Genotyping of all 87 tagging SNPS across the neuronal nAChR α and β subunits was first carried out in the UT (n = 439) and WI cohorts (n = 339), and single marker allelic tests using χ2 statistics were evaluated for association with FTND scores in early versus late onset samples (Table S3). The strongest association signals (P<0.005) to dichotomized FTND by age of onset were observed only in the early onset sample for six SNPs within the CHRNA5-A3-B4 gene cluster with significant allele test P values ranging from 4.8×10−3 to 5.0×10−4 (Table 1). No other nAChR SNP had a P value less than 0.02 in either the early or late onset group. These six CHRNA5-A3-B4 SNPs stratified into two groups of significant linkage disequilibrium (LD), and examination of phased resequencing haplotypes (Figure 1) revealed that these association signals occur within a ∼50 kb LD block-like structure spanning CHRNA5 and CHRNA3. This LD block in the resequencing samples is composed of four major haplotypes: Haplotype A (HA) = 38%, Haplotype B (HB) = 34%, Haplotype C (HC) = 20%, Haplotype D (HD) = 5%.
