Using human genetics to understand the epidemiological association between obesity, serum urate, and gout

Li Zhang; Wenqiang Zhang; Chenghan Xiao; Xueyao Wu; Huijie Cui; Peijing Yan; Chao Yang; Mingshuang Tang; Yutong Wang; Lin Chen; Yunjie Liu; Yanqiu Zou; Lars Alfredsson; Lars Klareskog; Yanfang Yang; Yuqin Yao; Jiayuan Li; Zhenmi Liu; Chunxia Yang; Xia Jiang; Ben Zhang

doi:10.1093/rheumatology/kead054

Using human genetics to understand the epidemiological association between obesity, serum urate, and gout

Rheumatology (Oxford). 2023 Oct 3;62(10):3280-3290. doi: 10.1093/rheumatology/kead054.

Authors

Li Zhang^{1

2}, Wenqiang Zhang^{1

2}, Chenghan Xiao³, Xueyao Wu^{1

2}, Huijie Cui^{1

2}, Peijing Yan^{1

2}, Chao Yang^{1

2}, Mingshuang Tang^{1

2}, Yutong Wang^{1

2}, Lin Chen^{1

2}, Yunjie Liu^{1

2}, Yanqiu Zou^{1

2}, Lars Alfredsson⁴, Lars Klareskog⁵, Yanfang Yang^{1

2}, Yuqin Yao⁶, Jiayuan Li^{1

2}, Zhenmi Liu³, Chunxia Yang^{1

2}, Xia Jiang^{1

2

4

7}, Ben Zhang^{1

2

6}

Affiliations

¹ Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
² Department of Epidemiology and Biostatistics, West China-PUMC C. C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
³ Department of Maternal, Child and Adolescent Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Division of Rheumatology, Department of Medicine and Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital (Solna), Stockholm, Sweden.
⁶ Department of Occupational and Environmental Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
⁷ Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.

PMID: 36734534
DOI: 10.1093/rheumatology/kead054

Abstract

Objectives: We aimed to clarify the genetic overlaps underlying obesity-related traits, serum urate, and gout.

Methods: We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci, and causal relationships between obesity (the exposure variable), gout (the primary outcome) and serum urate (the secondary outcome). Summary statistics were collected from the hitherto largest genome-wide association studies conducted for BMI (N = 806 834), waist-to-hip ratio (WHR; N = 697 734), WHR adjusted for BMI (WHRadjBMI; N = 694 649), serum urate (N = 288 649), and gout (Ncases = 13 179 and Ncontrols = 750 634).

Results: Positive overall genetic correlations were observed for BMI (rg = 0.27, P = 6.62 × 10-7), WHR (rg = 0.22, P = 6.26 × 10-7) and WHRadjBMI (rg = 0.07, P = 6.08 × 10-3) with gout. Partitioning the whole genome into 1703 LD (linkage disequilibrium)-independent regions, a significant local signal at 4q22 was identified for BMI and gout. The global and local shared genetic basis was further strengthened by the multiple pleiotropic loci identified in the cross-phenotype association study, multiple shared gene-tissue pairs observed by Transcriptome-wide association studies, as well as causal relationships demonstrated by Mendelian randomization [BMI-gout: OR (odds ratio) = 1.66, 95% CI = 1.45, 1.88; WHR-gout: OR = 1.57, 95% CI = 1.37, 1.81]. Replacing the binary disease status of gout with its latent pathological measure, serum urate, a similar pattern of correlation, pleiotropy and causality was observed with even more pronounced magnitude and significance.

Conclusion: Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis and pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.

Keywords: causal inference; genetic correlation; gout; obesity; pleiotropic loci.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Genome-Wide Association Study
Gout* / epidemiology
Gout* / genetics
Human Genetics
Humans
Obesity / epidemiology
Obesity / genetics
Polymorphism, Single Nucleotide
Uric Acid*

Substances

Uric Acid