Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

R S Desikan; A J Schork; Y Wang; A Witoelar; M Sharma; L K McEvoy; D Holland; J B Brewer; C-H Chen; W K Thompson; D Harold; J Williams; M J Owen; M C O'Donovan; M A Pericak-Vance; R Mayeux; J L Haines; L A Farrer; G D Schellenberg; P Heutink; A B Singleton; A Brice; N W Wood; J Hardy; M Martinez; S H Choi; A DeStefano; M A Ikram; J C Bis; A Smith; A L Fitzpatrick; L Launer; C van Duijn; S Seshadri; I D Ulstein; D Aarsland; T Fladby; S Djurovic; B T Hyman; J Snaedal; H Stefansson; K Stefansson; T Gasser; O A Andreassen; A M Dale; ADNI, ADGC, GERAD, CHARGE and IPDGC Investigators

doi:10.1038/mp.2015.6

Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

Mol Psychiatry. 2015 Dec;20(12):1588-95. doi: 10.1038/mp.2015.6. Epub 2015 Feb 17.

Authors

R S Desikan¹, A J Schork², Y Wang^{3

4}, A Witoelar⁴, M Sharma^{5

6}, L K McEvoy¹, D Holland³, J B Brewer^{1

3}, C-H Chen^{1

7}, W K Thompson⁷, D Harold⁸, J Williams⁸, M J Owen⁸, M C O'Donovan⁸, M A Pericak-Vance⁹, R Mayeux¹⁰, J L Haines¹¹, L A Farrer¹², G D Schellenberg¹³, P Heutink¹⁴, A B Singleton¹⁵, A Brice¹⁶, N W Wood¹⁷, J Hardy¹⁸, M Martinez¹⁹, S H Choi²⁰, A DeStefano^{20

21}, M A Ikram²², J C Bis²³, A Smith²⁴, A L Fitzpatrick²⁵, L Launer²⁶, C van Duijn²², S Seshadri^{21

27}, I D Ulstein²⁸, D Aarsland^{29

30

31}, T Fladby^{32

33}, S Djurovic⁴, B T Hyman³⁴, J Snaedal³⁵, H Stefansson³⁶, K Stefansson^{36

37}, T Gasser⁵, O A Andreassen^{4

7}, A M Dale^{1

2

3

7}; ADNI, ADGC, GERAD, CHARGE and IPDGC Investigators

Affiliations

¹ Department of Radiology, University of California, San Diego, La Jolla, CA, USA.
² Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA.
³ Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
⁴ NORMENT; Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁵ Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research University of Tubingen, Tubingen, Germany.
⁶ Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
⁷ Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
⁸ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Wales, UK.
⁹ The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
¹⁰ Department of Neurology, Taub Institute on Alzheimer's Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.
¹¹ Department of Molecular Physiology and Biophysics, Vanderbilt Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA.
¹² Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
¹³ Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁴ German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Paul-Ehrlich-Straße 15, Tübingen, Germany.
¹⁵ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
¹⁶ Sorbonne Université, UPMC Univ Paris 06, Paris, France.
¹⁷ UCL Genetics Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
¹⁸ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
¹⁹ INSERM UMR1043, CPTP, CHU Purpan, Toulouse, France.
²⁰ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
²¹ The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
²² Deparment of Epidemiology, Erasmus MC University Medical Center, Rotterdam, Netherlands.
²³ Deparment of Internal Medicine, University of Washington, Seattle, WA, USA.
²⁴ Icelandic Heart Association, Kopavogur, Iceland.
²⁵ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁶ Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Washington, DC, USA.
²⁷ Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
²⁸ Norwegian Centre for Dementia Research, Department of Old Age Psychiatry, Oslo University Hospital, Oslo, Norway.
²⁹ Department of Geriatric Psychiatry, Akershus University Hospital, Oslo, Norway.
³⁰ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
³¹ Alzheimer's Disease Research Centre, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
³² Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³³ Department of Neurology, Akershus University Hospital, Oslo, Norway.
³⁴ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
³⁵ Department of Geriatric Medicine, University Hospital Reykjavik, Reykjavik, Iceland.
³⁶ deCODE Genetics/Amgen, Reykjavik, Iceland.
³⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Abstract

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alleles
Alzheimer Disease / genetics*
Apolipoproteins E / genetics
Brain / pathology
Chromosomes, Human, Pair 17
Female
Genetic Loci
Genetic Pleiotropy
Genome-Wide Association Study
Humans
Male
Middle Aged
Parkinson Disease / genetics*
Polymorphism, Single Nucleotide
tau Proteins / genetics*

Substances

Apolipoproteins E
MAPT protein, human
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding