A commentary on fine mapping and resequencing of the PARK16 locus in Parkinson’s disease

It has been almost two decades since the first genetic form of Parkinson’s disease (PD), a point mutation in the α-synuclein gene (SNCA), was identified.¹ Remarkable technological advancements in recent times have accelerated genetic discovery for PD and nominated potential molecular pathways for therapeutic intervention strategies. To date, pathogenic mutations in six genes (SNCA, LRRK2, VPS35, PARKIN, PINK1 and DJ-1) have been confirmed to result in carriers presenting the clinical phenotype associated with PD, with the vast majority of these reporting a family history of the disease.¹ Furthermore, a recent large-scale meta-analysis of population-based genome-wide association studies (GWAS) has identified 24 independent genomic loci (including the familial genes SNCA and LRRK2) that influence susceptibility to the common sporadic form of PD.²

The loci nominated through GWAS approaches tend to be large genomic regions defined by patterns of linkage disequilibrium (LD) and contain multiple candidate genes. Thus, identifying the variant (or gene) responsible for modifying disease susceptibility within these loci remains challenging. In the previous issue, Pihlstrøm et al.³ attempt to fine-map and resequence the PARK16 locus in patient populations from Scandinavia. PARK16 was one of the first loci nominated through GWAS efforts in both Asian and European cohorts.^{4, 5} Although replications in Asian populations were consistently supportive, studies in Caucasian populations were initially controversial.³ The recent large-scale meta-GWAS in Caucasian samples has replicated the association and would appear to confirm this disease locus across ethnicities.² From these studies it would appear that PARK16 contains five candidate genes (SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1) and it remains unclear which specific gene and/or variant(s) is responsible for the observed association.

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

Access through your institution

or

Sign in or create an account

Continue with Google

Continue with ORCiD