Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease

Matteo D'Antonio; Jennifer P Nguyen; Timothy D Arthur; iPSCORE Consortium; Hiroko Matsui; Agnieszka D'Antonio-Chronowska; Kelly A Frazer

doi:10.1038/s41467-023-36638-2

Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease

Nat Commun. 2023 Feb 28;14(1):1132. doi: 10.1038/s41467-023-36638-2.

Authors

Matteo D'Antonio^#^{1

2

3}, Jennifer P Nguyen^#^{4

5}, Timothy D Arthur^{4

6}; iPSCORE Consortium; Hiroko Matsui⁷, Agnieszka D'Antonio-Chronowska⁸, Kelly A Frazer^{9

10}

Collaborators

Affiliations

¹ Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA. madantonio@ucsd.edu.
² Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA. madantonio@ucsd.edu.
³ Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA. madantonio@ucsd.edu.
⁴ Division of Biomedical Informatics, University of California, San Diego, La Jolla, CA, 92093, USA.
⁵ Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA.
⁶ Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA, 92093, USA.
⁷ Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA.
⁸ Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.
⁹ Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA. kafrazer@health.ucsd.edu.
¹⁰ Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, La Jolla, CA, 92093, USA. kafrazer@health.ucsd.edu.

^# Contributed equally.

Abstract

The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leverage spatiotemporal information on 966 RNA-seq cardiac samples and perform an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identify 2,578 eQTLs associated with a specific developmental stage-, tissue- and/or cell type. Colocalization between eQTL and GWAS signals of five cardiac traits identified variants with high posterior probabilities for being causal in 210 GWAS loci. Pulse pressure GWAS loci are enriched for colocalization with fetal- and smooth muscle- eQTLs; pulse rate with adult- and cardiac muscle- eQTLs; and atrial fibrillation with cardiac muscle- eQTLs. Fine mapping identifies 79 credible sets with five or fewer SNPs, of which 15 were associated with spatiotemporal eQTLs. Our study shows that many cardiac GWAS variants impact traits and disease in a developmental stage-, tissue- and/or cell type-specific fashion.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Atrial Fibrillation* / genetics
Blood Pressure
Fetus
Heart*
Humans
Myocardium

Abstract

Publication types

MeSH terms

Grants and funding