Transcriptomic signatures across human tissues identify functional rare genetic variation.

TitleTranscriptomic signatures across human tissues identify functional rare genetic variation.
Publication TypeJournal Article
Year of Publication2020
AuthorsFerraro, NM, Strober, BJ, Einson, J, Abell, NS, Aguet, F, Barbeira, AN, Brandt, M, Bucan, M, Castel, SE, Davis, JR, Greenwald, E, Hess, GT, Hilliard, AT, Kember, RL, Kotis, B, Park, YS, Peloso, G, Ramdas, S, Scott, AJ, Smail, C, Tsang, EK, Zekavat, SM, Ziosi, M, Ardlie, KG, Assimes, TL, Bassik, MC, Brown, CD, Correa, A, Hall, I, Im, HKyung, Li, X, Natarajan, P, Lappalainen, T, Mohammadi, P, Montgomery, SB, Battle, A
Corporate AuthorsTOPMed Lipids Working Group, GTEx Consortium
JournalScience
Volume369
Issue6509
Date Published2020 09 11
ISSN1095-9203
Abstract

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.

DOI10.1126/science.aaz5900
Alternate JournalScience
PubMed ID32913073
Grant ListU41 HG009494 / HG / NHGRI NIH HHS / United States
R01 MH090941 / MH / NIMH NIH HHS / United States
R01 MH090951 / MH / NIMH NIH HHS / United States
R01 MH090937 / MH / NIMH NIH HHS / United States
R01 MH090936 / MH / NIMH NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States
U01 HG007593 / HG / NHGRI NIH HHS / United States
R01 MH101822 / MH / NIMH NIH HHS / United States
U01 HG007598 / HG / NHGRI NIH HHS / United States
U01 MH104393 / MH / NIMH NIH HHS / United States
U41 HG002371 / HG / NHGRI NIH HHS / United States
R01 MH106842 / MH / NIMH NIH HHS / United States
R01 HL142028 / HL / NHLBI NIH HHS / United States
R01 GM122924 / GM / NIGMS NIH HHS / United States
R01 MH107666 / MH / NIMH NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States
UM1 HG008901 / HG / NHGRI NIH HHS / United States
R01 GM124486 / GM / NIGMS NIH HHS / United States
R01 HG010067 / HG / NHGRI NIH HHS / United States
R01 HG002585 / HG / NHGRI NIH HHS / United States
K99 HG009916 / HG / NHGRI NIH HHS / United States
R01 HG006855 / HG / NHGRI NIH HHS / United States
UL1 TR002550 / TR / NCATS NIH HHS / United States
R35 HG010718 / HG / NHGRI NIH HHS / United States
R01 MH109905 / MH / NIMH NIH HHS / United States
R01 HG010480 / HG / NHGRI NIH HHS / United States
R01 HG008150 / HG / NHGRI NIH HHS / United States
T32 HG000044 / HG / NHGRI NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States
UL1 TR001114 / TR / NCATS NIH HHS / United States
R01 AG066490 / AG / NIA NIH HHS / United States
R01 HL142015 / HL / NHLBI NIH HHS / United States
U01 HG009431 / HG / NHGRI NIH HHS / United States
U01 HG009080 / HG / NHGRI NIH HHS / United States
R01 MH109905 / MH / NIMH NIH HHS / United States
R01 HL142711 / HL / NHLBI NIH HHS / United States