Parkinson's disease age at onset genome‐wide association study: defining heritability, genetic loci, and α‐synuclein mechanisms

Blauwendraat, C. et al. (2019) Parkinson's disease age at onset genome‐wide association study: defining heritability, genetic loci, and α‐synuclein mechanisms. Movement Disorders, 34(6), pp. 866-875. (doi:10.1002/mds.27659) (PMID:30957308)

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Abstract

Background: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome‐wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives: To identify the genetic determinants of PD age at onset. Methods: Using genetic data of 28,568 PD cases, we performed a genome‐wide association study based on PD age at onset. Results: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome‐wide significant association signals, one at SNCA and the other a protein‐coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni‐corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α‐synuclein aggregation pathways. Remarkably, other well‐established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions: Overall, we have performed the largest age at onset of PD genome‐wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease‐linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Grosset, Dr Donald
Authors: Blauwendraat, C., Heilbron, K., Vallerga, C. L., Bandres‐Ciga, S., von Coelln, R., Pihlstrøm, L., Simón‐Sánchez, J., Schulte, C., Sharma, M., Krohn, L., Siitonen, A., Iwaki, H., Leonard, H., Noyce, A. J., Tan, M., Gibbs, J. R., Hernandez, D. G., Scholz, S. W., Jankovic, J., Shulman, L. M., Lesage, S., Corvol, J.‐C., Brice, A., van Hilten, J. J., Marinus, J., Eerola‐Rautio, J., Tienari, P., Majamaa, K., Toft, M., Grosset, D. G., Gasser, T., Heutink, P., Shulman, J. M., Wood, N., Hardy, J., Morris, H. R., Hinds, D. A., Gratten, J., Visscher, P. M., Gan‐Or, Z., Nalls, M. A., and Singleton, A. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Movement Disorders
Publisher:Wiley
ISSN:0885-3185
ISSN (Online):1531-8257
Published Online:07 April 2019

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