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

Nature Genetics volume 44, pages 545–551 (2012)Cite this article

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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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Figure 1: Genome-wide Manhattan plot for hippocampal volume.
Figure 2: Regional plots for SNPs associated with hippocampal volume.
Figure 3: Forest plots for association of SNPs with hippocampal volume.

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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

  1. Joshua C Bis, Charles DeCarli, Albert Vernon Smith, Fedde van der Lijn, Fabrice Crivello, Myriam Fornage, Stephanie Debette and Christophe Tzourio: These authors contributed equally to this work.

  2. Cornelia M van Duijn, Thomas H Mosley, Reinhold Schmidt, Christophe Tzourio, Lenore J Launer, M Arfan Ikram and Sudha Seshadri: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Medicine, Cardiovascular Health Research Unit, 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. Department of Neurology, Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, 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. Department of Medicine, Stroke and Ageing Research Centre, Southern Clinical School, 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. Department of Epidemiology, Genetic Epidemiology Unit, 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

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

  • Joshua C Bis
  • , Charles DeCarli
  • , Albert Vernon Smith
  • , Fedde van der Lijn
  • , Fabrice Crivello
  • , Myriam Fornage
  • , Stephanie Debette
  • , Joshua M Shulman
  • , Helena Schmidt
  • , Velandai Srikanth
  • , Maaike Schuur
  • , Lei Yu
  • , Seung-Hoan Choi
  • , Sigurdur Sigurdsson
  • , Benjamin F J Verhaaren
  • , Anita L DeStefano
  • , Jean-Charles Lambert
  • , Clifford R Jack Jr
  • , Maksim Struchalin
  • , Jim Stankovich
  • , Carla A Ibrahim-Verbaas
  • , Debra Fleischman
  • , Alex Zijdenbos
  • , Tom den Heijer
  • , Bernard Mazoyer
  • , Laura H Coker
  • , Christian Enzinger
  • , Patrick Danoy
  • , Najaf Amin
  • , Konstantinos Arfanakis
  • , Mark A van Buchem
  • , Renée F A G de Bruijn
  • , Alexa Beiser
  • , Carole Dufouil
  • , Juebin Huang
  • , Margherita Cavalieri
  • , Russell Thomson
  • , Wiro J Niessen
  • , Lori B Chibnik
  • , Gauti K Gislason
  • , Albert Hofman
  • , Aleksandra Pikula
  • , Philippe Amouyel
  • , Kevin B Freeman
  • , Thanh G Phan
  • , Ben A Oostra
  • , Jason L Stein
  • , Sarah E Medland
  • , Alejandro Arias Vasquez
  • , Derrek P Hibar
  • , Margaret J Wright
  • , Barbara Franke
  • , Nicholas G Martin
  •  & Paul M Thompson

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

  • Michael A Nalls
  • , Andre G Uitterlinden
  • , Rhoda Au
  • , Alexis Elbaz
  • , Richard J Beare
  • , John C van Swieten
  • , Oscar L Lopez
  • , Tamara B Harris
  • , Vincent Chouraki
  • , Monique M B Breteler
  • , Philip L De Jager
  • , James T Becker
  • , Meike W Vernooij
  • , David Knopman
  • , Franz Fazekas
  • , Philip A Wolf
  • , Aad van der Lugt
  • , Vilmundur Gudnason
  • , W T Longstreth Jr
  • , Matthew A Brown
  • , David A Bennett
  • , Cornelia M van Duijn
  • , Thomas H Mosley
  • , Reinhold Schmidt
  • , Christophe Tzourio
  • , Lenore J Launer
  • , M Arfan Ikram
  •  & Sudha Seshadri

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.

Corresponding author

Correspondence to Sudha Seshadri.

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The author declare no competing financial interests.

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Supplementary Tables 1–7, Supplementary Figures 1–3 and Supplementary Note (PDF 1133 kb)

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Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium., the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nat Genet 44, 545–551 (2012). https://doi.org/10.1038/ng.2237

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

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