Objective: To establish a causal direction and genetic relationship between olfactory function and Parkinson’s disease (PD).

Background: Degradation in olfactory function or hyposmia is a common prodromal symptom of PD [1], often presenting years before PD diagnosis. While the common understanding is that the early deterioration of smell is a reflection of selective vulnerability to the disease process, an alternative hypothesis is that an exposure that causes loss of olfactory function may lead to PD [2,3].

Method: We analyzed two genome-wide association study (GWAS) results for self-assessment of ability to smell and PD [4] with 1,427,780 and 27,693 participants respectively. To determine shared genetic architecture between the two traits, we used the linkage disequilibrium score (LDSC) regression [5] to identify genome-wide genetic correlation. Then Local Analysis of [co]Variant Association (LAVA) [6] to identify locus-level correlations. Mendelian randomization (MR) methods including MR-PRESSO [7] was used to find evidence for causal direction between PD and olfaction function.

Results: We found that the self-assessed ability to smell is a highly polygenic trait with 394 genomic loci. PD and self-assessed ability to smell had a small but significant genome-wide correlation (rg = -0.095, p = 0.006), concentrated in four genetic loci near GBA1, ANAPC4, SNCA, and MAPT (rg < -0.450, p < 6.36 x 10-4). MR-PRESSO showed strong evidence for PD causing a lower ability of smell (Effect = -0.0231, p = 2.96 x 10-11), but weaker evidence for lower ability to smell to PD (Effect = -0.5401, p = 0.0082).

Conclusion: This work highlights the heritability of olfactory function and its relationship to PD heritability. MR results suggest that hyposmia may be both a risk factor for and caused by PD, but further research is needed to better understand the causal relationship between the two traits.

References: References
1. Rees RN, Noyce AJ, Schrag A. The prodromes of Parkinson’s disease. Eur J Neurosci. John Wiley & Sons, Ltd; 2019;49:320–7.
2. Levine KS, Leonard HL, Blauwendraat C, Iwaki H, Johnson N, Bandres-Ciga S, et al. Virus exposure and neurodegenerative disease risk across national biobanks. Neuron. 2023;111:1086–93.e2.
3. Doty RL. Olfactory dysfunction in Parkinson disease. Nat Rev Neurol [Internet]. Nat Rev Neurol; 2012 [cited 2023 May 14];8. Available from: https://pubmed.ncbi.nlm.nih.gov/22584158/
4. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2019;18:1091–102.
5. Bulik-Sullivan BK, Loh P-R, Finucane HK, Ripke S, Yang J, Schizophrenia Working Group of the Psychiatric Genomics Consortium, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47:291–5.
6. Werme J, van der Sluis S, Posthuma D, de Leeuw CA. An integrated framework for local genetic correlation analysis. Nat Genet. 2022;54:274–82.
7. Verbanck M, Chen C-Y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bidirectional-relationship-between-olfaction-and-parkinsons-disease/