High-Throughput Sequencing Haplotype Analysis Indicates in LRRK2 Gene a Potential Risk Factor for Endemic Parkinsonism in Southeastern Moravia, Czech Republic

Kristyna Kolarikova,Julia Stellmachova,Petr Kanovsky,Katerina Mensikova,Martin Prochazka,Radek Vrtel,Radek Vodicka,Jan Geryk,Tomas Furst,Tereza Bartonikova

doi:10.3390/life12010121

Abstract

Parkinson’s disease and parkinsonism are relatively common neurodegenerative disorders. This study aimed to assess potential genetic risk factors of haplotypes in genes associated with parkinsonism in a population in which endemic parkinsonism and atypical parkinsonism have recently been found. The genes ADH1C, EIF4G1, FBXO7, GBA, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PINK1 PLA2G6, SNCA, UCHL1, and VPS35 were analyzed in 62 patients (P) and 69 age-matched controls from the researched area (C1). Variants were acquired by high-throughput sequencing using Ion Torrent workflow. As another set of controls, the whole genome sequencing data from 100 healthy non-related individuals from the Czech population were used (C2); the results were also compared with the Genome Project data (C3). We observed shared findings of four intron (rs11564187, rs36220738, rs200829235, and rs3789329) and one exon variant (rs33995883) in the LRRK2 gene in six patients. A comparison of the C1–C3 groups revealed significant differences in haplotype frequencies between ratio of 2.09 for C1, 1.65 for C2, and 6.3 for C3, and odds ratios of 13.15 for C1, 2.58 for C2, and 7.6 for C3 were estimated. The co-occurrence of five variants in the LRRK2 gene (very probably in haplotype) could be an important potential risk factor for the development of parkinsonism, even outside the recently described pedigrees in the researched area where endemic parkinsonism is present.

Highlights

The aim of this study was to assess the co-occurrence of rare variants, possibly in haplotype, in the set of genes associated with parkinsonism (ADH1C, EIF4G1, FBXO7, GBA, GIGYF2, HTRA2, LRRK2, MAPT, PARK2, PARK7, PINK1, PLA2G6, SNCA, UCHL1, and VPS35) in the parkinsonian patients and controls from the Hornacko region [36,37,38]
The shared occurrence of four rare intron and one exon variants in the LRRK2 gene was found in ten patients (Nr. 3, 17, 22, 23, 24, 26, 7 (11/32), 8 (19/32), 9 (21/32), and 10 (3/32)) (Table 2)
Many key factors have been identified in the past, which are putatively important in the development of neurodegenerative parkinsonism, including genetic predisposition, environmental risk factors, and lifestyle

Summary

Introduction

This article is an open access article. Parkinson disease (PD) is a very frequent neurodegenerative disease which affects. 1–2% of individuals in the population over 65 years of age and about 4% in the population over the age of 85 years [1,2]. Symptoms: bradykinesia, muscle rigidity, and postural instability [3]. The major risk factors which contribute to PD development are age, environmental factors [4,5], and genetic background. The familial form of PD (about 5%) is caused by causal variant with high penetrance. The variants with minor effect and environmental factors could contribute to sporadic form [6]. Genes associated with parkinsonism have been studied for many years.

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