Integrative modeling of transmitted and de novo variants identifies novel risk genes for congenital heart disease  

作　　者：Mo Li Xue Zeng Chentian Jin Sheng Chih Jin Weilai Dong Martina Brueckner Richard Lifton Qiongshi Lu Hongyu Zhao 

机构地区：[1]Department of Biostatistics,Yale School of Public Health,New Haven,CT 06510,USA [2]Department of Genetics,Yale University,New Haven,CT 06510,USA [3]Department of Molecular,Cellular&Developmental Biology,Yale University,CT 06510,USA [4]Department of Genetics,Washington University School of Medicine,St Louis,MO 63110,USA [5]Department of Pediatrics,Yale University,New Haven,CT 06510,USA [6]Laboratory of Human Genetics and Genomics,Rockefeller University,New York,NY 10065,USA [7]Department of Biostatistics and Medical Informatics,University of Wisconsin-Madison,Madison,Wl 53792,USA [8]Program of Computational Biology and Bioinformatics,Yale University,New Haven,CT 06510,USA

出　　处：《Quantitative Biology》2021年第2期216-227,共12页定量生物学（英文版）

基　　金：the National Institutes of Health(NIH)grants R01 GM134005,and the National Science Foundation(NSF)grants DMS 1902903.Dr.Sheng Chih Jin's effort was supported by the Pathway to Independence Award(K99/R00)program,grants K99HL143036-01A1 and R00HL143036-02.

摘　　要：Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for de novo mutations(DNMs)in congenital heart disease(CHD)probands.However,risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.Methods:In this manuscript,we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted variants.Through integrative modeling of multiple types of genetic variants,gene-level annotations,and reference data from large population cohorts,our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs only.Results:Applied to WES data of 2,645 CHD proband-parent trios,our method identified 15 significant genes,half of which are novel,leading to new insights into the genetic bases of CHD.Conclusion:These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.

关 键 词：rare variants gene-level association test congenital heart disease de novo mutation 

分 类 号：R541.1[医药卫生—心血管疾病]