A Novel Antisense Alu Insertion/Deletion Polymorphism of ALDH1A1 Modulates Risk of Parkinson's Disease

Background: Studies in animal models have suggested that aldehyde dehydrogenase 1 (encoded by ALDH1A1) protects against PD by reducing toxic metabolite of dopamine. Herein we aimed to investigate whether ALDH1A1 is genetically associated with PD susceptibility in humans. Methods: A Han Chinese population comprised of 506 sporadic PD patients and 533 controls was recruited to analyze six tag-single nucleotide polymorphisms (SNPs) of ALDH1A1, followed by haplotype analyses and further functional analyses of an associated insertion/deletion polymorphism. Findings: The tag-SNP rs7043217 was significantly associated with PD susceptibility with the T serving as a risk allele (P = 0.006, OR = 1.278, 95% CI =1.074-1.520). Multiple haplotypes led to abnormalities of PD risk, topped by a 4-SNP GGTA module in order of rs4646547, rs1888202, rs7043217 and rs647880 (P = 9.610 × 10-8, OR = 6.420, 95% CI = 2.944-13.998). An insertion/deletion polymorphism of a novel antisense Alu element, herein named Yb8c4, was identified in intron 4 of ALDH1A1, which was in complete linkage disequilibrium with rs7043217. The antisense Yb8c4 insertion displayed a suppressive activity on gene transcription. Interpretation: ALDH1A1 variation, as featured by the antisense Yb8c4 insertion/deletion polymorphism, modulates PD risk in human populations. Our results provide novel genetic insights into the role of ALDH1 in PD pathogenesis. Funding Statement: The study was supported in part by funding from National Natural Science Foundation of China (31701080, 81571087, 81771380 and 81771510), Zhejiang Provincial Natural Science Foundation (LD19H090001 and LZ19H090002), Science and Technology Department of Zhejiang Province (2018C37111), and Wenzhou Municipal Science and Technology Bureau (C20170003). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the ethics committee of the Second Affiliated Hospital and Yuying Children’s hospital, Wenzhou Medical University.