Canalization of the Polygenic Risk for Common Diseases and Traits in the UK Biobank Cohort.
Canalization of the Polygenic Risk for Common Diseases and Traits in the UK Biobank Cohort.
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英国生物库队列中常见疾病和性状的多基因风险的归一化。
DOI：
10.1093/molbev/msac053
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发表时间：
2022-04-11
影响因子：
10.7
通讯作者：
Gibson, Greg
中科院分区：
文献类型：
--
作者：
Nagpal, Sini;Tandon, Raghav;Gibson, Greg
关键词：
由于生物体在环境和遗传变异的不断扰动下发展和繁荣，物种可能进化出具有弹性的遗传结构。在英国生物库队列研究中，我们通过比较表型流行率作为多基因评分(PGS)在不同环境中的作用来寻找这一过程的证据，即通道化。对比了408,925人中151次接触的7种疾病和3种分类表型，发现在五分之一的比较中，患病率-风险曲线之间的偏差与PGS百分位数单调增加，这表明PGS-by-Environment(PGS×E)存在广泛的相互作用。在调整了等位基因效应大小对扰动环境中增加的患病率的依赖性后，多基因影响比预期更大或更小的情况被认为在教育程度、肥胖症和代谢状况2型糖尿病中尤其普遍。炎症性肠病分析显示相互作用较少，但证实吸烟和饮食的某些方面影响风险。值得注意的是，体重指数有更多的证据表明去钙化(在多基因风险的极端情况下遗传影响增加)，而腰臀比显示去钙化，反映了这些与体重相关的特征的结构上的不同进化压力。另有10%的比较显示，有证据表明，不同接触组之间的流行率发生了独立于PGS的相加变化。这些结果为人类预防疾病提供了第一个广泛的证据，并对个性化药物以及理解复杂特征的进化具有意义。这一发现可以通过https://canalization-gibsonlab.shinyapps.io/rshiny/.上的一款闪亮的R应用程序进行探索
Since organisms develop and thrive in the face of constant perturbations due to environmental and genetic variation, species may evolve resilient genetic architectures. We sought evidence for this process, known as canalization, through a comparison of the prevalence of phenotypes as a function of the polygenic score (PGS) across environments in the UK Biobank cohort study. Contrasting seven diseases and three categorical phenotypes with respect to 151 exposures in 408,925 people, the deviation between the prevalence–risk curves was observed to increase monotonically with the PGS percentile in one-fifth of the comparisons, suggesting extensive PGS-by-Environment (PGS×E) interaction. After adjustment for the dependency of allelic effect sizes on increased prevalence in the perturbing environment, cases where polygenic influences are greater or lesser than expected are seen to be particularly pervasive for educational attainment, obesity, and metabolic condition type-2 diabetes. Inflammatory bowel disease analysis shows fewer interactions but confirms that smoking and some aspects of diet influence risk. Notably, body mass index has more evidence for decanalization (increased genetic influence at the extremes of polygenic risk), whereas the waist-to-hip ratio shows canalization, reflecting different evolutionary pressures on the architectures of these weight-related traits. An additional 10 % of comparisons showed evidence for an additive shift of prevalence independent of PGS between exposures. These results provide the first widespread evidence for canalization protecting against disease in humans and have implications for personalized medicine as well as understanding the evolution of complex traits. The findings can be explored through an R shiny app at https://canalization-gibsonlab.shinyapps.io/rshiny/.
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影响因子：
9.8
作者：
Dudbridge F;Fletcher O
通讯作者：
Fletcher O
影响因子：
7.3
作者：
Hallgrimsson B;Green RM;Katz DC;Fish JL;Bernier FP;Roseman CC;Young NM;Cheverud JM;Marcucio RS
通讯作者：
Marcucio RS
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
30.8
作者：
Demange, Perline A.;Malanchini, Margherita;Nivard, Michel G.
通讯作者：
Nivard, Michel G.