Bidirectional Relationship Between Olfaction and Parkinson’s Disease

Background Hyposmia (loss of smell) is a common early symptom of Parkinson’s disease (PD). The shared genetic architecture between hyposmia and PD is unknown. Methods We leveraged genome-wide association study (GWAS) results for self-assessment of ‘ability to smell’ and PD diagnosis. Linkage disequilibrium score regression (LDSC) and Local Analysis of [co]Variant Association (LAVA) were used to identify genome-wide and local genetic correlations. Mendelian randomization was used to identify potential causal relationships. Results LDSC found that sense of smell negatively correlated at a genome-wide level with PD. LAVA found negative correlations in four genetic loci near GBA1, ANAPC4, SNCA , and MAPT . Using Mendelian randomization we found evidence for strong causal relationship between PD and liability towards poorer sense of smell, but weaker evidence for the reverse direction. Conclusions Hyposmia and PD share genetic liability in only a subset of the major PD risk genes. While there was definitive evidence that PD can lower the sense of smell, there was only suggestive evidence for the reverse. This work highlights the heritability of olfactory function and its relationship with PD heritability and provides further insight into the association between PD and hyposmia. ### Competing Interest Statement A.J.N. reports grants from Parkinson's UK, Barts Charity, Cure Parkinson's, NIHR, Innovate UK, Virginia Keiley benefaction, Alchemab, Aligning Science Across Parkinson's Global Parkinson's Genetics Program (ASAP-GP2) and Michael J Fox Foundation. We thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). For a complete overview of members, acknowledgements, and funding, please see the Supplemental data and/or . We thank the research participants and employees of 23andMe. The following members of the 23andMe Research Team contributed to this study: The following members of the 23andMe Research Team contributed to this study: Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K. Bell, Jessica Bielenberg, Jonathan Bowes, Katarzyna Bryc, Ninad S. Chaudhary, Daniella Coker, Sayantan Das, Emily DelloRusso, Sarah L. Elson, Nicholas Eriksson, Teresa Filshtein, Pierre Fontanillas, Will Freyman, Zach Fuller, Chris German, Julie M. Granka, Karl Heilbron, Alejandro Hernandez, Barry Hicks, David A. Hinds, Ethan M. Jewett, Yunxuan Jiang, Katelyn Kukar, Alan Kwong, Yanyu Liang, Keng-Han Lin, Bianca A. Llamas, Matthew H. McIntyre, Steven J. Micheletti, Meghan E. Moreno, Priyanka Nandakumar, Dominique T. Nguyen, Jared O'Connell, Aaron A. Petrakovitz, G. David Poznik, Alexandra Reynoso, Shubham Saini, Morgan Schumacher, Leah Selcer, Anjali J. Shastri, Janie F. Shelton, Jingchunzi Shi, Suyash Shringarpure, Qiaojuan Jane Su, Susana A. Tat, Vinh Tran, Joyce Y. Tung, Xin Wang, Wei Wang, Catherine H. Weldon, Peter Wilton, Corinna D. Wong. K.H. is a former employee of 23andMe Inc., and holds stock and stock options in 23andMe, Inc. This work was supported by the following grants and institutions: Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services (C.B.); National Institute of Neurological Disorders and Stroke (project numbers ZO1 AG000535 and ZIA AG000949 to C.B.) This research was funded by Aligning Science Across Parkinson's through the Michael J. Fox Foundation for Parkinson's Research (MJFF). ### Funding Statement This work was supported by the following grants and institutions: Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services (C.B.); National Institute of Neurological Disorders and Stroke (project numbers ZO1 AG000535 and ZIA AG000949 to C.B.) This research was funded by Aligning Science Across Parkinson's through the Michael J. Fox Foundation for Parkinson's Research (MJFF). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical & Independent (E&I) Review Services gave ethical approval for this work using data from 23andMe participants. All other data used (IPDGC GWAS summary statistics) are openly available to the public. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. 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