NCBI genome assembly build 36. The seven associated SNPs (markers indicated by an asterisk (*); plotted association results presented as a black circle (*)) were considered to be of potentially functional importance as they were located in the promoter, the 50-UTR or exons. The LD plot of the locus is based on the measure r2 and was generated with Haploview 3.32 using the genotypes of German control individuals. (C) Illustration of the EXO1 gene model highlighting the position of the seven potentially functional SNPs. EXO1 has several isoforms; here we refer to NM_130398 that contains 16 exons, 13 of which constitute the coding region (indicated by big boxes) whereas three exons (exon 1, exon 2 and alternative exon 2a) span the 50-UTR, and the last exon (nominal exon 15) contains coding sequence and the 30-UTR (small boxes). The seven SNPs analyzed in this study are located within functionally relevant regions: two SNPs in the 50-proximal promoter region (rs1776181A/G, rs1776180C/G), three SNPs in the 50-UTR (rs1776178A/G, rs1635517G/A, rs1776177C/T) and two non-synonymous SNPs in the coding region (rs735943A/G resulting in amino acid substitution H354R; rs4149965G/A resulting in V458M). ATG: start codon in nominal exon 3, TAA: stop codon in nominal exon 15. The position of the transcriptional start site as predicted by the Eponine prediction tool (http://www.sanger.ac.uk/Software/analysis/eponine/) is indicated by an asterisk (*). Genotyping was performed using the SNPlexTM Genotyping System and TaqMan1 SNP Genotyping Assays (Applied Biosystems, Foster City, USA). Analyzed SNPs had a minor allele frequency of at least 1% and a minimal overall Hardy-Weinberg equilibrium (HWE) in controls (P > 0.05). 

2.4. Statistical analysis
The genetic markers were subjected to allelic (CCA) and genotypic (CCG) case-control comparisons (χ2 test, P: P value obtained from an allele-based case-control comparison, using 1 degree of freedom (df); P: P value obtained from a genotype-based case-control CCG comparison, using a χ2 test with 2 df). Tagging SNPs of EXO1 and TCF3 were selected based on the HapMap genotypes of Utah residents with ancestry from northern and western Europe (CEU; http://www.hapmap.org/) and the pairwise tagging option implemented in the Haploview v3.32 program (Barrett et al., 2005; http://www.broad.mit.edu/mpg/haploview/) (minor allele frequency 0.03, pairwise r2 ≥ 0.8, P > 0.01; for tag SNPs, see Table S3). Haploview was also used for determining the LD measure r2 between SNPs in controls.

The seven EXO1 SNPs (Table 2) typed in the German sample and the functionally relevant SNP rs1776180 typed in the French set were analyzed by logistic regression using an additive model. 

2.6. Construction of plasmids
Plasmids for over-expression of human EXO1 protein in yeast cells were generated by inserting full-length EXO1 cDNA into expression vector pDB20 (Becker et al., 1991). Constructs for analysis of EXO1 50-UTR were designed by insertion of a 584 bp fragment of the 50-UTR region into vector pGL3control (Promega, Madison, WI). Constructs for analysis of EXO1 50-proximal promoter were designed by inserting 1199 bp of the EXO1 promoter region into vector pGL3Enhancer (Promega). Allele-specific constructs were established by site-directed mutagenesis using the QuickChange mutagenesis kit (Stratagene, La Jolla, CA). The over-expression construct pMyc-E47-EYFP was kindly provided by Naihe Jing (Shanghai Institutes for Biological Sciences, Shanghai, China). For RNAi-mediated knock-down of E47/TCF3 expression, two independent target sequences directed against E47/TCF3 mRNA were inserted into vector pSUPER.Neo + GFP (OligoEngine, Seattle, WA).