Shared molecular genetic factors influence subcortical brain morphometry and Parkinson’s disease risk

Abstract

Parkinson’s disease (PD) is a late-onset and genetically complex neurodegenerative disorder. Here we sought to identify genes and molecular pathways underlying the associations between PD and the volume of ten brain structures measured through magnetic resonance imaging (MRI) scans. We leveraged genome-wide genetic data from several cohorts, including the International Parkinson’s Disease Genomics Consortium (IPDG), the UK Biobank, the Adolescent Brain Cognitive Development (ABCD) study, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Enhancing Neuroimaging Genetics through Meta-Analyses (ENIGMA), and 23andMe. We observed significant positive genetic correlations between PD and intracranial and subcortical brain volumes. Genome-wide association studies (GWAS) - pairwise analyses identified 210 genomic segments with shared aetiology between PD and at least one of these brain structures. Pathway enrichment results highlight potential links with chronic inflammation, the hypothalamic-pituitary-adrenal pathway, mitophagy, disrupted vesicle-trafficking, calcium-dependent, and autophagic pathways. Investigations for putative causal genetic effects suggest that a larger putamen volume could influence PD risk, independently of the potential causal genetic effects of intracranial volume (ICV) on PD. Our findings suggest that genetic variants influencing larger intracranial and subcortical brain volumes, possibly during earlier stages of life, influence the risk of developing PD later in life.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes

“…First, we evaluated the genetic correlation between PD and BSPs, identifying significant positive genetic correlations with SA and ICV, consistent with previous studies. 16,39 A recent publication also reported similar positive correlations with specific brain volumes, further corroborated by our results. 39 However, LDSC analysis suggested nonsignificant genetic correlations with other brain structures.…”

“…16,39 A recent publication also reported similar positive correlations with specific brain volumes, further corroborated by our results. 39 However, LDSC analysis suggested nonsignificant genetic correlations with other brain structures. This divergence could stem from varying sample sizes, population characteristics, or methodologies across studies, underscoring the intricate genetic relationship between PD and certain brain regions.…”