Reply to: "Lack of Association between TWNK Rare Variants and Parkinson's Disease in a Chinese Cohort".

Abstract

We thank Dr. Chunyu Li and colleagues for their interest in our work1 and for further exploring the link between rare variants in TWNK and Parkinson's disease (PD). To this aim, they performed a burden analysis using data obtained from two cohorts of patients with PD and control subjects of Chinese ancestry who underwent whole-exome sequencing. They conclude against an association between rare variants in TWNK and PD.2 Recently, Drs. Senkevich and Gan-Or3 performed similar analyses in European cohorts, leading to the same conclusions. As mentioned in our previous correspondence,4 although we acknowledge the importance of replication studies, we raise some perplexities regarding the possible contribution of burden analyses for rare variants in TWNK and PD. Monoallelic TWNK variants are an established cause of several mitochondrial disorders, such as autosomal dominant progressive external ophthalmoplegia. To this regard, the screening of soft mitochondrial signs should be considered in selection criteria of both cases and controls in genetic association studies, keeping in mind that such syndromes could remain underdiagnosed until the advanced age. Moreover, none of the TWNK variants reported in our work in patients with PD was identified, strengthening their possible role of private variants. In conclusion, we agree that caution is needed when assessing the possible contribution of TWNK to the etiology of PD, which requires additional genetic and functional studies. However, we point out that association studies even when complemented by rare variant burden analyses may not be adequate to detect the pathogenic impact of rare variants with incomplete penetrance. Functional studies based on patient-derived cell models could help in the future to elucidate the effect of specific TWNK variants in the pathogenesis of PD. V.C. acknowledges the support of the Italian region Emilia-Romagna funding (ER-MITO project—Programma di ricerca Regione-Università 2010-2012, PRUa1RI-2012-008). A.D.F and V.C. acknowledge the Italian Ministry of Health (Ricerca Corrente funding). We are grateful to the patients and families for taking part in this study. (1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique. (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. M.P.: 1A, 1C, 3A. E.M.: 1A, 1C, 3B. L.C.: 1A, 1C, 3B. R.M.: 1A, 1C, 3B. V.C.: 1A, 3B. E.M.V.: 1A, 3B. A.D.F.: 1A, 1C, 3A, 3B. A.D.F. reports advisory board fees from Sanofi and speaking honoraria from Sanofi and Zambon. V.C. reports consultant and advisory board fees from GenSight Biologics, Pretzel Therapeutics, Stealth Biotherapeutics, and Chiesi Farmaceutici and speaker honoraria from Chiesi Farmaceutici, First Class, and Medscape. None of the other authors reports any conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.