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

doi:10.1038/mp.2015.6

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

Research output: Contribution to journal › Article › peer-review

119 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1588-1595
Number of pages	8
Journal	Molecular psychiatry
Volume	20
Issue number	12
DOIs	https://doi.org/10.1038/mp.2015.6
State	Published - Dec 1 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/mp.2015.6

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Desikan, R. S., Schork, A. J., Wang, Y., Witoelar, A., Sharma, M., McEvoy, L. K., Holland, D., Brewer, J. B., Chen, C. H., Thompson, W. K., Harold, D., Williams, J., Owen, M. J., O'Donovan, M. C., Pericak-Vance, M. A., Mayeux, R., Haines, J. L., Farrer, L. A., Schellenberg, G. D., ... Dale, A. M. (2015). Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Molecular psychiatry, 20(12), 1588-1595. https://doi.org/10.1038/mp.2015.6

Desikan, RS, Schork, AJ, Wang, Y, Witoelar, A, Sharma, M, McEvoy, LK, Holland, D, Brewer, JB, Chen, CH, Thompson, WK, Harold, D, Williams, J, Owen, MJ, O'Donovan, MC, Pericak-Vance, MA, Mayeux, R, Haines, JL, Farrer, LA, Schellenberg, GD, Heutink, P, Singleton, AB, Brice, A, Wood, NW, Hardy, J, Martinez, M, Choi, SH, Destefano, A, Ikram, MA, Bis, JC, Smith, A, Fitzpatrick, AL, Launer, L, Van Duijn, C, Seshadri, S, Ulstein, ID, Aarsland, D, Fladby, T, Djurovic, S, Hyman, BT, Snaedal, J, Stefansson, H, Stefansson, K, Gasser, T, Andreassen, OA & Dale, AM 2015, 'Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus', Molecular psychiatry, vol. 20, no. 12, pp. 1588-1595. https://doi.org/10.1038/mp.2015.6

@article{79d49b0354ff4ab693a313317ac3784b,

title = "Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus",

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.",

author = "Desikan, \{R. S.\} and Schork, \{A. J.\} and Y. Wang and A. Witoelar and M. Sharma and McEvoy, \{L. K.\} and D. Holland and Brewer, \{J. B.\} and Chen, \{C. H.\} and Thompson, \{W. K.\} and D. Harold and J. Williams and Owen, \{M. J.\} and O'Donovan, \{M. C.\} and Pericak-Vance, \{M. A.\} and R. Mayeux and Haines, \{J. L.\} and Farrer, \{L. A.\} and Schellenberg, \{G. D.\} and P. Heutink and Singleton, \{A. B.\} and A. Brice and Wood, \{N. W.\} and J. Hardy and M. Martinez and Choi, \{S. H.\} and A. Destefano and Ikram, \{M. A.\} and Bis, \{J. C.\} and A. Smith and Fitzpatrick, \{A. L.\} and L. Launer and \{Van Duijn\}, C. and S. Seshadri and Ulstein, \{I. D.\} and D. Aarsland and T. Fladby and S. Djurovic and Hyman, \{B. T.\} and J. Snaedal and H. Stefansson and K. Stefansson and T. Gasser and Andreassen, \{O. A.\} and Dale, \{A. M.\}",

note = "Funding Information: We would like to thank Drs. Irene Litvan, Subhojit Roy and Marilyn Albert for helpful comments on an earlier version of this manuscript. This research was supported by grants from the National Institutes of Health (R01AG031224, K01AG029218, K02NS067427, T32 EB005970, UO1AG032984, U24-AG041689, and R01 MH100351), the Research Council of Norway (\#213837, \#225989, \#223273, \#237250/EU JPND), the South East Norway Health Authority (2013-123), the Norwegian Health Association and the KG Jebsen Foundation. AJS was supported by NIH grants RC2DA029475 and R01HD061414 and the Robert J. Glushko and Pamela Samuelson Graduate Fellowship. Please see Supplementary Acknowledgements for ADGC and ADNI funding sources. Funding Information: Disclosures Dr. Anders M. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives funding through research agreements with General Electric Healthcare (GEHC) and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Dr. Linda K. McEvoy has stock options in CorTechs Labs, Inc. Dr. James B. Brewer holds stock options in CorTechs Labs, Inc and serves on the advisory board and receives financial support from the Eli Lilly Biomarker Unit (Amyvid). Dr. Brewer also receives research support from General Electric and Janssen Alzheimer Immunotherapy.",

year = "2015",

month = dec,

day = "1",

doi = "10.1038/mp.2015.6",

language = "English (US)",

volume = "20",

pages = "1588--1595",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "12",

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TY - JOUR

T1 - Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus

AU - Desikan, R. S.

AU - Schork, A. J.

AU - Wang, Y.

AU - Witoelar, A.

AU - Sharma, M.

AU - McEvoy, L. K.

AU - Holland, D.

AU - Brewer, J. B.

AU - Chen, C. H.

AU - Thompson, W. K.

AU - Harold, D.

AU - Williams, J.

AU - Owen, M. J.

AU - O'Donovan, M. C.

AU - Pericak-Vance, M. A.

AU - Mayeux, R.

AU - Haines, J. L.

AU - Farrer, L. A.

AU - Schellenberg, G. D.

AU - Heutink, P.

AU - Singleton, A. B.

AU - Brice, A.

AU - Wood, N. W.

AU - Hardy, J.

AU - Martinez, M.

AU - Choi, S. H.

AU - Destefano, A.

AU - Ikram, M. A.

AU - Bis, J. C.

AU - Smith, A.

AU - Fitzpatrick, A. L.

AU - Launer, L.

AU - Van Duijn, C.

AU - Seshadri, S.

AU - Ulstein, I. D.

AU - Aarsland, D.

AU - Fladby, T.

AU - Djurovic, S.

AU - Hyman, B. T.

AU - Snaedal, J.

AU - Stefansson, H.

AU - Stefansson, K.

AU - Gasser, T.

AU - Andreassen, O. A.

AU - Dale, A. M.

N1 - Funding Information: We would like to thank Drs. Irene Litvan, Subhojit Roy and Marilyn Albert for helpful comments on an earlier version of this manuscript. This research was supported by grants from the National Institutes of Health (R01AG031224, K01AG029218, K02NS067427, T32 EB005970, UO1AG032984, U24-AG041689, and R01 MH100351), the Research Council of Norway (#213837, #225989, #223273, #237250/EU JPND), the South East Norway Health Authority (2013-123), the Norwegian Health Association and the KG Jebsen Foundation. AJS was supported by NIH grants RC2DA029475 and R01HD061414 and the Robert J. Glushko and Pamela Samuelson Graduate Fellowship. Please see Supplementary Acknowledgements for ADGC and ADNI funding sources. Funding Information: Disclosures Dr. Anders M. Dale is a Founder of and holds equity in CorTechs Labs, Inc, and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives funding through research agreements with General Electric Healthcare (GEHC) and Medtronic, Inc. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. Dr. Linda K. McEvoy has stock options in CorTechs Labs, Inc. Dr. James B. Brewer holds stock options in CorTechs Labs, Inc and serves on the advisory board and receives financial support from the Eli Lilly Biomarker Unit (Amyvid). Dr. Brewer also receives research support from General Electric and Janssen Alzheimer Immunotherapy.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

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EP - 1595

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 12

ER -

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

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