Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.
Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.
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DOI：
10.1038/s41591-020-1133-8
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发表时间：
2021-01
期刊：
影响因子：
82.9
通讯作者：
Rader DJ
中科院分区：
文献类型：
--
作者：
Park J;Lucas AM;Zhang X;Chaudhary K;Cho JH;Nadkarni G;Dobbyn A;Chittoor G;Josyula NS;Katz N;Breeyear JH;Ahmadmehrabi S;Drivas TG;Chavali VRM;Fasolino M;Sawada H;Daugherty A;Li Y;Zhang C;Bradford Y;Weaver J;Verma A;Judy RL;Kember RL;Overton JD;Reid JG;Ferreira MAR;Li AH;Baras A;LeMaire SA;Shen YH;Naji A;Kaestner KH;Vahedi G;Edwards TL;Chen J;Damrauer SM;Justice AE;Do R;Ritchie MD;Rader DJ
对于大多数基因来说，罕见的功能丧失变异的临床影响尚未确定。将DNA测序数据与电子健康记录(EHR)相结合，可以增强我们对罕见基因变异对人类疾病的贡献的理解。通过利用与宾夕法尼亚医学生物库(PMBB)中的EHR数据相关联的10,900个完整的外显子组序列，我们解决了在外显子组范围内使用一组不同的EHR表型评估的每个单个基因的罕见预测功能丧失(PLOF)变异对人类疾病的累积影响的关联。在发现了97个与外显子组之间有显著表型关联的基因(p<；10−6)后，我们在PMBB以及其他三个医学生物库和基于种群的UK生物库(UKB)中复制了其中的26个。在这26个基因中，5个与先前报道的阳性对照相关，21个与以前未报道的表型相关，其中与青光眼、主动脉扩张症、糖尿病、肌肉营养不良和听力损失有关的基因。这些发现表明，在医学生物库中，将罕见的pLOF变异体聚集到“基因负担”中，对于使用EHR表型识别新的基因-疾病关联具有价值。我们认为，将这一方法应用于更多的个体，将提供所需的统计能力，以揭示罕见的遗传变异和疾病表型之间尚未探索的关系。
The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHR) could enhance our understanding of the contribution of rare genetic variation to human disease. By leveraging 10,900 whole exome sequences linked to EHR data in the Penn Medicine Biobank (PMBB), we addressed the association of the cumulative effects of rare predicted loss-of-function (pLOF) variants per individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (p < 10−6), we replicated 26 of these in PMBB, as well as in three other medical biobanks and the population-based UK Biobank (UKB). Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy, and hearing loss. These findings show the value of aggregating rare pLOF variants into “gene burdens” for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.
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影响因子：
9.3
作者：
Baron M;Veres A;Wolock SL;Faust AL;Gaujoux R;Vetere A;Ryu JH;Wagner BK;Shen-Orr SS;Klein AM;Melton DA;Yanai I
通讯作者：
Yanai I
DOI：
10.1002/ajmg.1320520208
发表时间：
1994-08-15
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
ELBEDOUR, K;ZUCKER, N;CARMI, R
通讯作者：
CARMI, R
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：
46.9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Bowl MR;Simon MM;Ingham NJ;Greenaway S;Santos L;Cater H;Taylor S;Mason J;Kurbatova N;Pearson S;Bower LR;Clary DA;Meziane H;Reilly P;Minowa O;Kelsey L;International Mouse Phenotyping Consortium;Tocchini-Valentini GP;Gao X;Bradley A;Skarnes WC;Moore M;Beaudet AL;Justice MJ;Seavitt J;Dickinson ME;Wurst W;de Angelis MH;Herault Y;Wakana S;Nutter LMJ;Flenniken AM;McKerlie C;Murray SA;Svenson KL;Braun RE;West DB;Lloyd KCK;Adams DJ;White J;Karp N;Flicek P;Smedley D;Meehan TF;Parkinson HE;Teboul LM;Wells S;Steel KP;Mallon AM;Brown SDM
通讯作者：
Brown SDM