Tau and alpha-synuclein and genetic susceptibility to Parkinson Disease in the Italian population

Several loci for familial Parkinson disease (PD) have been described, and over the last years significant efforts have been focused on investigating the contribution of common variants to PD risk. Recently, 3 independent GWAS have shown a genome-wide significant association of SNPs in the SNCA (alpha-synuclein) and MAPT (Tau) regions. In this frame, we genotyped a large Italian population of 920 PD patients (306 familial, 614 sporadic) and 920 controls for 13 markers located across the SNCA gene, and for 2 SNPs that define the MAPT H1 clade (previously associated with an increased risk of PD). Single-marker analysis demonstrated nominal evidence of association for: i) 5 SNPs in SNCA: 2 SNPs (rs356219, rs356220) in the 3’ region associated with increased risk of PD (P=0.05, OR[95% CI]=1.15[0.99-1.33], and P=0.05, OR[95% CI]=1.15[1.00-1.33]) and 3 SNPs (rs356186, rs2737029, and rs2197120) located in the intron 4 of the gene, associated with a reduced/increased risk of the disease (P=4.46E-04, OR[95% CI]=0.74[0.62-0.87]; P=0.03, OR[95% CI]=1.16[1.02-1.33]; and P=1.05E-03, OR[95% CI]=0.76[0.64-0.89]); ii) both SNPs (rs1800547, rs9468) identifying the MAPT H1 haplotype (P=8.13E-04, OR[95% CI]=0.75[0.63-0.89]; and P=8.36E-05, OR[95% CI]=0.72[0.61-0.85]). Moreover, we found a highly significant association between PD and a protective haplotype (P=7.53E-06; 14.1% in cases vs 19.9% in controls), spanning 83kb from intron 4 to the 3’ end of SNCA. Our findings provide additional evidence of SNCA and MAPT as major PD genes, and underline the concept that, at least in the Italian population, different allelic variants of SNCA (either protective or predisposing) can contribute to PD susceptibility.