Patterns of Linkage Disequilibrium of LRRK2 across Different Races: Implications for Genetic Association Studies

Huihua Li,Yik Ying Teo,Eng King Tan

doi:10.1371/journal.pone.0075041

Abstract

Genome Wide Association Studies (GWASs) have identified trait-associated polymorphisms via a hypothesis-free approach. However, it is challenging when attempting to reproduce GWAS findings in different populations as it fundamentally relies on the similar patterns of linkage disequilibrium (LD) between the unknown causal variants and the genotyped single nucleotide polymorphisms (SNPs). To address this potential limitation, we examined the regional LD pattern of leucine-rich repeat kinase 2 (LRRK2) gene, which is responsible for both autosomal dominant and sporadic Parkinson’s disease (PD), in Caucasians (CEU), Japanese (JPT) and Chinese (CHB) from HapMap and Chinese (CHS), Malays (MAS) and Indians (INS) from the Singapore Genome Variation Project (SGVP) utilizing the traditional heatmaps and targeted analysis of LRRK2 gene via Monte Carlo simulation through varLD scores of these ethnic groups. Both heatmaps and targeted analysis showed that LD pattern of JPT was different from that of INS (P=0.0001); while LD pattern of CEU was different from that in Asian except for INS (all P=0.0001). Our study suggests that there is a higher chance to detect associations between PD and those trait-associated SNPs of LRRK2 gene found in Caucasian studies in INS, while those found in Japanese studies are likely to be better replicated among CHB.

Highlights

In order to including all the single nucleotide polymorphisms (SNPs) close to leucine-rich repeat kinase 2 (LRRK2) gene investigated in Genome Wide Association Studies (GWASs) study, we extended the range of interest by 10 k, which resulted in our final region of interest from 38.705Mb to 39.049Mb
We compared the regional patterns of linkage disequilibrium surrounding these traitassociated SNPs between CEU and Asian first, followed by the comparison between JPT and the rest Asian ethnic groups (CHB, CHS, MAS and INS) separately to Association found in References rs1994090 12
With the assumption of the same causal variant in different populations, the different patterns of correlation between the underlying causal variant and the surrounding SNPs more likely leads to different SNPs emerging from genome wide scans in different populations and play an important role in the following replication studies which aims to reproduce the primary association signals found in GWASs by means of candidate gene approach

Summary

Introduction

Parkinson’s disease (PD), a chronic common neurodegenerative disorder, has an estimated 1%–2% of individuals in those over the age of 65 years, and more than 4% in those more than 85 years [1]. The disease is characterized by loss of dopamine due to the progressive loses of dopaminergic cells in the substantia nigra pars compacta. This leads to the typical motor dysfunction, which becomes evident when approximately 80% of striatal dopamine and 50% of nigral neurons are lost [2]. G2385R and R1628P, which are important risk factors of PD, occur predominantly in the Asian populations [9,14,15,16,17], and are very rare or absent in other populations These observations suggest that LRRK2 mutation/variant frequency is ethnicity-dependent

Methods

Results

Conclusion