目的:我们旨在阐明肥胖相关性状的遗传重叠,血清尿酸,还有痛风.
方法:我们进行了全面的全基因组交叉性状分析,以确定遗传相关性,多效性位点和肥胖(暴露)之间的因果关系,痛风(主要结果)和血清尿酸(次要结果)。摘要统计数据是从迄今为止最大的全基因组关联研究中收集的体重指数(BMI;N=806834),腰臀比(WHR;N=697734),根据BMI调整的WHR(WHRadjBMI;N=694649),血清尿酸(N=288649),和痛风(Ncase=13179和Ncontrol=750634)。
结果:观察到BMI的总体遗传正相关(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)伴痛风。将整个基因组划分为1,703个不依赖LD的区域,在4q22时发现BMI和痛风的显著局部信号.在交叉表型关联研究中确定的多个多效性基因座进一步加强了全球和局部共享的遗传基础。通过全转录组关联研究观察到多个共有的基因-组织对,以及孟德尔随机化证实的因果关系(BMI-痛风:OR=1.66,95CI=1.45-1.88;WHR-痛风:OR=1.57,95CI=1.37-1.81).用潜在的病理测量血清尿酸代替痛风的二元疾病状态,类似的相关性模式,多功能性,并观察到因果关系,其幅度和意义更加明显。
结论:我们全面的全基因组交叉性状分析证明了共同的遗传基础,多效性基因座,以及肥胖之间的因果关系,血清尿酸,和痛风,突出了这些复杂特征背后的内在联系。
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.