After analyzing the entire protein coding region of OMI/HTRA2
(RefSeq NM_013247) in a total of 644 PD patients and 828 neurologically normal controls, we identified the c.1195G>A substitution in exon 7 (leading to p.G399S), previously identified as a mutation associated with PD by Strauss et al
), in a total of five PD patients (0.77%) and six neurologically normal control individuals (0.72%). The PD patients carrying this substitution were ND00428
Both ND00428 and ND00154 were diagnosed with YOPD with ages at onset of 38 and 30, respectively. ND01247, ND09816 and ND00148 were all diagnosed with late-onset PD with ages at onset of 56, 65 and 77, respectively.
The control samples carrying p.G399S were ND01699, ND05065, ND10345, ND03376, ND10860 and ND08025. These samples were derived from panels NDPT002, NDPT006, NDPT019, NDPT020, NDPT0 21 and NDPT023 with ages at sampling of 85, 70, 25, 42, 46 and 62 years, respectively. Fisher's exact association test showed no association of p.G399S and PD (Table ).
Minor allele frequencies (MAF), Fisher's exact test P-values, odds ratios (OR) and 95% confidence intervals (CI 95%) for variants p.G399S and p.A141S after analysis with Plink v0.99s
Fisher's exact association test was performed considering either YOPD or late-onset PD samples, along with their corresponding age-matched controls. Using the threshold of appearance of PD at or before 40 years, 106 samples were considered as YOPD and 538 as late-onset PD. Using this same criterion for the age at sampling in the control population, 141 and 687 samples were used as age-matched controls for YOPD and late-onset PD, respectively. No association was seen after these analyses (Table ).
Table also shows the frequency of genotypes of the variant c.421G>T in exon 1 of OMI/HTRA2
(leading to p.A141S). The T allele of this variant has previously been associated with PD (21
); however, we failed to find such an association in our data set performing Fisher's exact association test considering all samples and only YOPD and late-onset PD cases independently, along with their corresponding age, neurologically normal controls (Table ). Only ND4314
(two neurologically normal control individuals of 49 and 55 years, respectively) were homozygous for this change.
We also failed to find the synonymous p.F149F variant, previously identified by Strauss et al., in our population.
In addition to these variants, we identified eight novel coding variants, both synonymous (p.V109V, p.L118L, p.R209R and p.L367L) and non-synonymous (p.W12C, p.P128L, p.F172V and p.A227S), in both cases and control samples. None of these seem to be causative of disease in our population (Table ).
Minor allele frequencies, χ2 values, P-values, OR, CI 95% and Fisher's exact test P-values for all new variants found in our data set, as well as three SNPs within OMI/HTRA2
Eight SNPs have been described within the OMI/HTRA2 coding region, two being exonic and six residing within introns. Of these, only rs2231249, rs2231248, rs11538692, rs2241027 and rs2241028 were within our sequencing boundaries and, thus, were genotyped. Variants rs2231248 (exon 1), rs2241027 (intron 4) and rs2241028 (intron 5) had at least one sample with a variant allele; however, none of these SNPs showed association with PD using Fisher's exact association test (Table ). In addition, none of the variants tested showed association with disease when comparing young-onset cases with controls with age at collection >40 years (data not shown).