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. 2012 Mar;18(3):257-62.
doi: 10.1016/j.parkreldis.2011.10.014. Epub 2011 Nov 21.

SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population

Luca Trotta  1 , Ilaria Guella, Giulia Soldà, Francesca Sironi, Silvana Tesei, Margherita Canesi, Gianni Pezzoli, Stefano Goldwurm, Stefano Duga, Rosanna Asselta
Affiliations

SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population

Luca Trotta et al. Parkinsonism Relat Disord. 2012 Mar.

Abstract

Background: Significant efforts have been focused on investigating the contribution of common variants to Parkinson disease (PD) risk. Several independent GWAS and metanalysis studies have shown a genome-wide significant association of single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) regions. Here we investigated the role of SNCA and MAPT as PD susceptibility genes in a large Italian population of 904 patients and 891 controls. An evaluation of gene-gene and gene-environment interactions in association with PD was also attempted.

Methods: The SNCA Rep1 microsatellite was genotyped by a fluorescent PCR assay, whereas the SNPlex genotyping system was used to genotype 12 additional markers across the SNCA gene, and 2 SNPs tagging the risk MAPT H1 haplotype.

Results: Single-marker analysis demonstrated nominal evidence of association for: i) the 261-bp-long allele of Rep1; ii) 7 SNPs in the SNCA region (top SNP: rs356186, P = 3.08 × 10(-04), intron 4); iii) both SNPs identifying the MAPT H1 haplotype (P = 4.63 × 10(-04) and P = 4.23 × 10(-04) for rs1800547 and rs9468, respectively). Moreover, we found a highly significant protective haplotype spanning ∼83 kb from intron 4 to the 3' end of SNCA (P = 1.29 × 10(-05)).

Conclusions: Our findings strongly confirm SNCA and MAPT as major PD susceptibility genes for idiopathic PD in the Italian population. Interaction analyses did not evidence either epistatic effects between the two loci or gene-environment interactions.

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Figures

Fig. 1
Fig. 1
LD structure of the SNCA locus. The structure of the SNCA gene is shown (drawn to scale; exons are represented by boxes, introns by horizontal lines, which also indicate the transcriptional direction of the gene). At the top of the gene, the ruler indicates the gene size, whereas numbers below the ruler depict the position within chromosome 4 (UCSC Genome Browser, Mar. 2006 release, NCBI36/hg18). Genotyped polymorphisms are listed, and their locations are shown by lines relative to the SNCA gene. Below the gene scheme, associated haplotypes identified in this (continuous) or previous (dashed) works are indicated as horizontal lines; the overlapping region is shaded in gray; numbers beside previously-reported haplotypes correspond to: 1) ; 2) ; 3) ; 4) . Only SNPs shared among our and other haplotypes are indicated with a vertical hyphen in haplotypes 1–4; capital letters indicate alleles exerting a protective effect, small letters indicate alleles exerting a predisposing effect. For the Rep1 microsatellite, only the two most frequent alleles were considered: the 259 bp-long allele was named 1, the 261 bp-long allele was named 2. In the lower part of the figure, the LD structure of the SNCA locus is shown. Pair-wise LD values, estimated for the genotyped SNPs, are represented by boxes. The standard color scheme of Haploview was used to display the strength of LD: black indicates strong LD, grey intermediate, whereas white denotes no LD. r2 values are shown within the boxes.
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