Bidirectional relationship between olfaction and Parkinson's disease

Abstract

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.

Keywords: Mendelian randomization; Parkinson’s disease; genetics; hyposmia; loss of smell.

Figure 1.

Study Design

Figure -

LocusCompare plots of LAVA results and MR results on PD and ability to smell. A-D) LocusCompare plots of GBA1, ANAPC4, SNCA, and MAPT loci with PD and ability to smell. Lead SNP is the SNP with the lowest sum of the P values from both studies. LD r² value relative to the lead SNP is indicated by color. E-F) Scatter and forest plots of MR results before removal of the heterogeneity outliers. G-H) Scatter and forest plots of MR results after removal of heterogeneity outliers determined by MR-PRESSO.