Medical College of Wisconsin
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Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation. Nat Commun 2025 Nov 22;16(1):10615

Date

11/23/2025

Pubmed ID

41274869

Pubmed Central ID

PMC12660940

DOI

10.1038/s41467-025-64336-8

Scopus ID

2-s2.0-105023301133 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In Framingham Heart Study (FHS, n = 2622) discovery, we identify over 1.1 million cis-irQTLs (minor allele frequency [MAF] ≥ 0.01, ±1 Mb of 10,883 isoform transcripts, P < 5 × 10-8) across 4,971 genes. Among 11,425 sentinel cis-irQTLs, 72% replicate (P < 1 × 10-4) in the Women's Health Initiative (WHI; n = 2005). Notably, 20% of cis-irQTLs have no significant association with overall gene expression, indicating isoform-specific regulation. These variants are enriched at splice donor/acceptor sites and genome-wide association study loci (P < 1 × 10-10). We also identify 1870 sentinel trans-irQTLs (MAF ≥ 0.01, P < 1.5 × 10-13) for 1,084 isoforms across 590 genes, and 2327 rare cis-irQTLs (0.003 < MAF < 0.01) for 2467 isoforms of 1428 genes in FHS, with external replication rates of 61% and 41% in WHI, respectively. We highlight rs12898397 in ULK3, which alters splice site usage and reduces expression of a full-length isoform. Mendelian randomization supports a causal role between this isoform shift and reduced diastolic blood pressure. These findings highlight the power of irQTL mapping to uncover transcript-specific regulatory mechanisms underlying complex traits.

Author List

Liu C, Joehanes R, Ma J, Xie J, Yang J, Wang M, Huan T, Hwang SJ, Wen J, Sun Q, Demirkale CY, Heard-Costa NL, Orchard P, Carson AP, Haessler JW, Raffield LM, Reiner AP, Franceschini N, Auer PL, Kooperberg C, Li Y, O'Connor G, Murabito JM, Munson P, Levy D

Author

Paul L. Auer PhD Professor in the Data Science Institute department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Female
Gene Expression Profiling
Gene Frequency
Genome, Human
Genome-Wide Association Study
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Protein Isoforms
Quantitative Trait Loci
Transcriptome
Whole Genome Sequencing