Abstract
Many individuals with Parkinson’s disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency <5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer’s disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G>A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G>A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.
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Acknowledgements
We are very grateful to Jelena Golic, Susanne Lindhof, Katja Junghans, Regina Feldmann and Sybille Frischholz at the Institute for Human Genetics at the Helmholtz Zentrum München for expert technical assistance.
All variants were submitted to dbSNP and received the NCBI numbers ss1399967350 to ss1399967376.
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This study was funded exclusively by in-house institutional funding from the Technische Universität München and the Helmholtz Zentrum München, Munich, Germany. There was no industry sponsorship. The KORA-Age project was funded by the German Ministry for Education and Research (BMBF) FKZ 01ET0713 and 01ET1003. BM has received grants from TEVA-Pharma, Desitin, Boehringer-Ingelheim and GE Healthcare and honoraria for consultancy from Bayer Schering Pharma AG and for presentations from GlaxoSmithKline and Orion Pharma as well as travel and meeting expenses from Boehringer-Ingelheim and Novartis. DH is currently employed by the Medical University of Vienna, Austria, and received research support through the National Institute of Neurological Disorders and Stroke Intramural Research Program and the Austrian Science Fund (FWF). He serves as member of the Medical Advisory Board of the International Essential Tremor Foundation and received honoraria and conference support from Ipsen and UCB. Walter Pirker received speaker honoraria from AOP Orphan Pharma, Medtronic Inc., Novartis, Boehringer-Ingelheim, Abbott Pharm and UCB as well as travel compensation from Ipsen Pharma, Boehringer-Ingelheim and Medtronic, Inc. BB and MJM receive research support from the Hungarian National Innovation Office (TÁMOP-4-2-1/B-03/1/KMR-2010-001). The functional analyses were supported by the European Research Council under the European Union's Seventh Framework Program (FP7/20072013)/ ERC Grant Agreement No. 321366-Amyloid (advanced grant to CH) and the general legacy of Mrs Ammer (to the Ludwig-Maximilians University/the chair of C.H.). PP is funded by a grant of the Spanish Ministry of Science and Innovation SAF-2010-22329-C02-01: 2011–2013. XE is funded by the Spanish Plan Nacional SAF-2008-00357 (NOVADIS); the Generalitat de Catalunya AGAUR 2009 SGR-1502; and the European Commission 7th Framework Program, Project No 261123 (GEUVADIS) and Project No 262055 (ESGI). JW serves on a scientific advisory board for UCB and has received speaker honoraria from UCB and Vifor Pharma. The remaining authors declare no conflict of interest.
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Schulte, E., Fukumori, A., Mollenhauer, B. et al. Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease. Eur J Hum Genet 23, 1328–1333 (2015). https://doi.org/10.1038/ejhg.2014.300
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DOI: https://doi.org/10.1038/ejhg.2014.300
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