Department of Epidemiology and Biostatistics, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
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.
Rheumatology (Oxford). 2023 Oct 3;62(10):3280-3290. doi: 10.1093/rheumatology/kead054.
We aimed to clarify the genetic overlaps underlying obesity-related traits, serum urate, and gout.
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).
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.
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.
我们旨在阐明与肥胖相关特征、血清尿酸和痛风相关的遗传重叠。
我们进行了全面的全基因组跨性状分析，以确定肥胖（暴露变量）、痛风（主要结果）和血清尿酸（次要结果）之间的遗传相关性、多效性位点和因果关系。汇总统计数据来自迄今为止最大的 BMI（N=806834）、腰臀比（WHR；N=697734）、BMI 校正的 WHR（WHRadjBMI；N=694649）、血清尿酸（N=288649）和痛风（Ncases=13179 和 Ncontrols=750634）的全基因组关联研究。
观察到 BMI（rg=0.27，P=6.62×10-7）、WHR（rg=0.22，P=6.26×10-7）和 WHRadjBMI（rg=0.07，P=6.08×10-3）与痛风之间存在总体上正的遗传相关性。将整个基因组分成 1703 个 LD（连锁不平衡）独立区域，在 4q22 区域发现了 BMI 和痛风的显著局部信号。通过跨表型关联研究鉴定的多个多效性位点、通过全转录组关联研究观察到的多个共享基因组织对，以及孟德尔随机化（BMI-痛风：OR=1.66，95%CI=1.45，1.88；WHR-痛风：OR=1.57，95%CI=1.37，1.81）所证明的因果关系，进一步加强了全球和局部共享遗传基础。用血清尿酸替代痛风的潜在病理测量，替换二元疾病状态，观察到类似的相关性、多效性和因果关系模式，且关联的幅度和显著性更为显著。
我们的全基因组跨性状分析表明，肥胖、血清尿酸和痛风之间存在遗传基础和多效性位点，以及因果关系，突出了这些复杂特征之间的内在联系。
