Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Abstract

The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

Keywords: Genetics; Interaction; LRRK2; MAPT; Parkinson's disease; SNCA.

Figure 1

A) Individual and combined effects of SNCA rs181489, MAPT rs1052553, and LRRK2 p.R1398H on risk of PD in the Caucasian series. For SNCA rs181489, the risk genotype was CT or TT (i.e. presence of the minor allele); B) Individual and combined effects of SNCA rs356129, MAPT rs1052553, and LRRK2 p.R1398H on risk of PD in the Caucasian series. For SNCA rs356129, the risk genotype was AG or GG (i.e. presence of the minor allele); C) Individual and combined effects of SNCA rs11931074, MAPT rs1052553, and LRRK2 p.R1398H on risk of PD in the Caucasian series. For SNCA rs11931074, the risk genotype was GT or TT (i.e. presence of the minor allele); D) Individual and combined effects of SNCA rs2583988, MAPT rs1052553, and LRRK2 p.R1398H on risk of PD in the Caucasian series. For SNCA rs2583988, the risk genotype was CT or TT (i.e. presence of the minor allele). Figures 1A–1D) For MAPT rs1052553, the risk genotype was AA (i.e. presence of two copies of the major allele); for LRRK2 p.R1398H, the protective genotype was GA or AA (i.e. presence of the minor allele); NA indicates that a given SNP was not involved in the particular portion of the analysis.

Figure 2

A) Individual and combined effects of SNCA rs356219, SNCA rs11931074, and LRRK2 p.R1398H on risk of PD in the Asian series. SNCA rs356219 and rs11931074 were considered under a recessive model (i.e. presence vs. absence of two copies of the minor allele). For SNCA rs356219, the risk genotype was GG. For SNCA rs11931074, the risk genotype was TT; B) Individual and combined effects of SNCA rs356219, SNCA rs11931074, and LRRK2 p.R1398H on risk of PD in the Asian series. SNCA rs356219 and rs11931074 were considered under a dominant model (i.e. presence vs. absence of the minor allele). For SNCA rs356219, the risk genotype was AG or GG. For SNCA rs11931074, the risk genotype was GT or TT. Figures 2A–2B) For LRRK2 p.R1398H, the protective genotype was GA or AA (i.e. presence of the minor allele); NA indicates that a given SNP was not involved in the particular portion of the analysis.