Parkinson’s Disease rs117896735 Variant Regulates INPP5F Expression in Brain Tissues and Increases Risk of Alzheimer’s Disease

Article type: Research Article

Authors: Xue, Feng^{a; 1} | Gao, Luyan^{b; 1} | Chen, TingTing^c | Chen, Hongyuan^d | Zhang, Haihua^e | Wang, Tao^f | Han, Zhifa^g | Gao, Shan^e | Wang, Longcai^h | Hu, Yangⁱ | Tang, Jiangwei^b | Huang, Lei^b | Liu, Guiyou^{e; f; j; *} | Zhang, Yan^{k; *}

Affiliations: [a] Department of Neurosurgery, Tianjin Hospital of ITCWM Nan Kai Hospital, Tianjin, China | [b] Department of Neurology, Tianjin Fourth Central Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Central Clinical College of Tianjin Medical University, Tianjin, China | [c] Department of Oncology, Tianjin Hospital of ITCWM Nan Kai Hospital, Tianjin, China | [d] Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China | [e] Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China | [f] Chinese Institute for Brain Research, Beijing, China | [g] School of Medicine, School of Pharmaceutical Sciences, THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China | [h] Department of Anesthesiology, The Affiliated Hospital of Weifang Medical University, Weifang, China | [i] School of Life Science and Technology, Harbin Institute of Technology, Harbin, China | [j] Beijing Key Laboratory of Hypoxia Translational Medicine, National Engineering Laboratory of Internet Medical Diagnosis and Treatment Technology, Xuanwu Hospital, Capital Medical University, Beijing, China | [k] Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang, China

Correspondence: [*] Correspondence to: Guiyou Liu, Beijing Institute for Brain Disorders, Capital Medical University, Room 725, Morphology Building, No.10, Xitoutiao, You’an Men Wai, Fengtai District, Beijing 100069, China. E-mail: [email protected].; Yan Zhang, Department of Pathology, The Affiliated Hospital of Weifang Medical University, Weifang 261053, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Both INPP5D and INPP5F are members of INPP5 family. INPP5F rs117896735 variant was associated with Parkinson’s disease (PD) risk, and INPP5D was an Alzheimer’s disease (AD) risk gene. However, it remains unclear about the roles of INPP5F rs117896735 variant in AD. Objective:We aim to investigate the roles of rs117896735 in AD. Methods:First, we conducted a candidate variant study to evaluate the association of rs117896735 variant with AD risk using the large-scale AD GWAS dataset. Second, we conducted a gene expression analysis of INPP5F to investigate the expression difference of INPP5F in different human tissues using two large-scale gene expression datasets. Third, we conducted an expression quantitative trait loci analysis to evaluate whether rs117896735 variant regulate the expression of INPP5F. Fourth, we explore the potentially differential expression of INPP5F in AD and control using multiple AD-control gene expression datasets in human brain tissues and whole blood. Results:We found that 1) rs117896735 A allele was associated with the increased risk of AD with OR = 1.15, 95% CI 1.005–1.315, p = 0.042; 2) rs117896735 A allele could increase INPP5F expression in multiple human tissues; 3) INPP5F showed different expression in different human tissues, especially in brain tissues; 4) INPP5F showed significant expression dysregulation in AD compared with controls in human brain tissues. Conclusion:Conclusion: We demonstrate that PD rs117896735 variant could regulate INPP5F expression in brain tissues and increase the risk of AD. These finding may provide important information about the role of rs117896735 in AD.

Keywords: Alzheimer’s disease, eQTLs, genome-wide association study, INPP5F, Parkinson’s disease

DOI: 10.3233/JAD-220086

Journal: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 67-77, 2022