Category: Parkinson's Disease: Genetics
Objective: WD often includes parkinsonism and copper dysregulation is implicated in Parkinson’s disease (PD), we investigated whether heterozygous ATP7B variants are associated with increased PD risk.
Background: Wilson disease (WD) is an autosomal recessive copper-transport disorder due to biallelic ATP7B variants, causing copper overload and multiorgan dysfunction. Prevalence is ~1:30.000, but higher in some populations (e.g., Sardinia, Croatia, Israel, Costa Rica) due to founder variants.
Method: We included 613 PD (268 from Mondino-Pavia and 345 from INSB-Bologna) and 3182 controls (1228 from Mondino-Pavia, 274 from INSB-Bologna and 1680 healthy Italian controls from Network for Italian Genomes -NIG database) who underwent exome or genome sequencing. Low-quality data were excluded. Variants classified as pathogenic/likely-pathogenic (P/LP) based on ACMG criteria were retained.
We administered the FAMPARK questionnaire (FAMiliar study for PARKinson’s disease), a structured family-history survey, to 115 unrelated WD probands (55 from Sardinia) to screen for PD occurrence among relatives.
Results: In the Pavia and Bologna cohorts, 16 PD (2.6%) and 47 controls (1.5%) carried P/LP ATP7B variants. The frequency in local controls was similar to that in the NIG cohort (1.4%). Chi-square comparison was marginally significant (p=0.04) with an OR of 1.79 (C.I. [1.01-3.17]). Among 115 WD probands, 21 (23%) had a relative with a clinical diagnosis of PD, including 6 first-degree, 12 second-degree, and 3 third-degree. Two families (11%) had ≥2 PD-affected relatives.
Conclusion: Our findings suggest a possible enrichment of ATP7B P/LP heterozygous variants in PD subjects compared to the general population, warranting further investigation. We aim to leverage GP2 resources to perform a burden analysis of deleterious ATP7B variants in large multi-ancestry cohorts, to clarify the potential contribution of this gene to PD risk.
To cite this abstract in AMA style:
P. Mitrotti, M. Avenali, P. Dimartino, R. Minardi, G. Pisano, I. Palmieri, A. Fiorentino, L. Malfer, M. Khani, P. Reyes, G. Cossu, V. Carelli, EM. Valente. Investigating the role of ATP7B heterozygous variants in Parkinson’s Disease [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/investigating-the-role-of-atp7b-heterozygous-variants-in-parkinsons-disease/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-role-of-atp7b-heterozygous-variants-in-parkinsons-disease/