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Reply: Saposin D variants are not a common cause of familial Parkinson's disease among Italians; and Lack of evidence for genetic association of saposins A, B, C and D with Parkinson's disease.
Brain ( IF 10.6 ) Pub Date : 2020-08-13 , DOI: 10.1093/brain/awaa215 Yutaka Oji 1 , Taku Hatano 1 , Manabu Funayama 2 , Nobutaka Hattori 1
Brain ( IF 10.6 ) Pub Date : 2020-08-13 , DOI: 10.1093/brain/awaa215 Yutaka Oji 1 , Taku Hatano 1 , Manabu Funayama 2 , Nobutaka Hattori 1
Affiliation
We thank Facchi and colleagues, and Sosero and colleagues for their interest in our article and for their analysis of PSAP variants using a Western European cohort study of Parkinson’s disease (Facchi et al., 2020; Sosero et al., 2020). We reported three pathogenic PSAP mutations (c.1358A>C, p.Q453P; c.1431G>A, p.C451_L477del; and c.1235G>A, p.C412Y) for Japanese patients with autosomal dominant Parkinson’s disease (Oji et al., 2020). Three carriers of the p.Q453P variant in Family 1 did not have Parkinson’s disease, which implicated that PSAP variants that contributed to Parkinson’s disease risk possibly have only a modest effect. We additionally performed whole-exome sequencing, which did not reveal any previously identified Parkinson’s disease-causing mutations (Oji et al., 2020). Interestingly, the c.1431G>A variant (rs1409969130) is a rare variant that is only found in the South Asian gnomAD database. We also reported that rs885828, which is in perfect linkage disequilibrium with rs4747203, identified as significantly different in the Japanese cohort and the combined data of the Japanese and Taiwanese cohorts compared with the East Asian controls, but not in the Taiwanese single cohort. This could possibly be because of differences in the population and/or the average age at onset of Parkinson’s disease in Japanese patients, which was significantly younger than Taiwanese patients (P = 2.06 × 10−44, Welch’s t-test) (Oji et al., 2020). Furthermore, rs885828 was not identified to be significantly different from Japanese controls from a previously published genome-wide association study, as discussed in our paper (Satake et al., 2009; Oji et al., 2020). Our case-control association study included only a small sample size and a further, larger sample size study will be needed. Furthermore, we also searched the gnomAD database on 3 May 2020, and found rs885828 and rs4747203 with different frequencies between East Asians (0.6213 and 0.6223, respectively) and Europeans (0.3516 and 0.3515, respectively), as reported by Facchi et al. (2020). The two intronic variants were not found to be significantly different in the European large cohort, reported by Facchi et al. (2020) and Sosero et al. (2020), which may suggest that the frequencies of PSAP variants differ between ethnic groups in association with Parkinson’s disease. We should also be careful to conclude the pathogenesis of PSAP intronic variants around saposin D domain-coding exons because we did not analyse the pathogenic significance of rs885828 (and rs4747203) in our paper. According to Facchi and colleagues, further studies will be needed to elucidate how rs885828 (and rs4747203), as the expression quantitative trait locus, is associated with Parkinson’s disease. Interestingly, Miller et al. (2006) reported that prosaposin (PSAP) was upregulated in the substantia nigra of Parkinson’s disease patients compared with non-Parkinson’s disease control patients, which suggests that PSAP expression levels might be associated with dopaminergic neurodegeneration.
更新日期：2020-09-20
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