Polygenic Liability to Alzheimer’s Disease Is Associated with a Wide Range of Chronic Diseases: A Cohort Study of 312,305 Participants

Article type: Research Article

Authors: Wu, Bang-Sheng^a | Zhang, Ya-Ru^a | Yang, Liu^a | Zhang, Wei^b | Deng, Yue-Ting^a | Chen, Shi-Dong^a | Feng, Jian-Feng^{b; c} | Cheng, Wei^{b; d; e; *} | Yu, Jin-Tai^{a; *}

Affiliations: [a] Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China | [b] Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China | [c] Department of Computer Science, University of Warwick, Coventry, UK | [d] Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China | [e] Fudan ISTBI—ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, Jinhua, China

Correspondence: [*] Correspondence to: Prof. Jin-Tai Yu, Huashan Hospital, Shanghai Medical College, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China. Tel.: +86 21 52888160; Fax: +86 21 62483421; E-mail: jintai_yu@fudan.edu.cn, and Prof. Wei Cheng, Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China. E-mail: wcheng@fudan.edu.cn.

Abstract: Background: Alzheimer’s disease (AD) patients rank among the highest levels of comorbidities compared to persons with other diseases. However, it is unclear whether the conditions are caused by shared pathophysiology due to the genetic pleiotropy for AD risk genes. Objective: To figure out the genetic pleiotropy for AD risk genes in a wide range of diseases. Methods:We estimated the polygenic risk score (PRS) for AD and tested the association between PRS and 16 ICD10 main chapters, 136 ICD10 level-1 chapters, and 377 diseases with cases more than 1,000 in 312,305 individuals without AD diagnosis from the UK Biobank. Results: After correction for multiple testing, AD PRS was associated with two main ICD10 chapters: Chapter IV (endocrine, nutritional and metabolic diseases) and Chapter VII (eye and adnexa disorders). When narrowing the definition of the phenotypes, positive associations were observed between AD PRS and other types of dementia (OR = 1.39, 95% CI [1.34, 1.45], p = 1.96E-59) and other degenerative diseases of the nervous system (OR = 1.18, 95% CI [1.13, 1.24], p = 7.74E-10). In contrast, we detected negative associations between AD PRS and diabetes mellitus, obesity, chronic bronchitis, other retinal disorders, pancreas diseases, and cholecystitis without cholelithiasis (ORs range from 0.94 to 0.97, FDR < 0.05). Conclusion: Our study confirms several associations reported previously and finds some novel results, which extends the knowledge of genetic pleiotropy for AD in a range of diseases. Further mechanistic studies are necessary to illustrate the molecular mechanisms behind these associations.

Keywords: Alzheimer’s disease, genetic pleiotropy, PheWAS, polygenic risk score

DOI: 10.3233/JAD-220740

Journal: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 437-447, 2023