Lrrk2 R1441G-related Parkinson's disease: evidence of a common founding event in the seventh century in Northern Spain

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene together represent the most common genetic determinant of Parkinson's disease (PD) identified to date. The vast majority of patients with LRRK2-related PD reported in the literature carry one of three pathogenic substitutions: G2019S, R1441C, or R1441G. While G2019S and R1441C are geographically widespread, R1441G is most prevalent in the Basque Country and is rare outside of Northern Spain. We sought to better understand the processes that have shaped the current distribution of R1441G. We performed a haplotype analysis of 29 unrelated PD patients heterozygous for R1441G and 85 wild-type controls using 20 markers that spanned 15.1 Mb across the LRRK2 region. Nine of the patients were of Basque origin and 20 were non-Basques. We inferred haplotypes using a Bayesian approach and utilized a maximum-likelihood method to estimate the age of the most recent common ancestor. Significant but incomplete allele sharing was observed over a distance of 6.0 Mb and a single, rare ten-marker haplotype 5.8 Mb in length was seen in all mutation carriers. We estimate that the most recent common ancestor lived 1,350 (95% CI, 1,020-1,740) years ago in approximately the seventh century. We hypothesize that R1441G originated in the Basque population and that dispersion of the mutation then occurred through short-range gene flow that was largely limited to nearby regions in Spain.

Fig. 1

Genotypes for 20 markers surrounding the LRRK2 R1441G mutation. A single ten-marker haplotype (indicated by dark gray shading) was shared by all 29 mutation carriers. Incomplete but significant allele sharing is denoted by light gray shading and the frequency of each shared allele in 170 control chromosomes is displayedinthe lower right-hand margin. In instances in which phase could not be unambiguously determined, both alleles are shown. Disease haplotypes inferred using PHASE are indicated in bold type

Fig. 2

R1441G distribution in Spain. Mutation carrier frequencies based on previous studies [–14] are shown for four different regions in Northern Spain