Phenotype risk scores identify patients with unrecognized Mendelian disease patterns

被引：131

作者：

Bastarache, Lisa ^{[1
]}

Hughey, Jacob J. ^{[1
]}

Hebbring, Scott ^{[2
]}

Marlo, Joy ^{[1
]}

Zhao, Wanke ^{[3
]}

Ho, Wanting T. ^{[3
]}

Van Driest, Sara L. ^{[4
,5
]}

McGregor, Tracy L. ^{[5
]}

Mosley, Jonathan D. ^{[4
]}

Wells, Quinn S. ^{[4
,6
]}

Temple, Michael ^{[1
]}

Ramirez, Andrea H. ^{[4
]}

Carroll, Robert ^{[1
]}

Osterman, Travis ^{[1
,4
]}

Edwards, Todd ^{[4
]}

Ruderfer, Douglas ^{[4
]}

Edwards, Digna R. Velez ^{[7
]}

Hamid, Rizwan ^{[5
]}

Cogan, Joy ^{[5
]}

Glazer, Andrew ^{[4
]}

Wei, Wei-Qi ^{[1
]}

Feng, QiPing ^{[6
]}

Brilliant, Murray ^{[2
]}

Zhao, Zhizhuang J. ^{[3
]}

Cox, Nancy J. ^{[4
]}

Roden, Dan M. ^{[1
,4
,6
]}

Denny, Joshua C. ^{[1
,4
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN 37235 USA

[2] Marshfield Clin Res Inst, Ctr Human Genet, Marshfield, WI USA

[3] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA

[4] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37235 USA

[5] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Med Ctr, Dept Obstet & Gynecol, Nashville, TN 37232 USA

来源：

SCIENCE | 2018年 / 359卷 / 6381期

关键词：

PHENOME-WIDE ASSOCIATION; SEQUENCE VARIANTS; GENETIC-VARIANTS; GENOMICS; RARE; PATHOGENICITY; GUIDELINES; MUTATIONS; RECORDS;

D O I：

10.1126/science.aal4043

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genetic association studies often examine features independently, potentially missing subpopulations with multiple phenotypes that share a single cause. We describe an approach that aggregates phenotypes on the basis of patterns described by Mendelian diseases. We mapped the clinical features of 1204 Mendelian diseases into phenotypes captured from the electronic health record (EHR) and summarized this evidence as phenotype risk scores (PheRSs). In an initial validation, PheRS distinguished cases and controls of five Mendelian diseases. Applying PheRS to 21,701 genotyped individuals uncovered 18 associations between rare variants and phenotypes consistent with Mendelian diseases. In 16 patients, the rare genetic variants were associated with severe outcomes such as organ transplants. PheRS can augment rare-variant interpretation and may identify subsets of patients with distinct genetic causes for common diseases.

引用

页码：1233 / +

页数：7

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