150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility.
150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility.
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DOI：
10.1016/j.xgen.2023.100326
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发表时间：
2023-07-12
期刊：
影响因子：
--
通讯作者：
Wray, Naomi R.
中科院分区：
文献类型：
--
作者：
Wu, Yeda;Goleva, Slavina B.;Breidenbach, Lindsay B.;Kim, Minsoo;Macgregor, Stuart;Gandal, Michael J.;Davis, Lea K.;Wray, Naomi R.
我们对724,372名个体进行了肠道憩室病(DivD)的全基因组关联研究(Gwas)分析，并确定了150个独立的全基因组显著DNA变异。Gwas结果与人类肠道单细胞RNA测序数据的整合表明，肠道肌细胞、间皮细胞和基质细胞，以及肠系膜神经元和神经胶质细胞参与了DivD的发育。根据多条证据对95个基因进行了优先排序，其中包括SLC9A3，这是一种用于治疗肠易激综合征便秘亚型的Tenapanor的药物靶基因。DivD多基因评分可以进行有效的风险预测(曲线下面积，0.688；95%可信区间，0.645-0.732)，与其余人群相比，前20%的多基因评分与∼相关，Divd风险增加3.6%。我们的统计和生物信息学分析表明，DivD的机制是通过结肠结构、肠道运动、胃肠粘液和离子稳态来实现的。我们的分析通过遗传学加强了胃肠道疾病和肠道神经系统之间的联系。在∼724,000名个体中确定了150个风险变异。派生的多基因评分显著预测了DivD的风险，其AUC值为0.69潜在的DivD机制：结肠结构、肠道动力、胃肠道粘液和离子稳态优先基因DivD编码IBS的药物靶点，IBS是一种常见的并存疾病Wu等人。通过整合来自多个生物库的724,000多名个体的基因和医院记录数据，研究肠道憩室病(DivD)的遗传结构。作者确定了150个风险变量，后续分析发现几种细胞类型，包括肠道肌细胞、间皮细胞和基质细胞，以及肠系膜神经元和神经胶质细胞，与疾病的发展有关。优先考虑的基因包括为肠易激综合征便秘亚型编码治疗靶点的基因，肠易激综合征是一种常见的DivD并存疾病。对DivD与其他复杂性状的遗传相关性的系统估计突出了DivD与DivD的一些潜在的因果和多效性关系。
We conducted a genome-wide association study (GWAS) analysis of diverticular disease (DivD) of intestine within 724,372 individuals and identified 150 independent genome-wide significant DNA variants. Integration of the GWAS results with human gut single-cell RNA sequencing data implicated gut myocyte, mesothelial and stromal cells, and enteric neurons and glia in DivD development. Ninety-five genes were prioritized based on multiple lines of evidence, including SLC9A3, a drug target gene of tenapanor used for the treatment of the constipation subtype of irritable bowel syndrome. A DivD polygenic score (PGS) enables effective risk prediction (area under the curve [AUC], 0.688; 95% confidence interval [CI], 0.645–0.732) and the top 20% PGS was associated with ∼3.6-fold increased DivD risk relative to the remaining population. Our statistical and bioinformatic analyses suggest that the mechanism of DivD is through colon structure, gut motility, gastrointestinal mucus, and ionic homeostasis. Our analyses reinforce the link between gastrointestinal disorders and the enteric nervous system through genetics. Diverticular disease (DivD) GWAS identifies 150 risk variants in ∼724,000 individuals The derived polygenic score significantly predicts DivD risk with AUC of 0.69 Potential DivD mechanisms: colon structure, gut motility, gastrointestinal mucus, and ionic homeostasis Prioritized gene for DivD encodes drug target for IBS, a commonly comorbid disorder Wu et al. investigate the genetic architecture of diverticular disease (DivD) of intestine by integrating the genotype and hospital record data from over 724,000 individuals across multiple biobanks. The authors identify 150 risk variants, and follow-up analyses implicate several cell types, including gut myocytes, mesothelial and stromal cells, and enteric neurons and glia, in disease development. Prioritized genes include a gene encoding therapeutic target for the constipation subtype of irritable bowel syndrome, a commonly comorbid disorder with DivD. Systematic estimation of genetic correlations of DivD with other complex traits highlights some potentially causal and pleiotropic relationships with DivD.
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影响因子：
12.3
作者：
Dennis JK;Sealock JM;Straub P;Lee YH;Hucks D;Actkins K;Faucon A;Feng YA;Ge T;Goleva SB;Niarchou M;Singh K;Morley T;Smoller JW;Ruderfer DM;Mosley JD;Chen G;Davis LK
通讯作者：
Davis LK
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
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
3.7
作者：
Böttner M;Barrenschee M;Hellwig I;Harde J;Egberts JH;Becker T;Zorenkov D;Schäfer KH;Wedel T
通讯作者：
Wedel T
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.