Phenome-Wide Association Analysis Reveals Novel Links Between Genetically Determined Levels of Liver Enzymes and Disease Phenotypes

作     者：Zhenqiu Liu Chen Suo Yanfeng Jiang Renjia Zhao Tiejun Zhang Li Jin Xingdong Chen 

作者机构：State Key Laboratory of Genetic EngineeringHuman Phenome InstituteSchool of Life SciencesFudan UniversityShanghai 200438China Fudan University Taizhou Institute of Health SciencesTaizhou 225316China Key Laboratory of Public Health SafetyFudan UniversityMinistry of EducationShanghai 200032China Department of EpidemiologySchool of Public HealthFudan UniversityShanghai 200032China 

出 版 物：《Phenomics》 (表型组学（英文）)

年 卷 期：2022年第2卷第5期

页      面：295-311页

学科分类：0710[理学-生物学] 1002[医学-临床医学] 10[医学] 

基　　金：This work was supported by the National Postdoctoral Program for Innovative Talents(grant number:BX2021077) National Natural Science Foundation of China(grant numbers:91846302,82073637) the National Key Research and Development Program of China(grant numbers:2017YFC0907000,2017YFC0907500,2019YFC1315804,2019FY101103) key basic research grants from the Science and Technology Commission of Shanghai Municipality(grant number:16JC1400500) the Shanghai Municipal Science and Technology Major Project(grant number:2017SHZDZX01) Three-Year Action Plan for Strengthening Public Health System in Shanghai(grant number:GWV-10.2-YQ32) Innovation Grant from Science and Technology Commission of Shanghai Municipality,China(grant number:20ZR1405600). 

主　　题：Liver enzyme Disease phenotype GWAS Mendelian randomization 

摘      要：Serum liver enzymes(alanine aminotransferase[ALT],aspartate aminotransferase[AST],λ-glutamyl transferase[GGT]and alkaline phosphatase[ALP])are the leading biomarkers to measure liver injury,and they have been reported to be associated with several intrahepatic and extrahepatic diseases in observational studies.We conducted a phenome-wide association study(PheWAS)to identify disease phenotypes associated with genetically predicted liver enzymes based on the UK Biobank cohort.Univariable and multivariable Mendelian randomization(MR)analyses were performed to obtain the causal esti-mates of associations that detected in PheWAS.Our PheWAS identified 40 out of 1,376 pairs(16,17,three and four pairs for ALT,AST,GGT and ALP,respectively)of genotype-phenotype associations reaching statistical significance at the 5%false discovery rate threshold.A total of 34 links were further validated in Mendelian randomization analyses.Most of the disease phenotypes that associated with genetically determined ALT level were liver-related,including primary liver cancer and alcoholic liver damage.The disease outcomes associated with genetically determined AST involved a wide range of phenotypic categories including endocrine/metabolic diseases,digestive diseases,and neurological disorder.Genetically predicted GGT level was associated with the risk of other chronic non-alcoholic liver disease,abnormal results of function study of liver,and cholelithiasis.Genetically determined ALP level was associated with pulmonary heart disease,phlebitis and thrombophlebitis of lower extremities,and hypercholesterolemia.Our findings reveal novel links between liver enzymes and disease phenotypes providing insights into the full understanding of the biological roles of liver enzymes.