Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Keywords: APOE; Lewy body diseases; dementia; genome-wide association studies.

Graphical Abstract

Figure 1

Manhattan plot of LBD-D versus LBD-ND. A Manhattan plot representing the results of the case–case genome-wide association study results (n = 2908 Lewy body disorders with dementia and n = 4896 Lewy body disorders without dementia), where 6 877 765 variants have been analysed under a logistic regression model. The plot highlights genome-wide significant single nuclear variants on chromosome 4 (rs7668531, P = 3.25e⁻¹²), 12 (rs17442721, P = 1.44e⁻⁰⁸) and 19 (rs429358, P = 3.25e⁻⁵⁷). Negative logarithm P-value is represented on the y-axis, while chromosome position is represented on the x-axis. The dotted line indicates genome-wide significant threshold (5 × 10⁻⁸).

Figure 2

Regional association plot for eQTL and GWAS signals. Results from colocalization analysis presented via regional association plot for expression quantitative trait loci and (A) genome-wide association signals in the region close to LRRK2 (posterior probability H4 = 0.72, 4026 variants analysed) and (B) in the region close to FAM181B (posterior probability H4 = 0.70, 4357 variants analysed). Negative logarithm P-value is represented on the y-axis, while chromosome position is represented on the x-axis.

Figure 3

Polygenic risk score from Parkinson’s disease, Alzheimer’s disease and dementia with Lewy bodies GWAS. Violin plot comparing z-transformed (A) Parkinson's disease, (B) Alzheimer's disease and (C) dementia with Lewy body polygenic risk score (PRS) distributions in Lewy body disease with dementia (LBD-D, n = 2908) with those without (LBD-ND, n = 4896). The centreline of the box plot represents the median, and the box limits are the interquartile range. Dots correspond to outliers. A general linear regression model was applied to assess the odds PRS-predicted dementia. High Parkinson’s disease PRS predicts lower odds of developing dementia (OR = 0.74, 95% CI = 0.56–0.98, P = 0.03), while high dementia with Lewy bodies PRS predicts increased odds of developing dementia (OR = 2.69, 95% CI = 0.69–10.42, P = 0.01).