Genetic regulatory variation in populations informs transcriptome analysis in rare disease.

TitleGenetic regulatory variation in populations informs transcriptome analysis in rare disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsMohammadi, P, Castel, SE, Cummings, BB, Einson, J, Sousa, C, Hoffman, P, Donkervoort, S, Jiang, Z, Mohassel, P, A Foley, R, Wheeler, HE, Im, HKyung, Bonnemann, CG, MacArthur, DG, Lappalainen, T
JournalScience
Volume366
Issue6463
Pagination351-356
Date Published2019 10 18
ISSN1095-9203
Abstract

Transcriptome data can facilitate the interpretation of the effects of rare genetic variants. Here, we introduce ANEVA (analysis of expression variation) to quantify genetic variation in gene dosage from allelic expression (AE) data in a population. Application of ANEVA to the Genotype-Tissues Expression (GTEx) data showed that this variance estimate is robust and correlated with selective constraint in a gene. Using these variance estimates in a dosage outlier test (ANEVA-DOT) applied to AE data from 70 Mendelian muscular disease patients showed accuracy in detecting genes with pathogenic variants in previously resolved cases and led to one confirmed and several potential new diagnoses. Using our reference estimates from GTEx data, ANEVA-DOT can be incorporated in rare disease diagnostic pipelines to use RNA-sequencing data more effectively.

DOI10.1126/science.aay0256
Alternate JournalScience
PubMed ID31601707
PubMed Central IDPMC6814274
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
UL1 TR001114 / TR / NCATS NIH HHS / United States
R01 MH107666 / MH / NIMH NIH HHS / United States
R01 MH106842 / MH / NIMH NIH HHS / United States
UM1 HG008901 / HG / NHGRI NIH HHS / United States
R15 HG009569 / HG / NHGRI NIH HHS / United States
K99 HG009916 / HG / NHGRI NIH HHS / United States
UL1 TR002550 / TR / NCATS NIH HHS / United States
R01 GM122924 / GM / NIGMS NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States