AUTHOR=Landoulsi Zied , Pachchek Sinthuja , Bobbili Dheeraj Reddy , Pavelka Lukas , May Patrick , Krüger Rejko ,  the NCER-PD Consortium 

TITLE=Genetic landscape of Parkinson’s disease and related diseases in Luxembourg

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1282174

DOI=10.3389/fnagi.2023.1282174

ISSN=1663-4365

ABSTRACT=<sec id="sec1"><title>Objectives</title><p>To explore the genetic architecture of PD in the Luxembourg Parkinson’s Study including cohorts of healthy people and patients with Parkinson’s disease (PD) and atypical parkinsonism (AP).</p></sec><sec id="sec2"><title>Methods</title><p>809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (<italic>LRRK2</italic>, <italic>SNCA</italic>, <italic>VPS35</italic>, <italic>PRKN</italic>, <italic>PARK7</italic>, <italic>PINK1</italic> and <italic>ATP13A2</italic>). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs.</p></sec><sec id="sec3"><title>Results</title><p>We identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in <italic>LRRK2</italic>, <italic>PINK1</italic> and <italic>PRKN</italic>. Eleven rare CNVs were detected in <italic>PRKN</italic> including seven duplications and four deletions. The majority of <italic>PRKN</italic> SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk.</p></sec><sec id="sec4"><title>Conclusion</title><p>We performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson’s Study. Heterozygous SNVs and CNVs in <italic>PRKN</italic> were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare <italic>LRRK2</italic> SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.</p></sec>