Objective: To investigate genetic factors underlying age at onset (AAO) variability in PD in the largest diverse European cohort to date.

Background: Genetic factors substantially influence Parkinson’s disease (PD) risk, and emerging evidence indicates they also contribute to variation in AAO. Previous genome-wide association studies (GWAS) have identified AAO-associated signals at SNCA, TMEM175, and BST1, yet, the majority of genetic contributors to AAO remain unknown.

Method:

We performed a PD AAO GWAS meta-analysis leveraging data for 50,859 individuals diagnosed with PD, including participants from the Global Parkinson’s Genetics Program (GP2), the International Parkinson’s Disease Genomics Consortium (IPDGC), the UK Biobank (UKB), and the Fox Insight Genetics Study (FIGS), FinnGen, and deCODE Genetics.

Results: The combined analysis identified four genome-wide significant loci associated with PD age at onset. We replicated the established SNCA signal (rs356182) and, for the first time, achieved genome-wide significance at the GBA1 locus (rs76763715, p.N409S). We further nominate two novel AAO-associated loci: rs10847864 near HIP1R, a gene previously implicated in PD risk, and rs145762710, with FSCB as the nearest annotated coding gene.

Conclusion: This study represents the largest meta-analysis of PD AAO across European populations to date. Our findings suggest partial overlap between the genetic architecture of PD risk and AAO, illustrated by variants near SNCA, GBA1, and HIP1R. While replication of the SNCA and GBA1 signals reinforces their established roles in PD, the nomination of HIP1R and FSCB as AAO-associated loci highlights candidates that warrant further investigation. Improving our understanding of the genetic factors that influence AAO may inform research into the biological mechanisms and disease-modifying pathways relevant to PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-modifiers-of-age-at-onset-for-parkinsons-disease-in-european-populations/