Dissecting shared genetic architecture between obesity and multiple sclerosisResearch in context
Ruijie Zeng,
Rui Jiang,
Wentao Huang,
Jiaxuan Wang,
Lijun Zhang,
Yuying Ma,
Yanjun Wu,
Meijun Meng,
Hekui Lan,
Qizhou Lian,
Felix W. Leung,
Weihong Sha,
Hao Chen
Affiliations
Ruijie Zeng
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
Rui Jiang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China; School of Medicine, South China University of Technology, Guangzhou 510006, China
Wentao Huang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
Jiaxuan Wang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
Lijun Zhang
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; School of Medicine, South China University of Technology, Guangzhou 510006, China
Yuying Ma
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
Yanjun Wu
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
Meijun Meng
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
Hekui Lan
Department of Paediatrics, Zhujiang Hospital of Southern Medical University, Guangzhou, China
Qizhou Lian
Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Cord Blood Bank, Guangzhou Institute of Eugenics and Perinatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China
Felix W. Leung
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Sepulveda Ambulatory Care Center, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, CA, USA; Corresponding author. David Geffen School of Medicine, University of California Los Angeles, Los Angeles 90024, CA, USA.
Weihong Sha
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China; School of Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Corresponding author. Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Hao Chen
Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China; School of Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China; Corresponding author. Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Summary: Background: Observational studies have associated obesity with an increased risk of multiple sclerosis (MS). However, the role of genetic factors in their comorbidity remains largely unknown. Our study aimed to investigate the shared genetic architecture underlying obesity and MS. Methods: By leveraging data from genome-wide association studies, we investigated the genetic correlation of body mass index (BMI) and MS by linkage disequilibrium score regression and genetic covariance analyser. The casualty was identified by bidirectional Mendelian randomisation. Linkage disequilibrium score regression in specifically expressed genes and multimarker analysis of GenoMic annotation was utilised to explore single-nucleotide polymorphism (SNP) enrichment at the tissue and cell-type levels. Shared risk SNPs were derived using cross-trait meta-analyses and Heritability Estimation from Summary Statistics. We explored the potential functional genes using summary-data-based Mendelian randomization (SMR). The expression profiles of the risk gene in tissues were further examined. Findings: We found a significantly positive genetic correlation between BMI and MS, and the causal association of BMI with MS was supported (β = 0.22, P = 8.03E-05). Cross-trait analysis yielded 39 shared risk SNPs, and the risk gene GGNBP2 was consistently identified in SMR. We observed tissue-specific level SNP heritability enrichment for BMI mainly in brain tissues for MS in immune-related tissues, and cell-type-specific level SNP heritability enrichment in 12 different immune cell types in brain, spleen, lung, and whole blood. The expressions of GGNBP2 were significantly altered in the tissues of patients with obesity or MS compared to those of control subjects. Interpretation: Our study indicates the genetic correlation and shared risk genes between obesity and MS. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics. Funding: This work was funded by the National Natural Science Foundation of China (82171698, 82170561, 81300279, and 81741067), the Program for High-level Foreign Expert Introduction of China (G2022030047L), the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province (2021B1515020003), Natural Science Foundation of Guangdong Province (2022A1515012081), the Foreign Distinguished Teacher Program of Guangdong Science and Technology Department (KD0120220129), the Climbing Programme of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital (DFJH201803, KJ012019099, KJ012021143, and KY012021183), and in part by VA Clinical Merit and ASGE clinical research funds (FWL).
