K.A., M.A.v.B., A.B., C. Dufouil, J.H., W.J.N., G.K.G., P.A., K.B.F., T.G.P., B.A.O., A.G.U., R.A., A.E., R.J.B., J.C.v.S., M.M.B.B., M.W.V., P.A.W., A.v.d.L., V.G., M.A.B., D.A.B., C.M.v.D., T.H.M., R.S., C.T., L.J.L., M.A.I. and S. Seshadri. Statistical analysis and interpretation of the data were performed by J.C.B., C. DeCarli, A.V.S., F.v.d.L., M.F., S.D., J.M.S., H.S., V.S., M. Schuur, L.Y., S.-H.C., B.F.J.V., A.L.D., M. Struchalin, J.S., C.A.I.-V., N.A., R.F.A.G.d.B., M.C., R.T., L.B.C., G.K.G., P.A., A.E., R.J.B., P.L.D.J., M.A.B., D.A.B., R.S., L.J.L. and M.A.I. The manuscript was drafted by J.C.B., C. DeCarli, J.M.S., H.S., M. Schuur, B.M., P.L.D.J., L.J.L. and S. Seshadri, and critical revision of the manuscript was performed by J.C.B., C. DeCarli, F.v.d.L., M.F., S.D., J.M.S., H.S., V.S., S.-H.C., S. Sigurdsson, A.L.D., J.-C.L., J.S., C.A.I.-V., A.Z., T.d.H., L.H.C., C.E., P.D., C. Dufouil, M.C., R.T., W.J.N., L.B.C., A.H., A.P., K.B.F., T.G.P., J.L.S., S.E.M., A.A.V., D.P.H., M.J.W., B.F., N.G.M., P.M.T., M.A.N., A.G.U., A.E., R.J.B., O.L.L., T.B.H., V.C., M.M.B.B., J.T.B., M.W.V., D.K., F.F., P.A.W., A.v.d.L., V.G., W.T.L., M.A.B., C.M.v.D., T.H.M., R.S., C.T., L.J.L., M.A.I. and S. Seshadri. Funding was obtained by M.F., H.S., V.S., C. Dufouil, W.J.N., A.H., B.A.O., A.G.U., J.C.v.S., T.B.H., V.C., M.M.B.B., F.F., P.A.W., A.v.d.L., V.G., D.A.B., C.M.v.D., T.H.M., R.S., C.T., L.J.L. and S. Seshadri.

    Competing interests

    The author declare no competing financial interests.

    Corresponding author

    Correspondence to Sudha Seshadri.

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      Supplementary Text and Figures

      Supplementary Tables 1–7, Supplementary Figures 1–3 and Supplementary Note

    About this article

    Publication history

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    DOI

    https://doi.org/10.1038/ng.2237

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