Growth Differentiation Factor 15 Is Associated With Alzheimer’s Disease Risk
Pengfei Wu, Xinghao Zhang, Ping Zhou, Rui Yin, Xiaoting Zhou, Wan Zhang
Abstract
Background Previous observational studies have suggested that associations exist between growth differentiation factor 15 (GDF-15) and neurodegenerative diseases. We aimed to investigate the causal relationships between GDF-15 and Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Methods Using summary-level datasets from genome-wide association studies of European ancestry, we performed a two-sample Mendelian randomization (MR) study. Genetic variants significantly associated ( p < 5 × 10 –8 ) with GDF-15 were selected as instrumental variables ( n = 5). An inverse-variance weighted method was implemented as the primary MR approach, while weighted median, MR–Egger, leave-one-out analysis, and Cochran’s Q -test were conducted as sensitivity analyses. All analyses were performed using R 3.6.1 with relevant packages. Results MR provided evidence for the association of elevated GDF-15 levels with a higher risk of AD (odds ratio = 1.14; 95% confidence interval, 1.04–1.24; p = 0.004). In the reverse direction, Mendelian randomization suggested no causal effect of genetically proxied risk of AD on circulating GDF-15 ( p = 0.450). The causal effects of GDF-15 on PD ( p = 0.597) or ALS ( p = 0.120) were not identified, and the MR results likewise did not support the association of genetic liability to PD or ALS with genetically predicted levels of GDF-15. No evident heterogeneity or horizontal pleiotropy was revealed by multiple sensitivity analyses. Conclusion We highlighted the role of GDF-15 in AD as altogether a promising diagnostic marker and a therapeutic target.