Objective: To investigate the relationship between Parkinson’s disease-polygenic risk score (PD-PRS) and brain morphology in a large sample of healthy individuals.

Background: PD is caused by pathogenic a-synuclein accumulation and neurodegeneration. Until recently, it was thought to consist of either rare familial forms or more common cases of environmental origin. There is now clear evidence of a genetic influence in sporadic cases as GWAS studies have identified numerous loci with small cumulative effects. Together, these make up a PRS. Several of the identified loci impact a-synuclein synthesis or clearance. Studies have reported a correlation between PD-PRS and age at onset1, cognitive decline and motor progression in PD2.

Method: 11,669 participants from UK BioBank without neurological or cardiovascular disorders were included. Exclusion criteria for participants were relation to another closer than cousin, sex mismatch, and non-European ancestry. PD-PRS was calculated using the genetic variants of the largest genome-wide association study of PD to date3. Furthermore, cortical and subcortical volumes of 78 brain regions were obtained from the Imaging-derived Phenotypes. These were measured using Freesurfer software and scaled for total brain volume. General Linear Models were run between each brain parcel and PRS, accounting for age, gender, BMI and the top 20 principal components of the GWAS to adjust for population stratification.

Results: After multiple comparison correction, PRS showed significant negative correlation with volume of total gray matter, subcortical gray matter, bilateral cortex, putamen, insula, lateral and medial orbitofrontal cortex, superior frontal gyrus, right parahippocampal gyrus, thalamus, left entorhinal and inferior temporal cortex. In addition, PRS was positively correlated with volume of bilateral cerebral white matter.

Conclusion: Studying a large sample of participants, we find that adults with higher PD genetic susceptibility have considerable whole brain and regional atrophy, particularly in regions that are involved in PD proper. In light of recent reports of 40% incidence of synuclein pathology in asymptomatic elderly4 we propose that the PD-PRS may lead to a mild synucleinopathy that could represent a latent asymptomatic form of PD. This subclinical synucleinopathy could render individuals more vulnerable to the environmental insults that trigger full-blown PD.

References: Valentina Escott-Price, Mike A. Nalls, Huw R. Morris et al. Polygenic Risk of Parkinson Disease Is Correlated with Disease Age at Onset. ANN NEUROL 2015; 77:582–591. Paul KC, Schulz J, Bronstein JM et al. Association of Polygenic Risk Score with Cognitive Decline and Motor Progression in Parkinson Disease. JAMA Neurol. 2018; 75(3):360-366. Mike A. Nalls, Cornelis Blauwendraat, Costanza L. Vallerga 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(12):1091-1102. Anna Raunio, Karri Kaivola, Jarno Tuimala et al. Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85+. Acta Neuropath 2019; 138, 771–782.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-polygenic-risk-score-and-brain-structure-in-neurologically-healthy-individuals/