C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease.
Bottom Line: We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk.However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls.Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP.
Affiliation: University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, 1501 NW 10th Ave, Miami, FL, 33136, USA.Show MeSH
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Mentions: The positive controls (ALS patients) had a maximum number of repeats greater than 50. The averagemaximum number of RCs in the initial clinical dataset was 6.9 in the controls and 8.2 in the cases(ranging ≤4 to ≥30) (Fig. 1). There was nosignificant contribution of repeats >30 in the PD cases. However, the PD cases had moreintermediate size repeats (>20 repeats to 30+) versus controls. As the majority ofcontrols in the literature are reported to have less than 20 repeats, we used this value as a firsta priori threshold for normal versus intermediate RCs (DeJesus-Hernandez et al.,2011; Renton et al., 2011; Millecamps et al., 2012; Sabatelli et al.,2012). We found eight PD patients, one ETP patient and onecontrol with intermediate RCs (Table 1) in our initialdataset. The one-tailed Fisher's exact test in the initial dataset showed significantassociation of the intermediate RCs with an increased risk for PD (p =0.008; two-tailed p = 0.010). The odds ratio for the intermediate RCs inthis original dataset is 9.6 [95% CI: 1.32 – 421] (two-tailed). Theconfidence interval is very wide, likely due to the rarity of the intermediate repeat. Even whenusing the second, more stringent a priori threshold of 23 RCs—the commonmaximum number of repeats reported in controls—marginal significance was obtained (ratiopatients:controls 4:0; one/two-tailed p = 0.05). The intermediate RC resultsin the clinical NINDS replication dataset are shown in Figure 2 and Table 2. Patient ND09224 was reported beforeby Majounie et al. (2012a); differences in interpretation ofthe peak pattern might account for the variance in reported repeat copies. Again, the number of PDcases with intermediate repeats was twice that of controls, although the overall number ofindividuals with intermediate repeats was not large enough to reach significance (>20 copies;ratio patients:controls 5:2, one-tailed p = 0.09, two-tailedp = 0.12; >23 copies; ratio patients:controls 3:0, one/two-tailedp = 0.06). However, importantly, the pooled analysis of both clinicaldatasets (patients N = 889/controls N = 1144) (Fig.3) had more power and obtained a lowerp-value than seen in either dataset: >20RCs; patients:controls 14:3 (risk OR6.1 [95% CI: 1.68–33.1] (two-tailed); one-tailed p= 0.001, two-tailed p = 0.002), >23RCs; patients 7: controls 0(one/two-tailed p = 0.003), indicating that the replication datasetstrengthens the signal from the original dataset.
Affiliation: University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, 1501 NW 10th Ave, Miami, FL, 33136, USA.