Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation

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<sup>-8</sup>) across 4,971 genes. Among 11,425 sentinel cis-irQTLs, 72% replicate (P < 1 × 10<sup>-4</sup>) 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<sup>-10</sup>). We also identify 1870 sentinel trans-irQTLs (MAF ≥ 0.01, P < 1.5 × 10<sup>-13</sup>) 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.

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Publication Details

Journal
Nature Communications
Published
2025-11-22
DOI
https://doi.org/10.1038/s41467-025-64336-8
Citations
1
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
1.82

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article

Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation

Charles Kooperberg, Daniel L. Levy, Nora Franceschini, Tianxiao Huan et al.
1 citations
Nature Communications
Genetic Associations and Epidemiology
1.82
article

Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation

Charles Kooperberg, Daniel L. Levy, Nora Franceschini, Tianxiao Huan, Peter J. Munson, Jiantao Ma, Jia Wen, Joanne M. Murabito, Laura M. Raffield, Jiuyong Xie, Peter Orchard, Roby Joehanes, Quan Sun, Nancy L. Heard‐Costa, George T. O’Connor, Paul Livermore Auer, Jian Yang, Alex P. Reiner, April P. Carson, Chunyu Liu, Yun Li, Shih‐Jen Hwang, Jeffrey Haessler, Cumhur Yusuf Demirkale, Mengyao Wang
article en
1 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<sup>-8</sup>) across 4,971 genes. Among 11,425 sentinel cis-irQTLs, 72% replicate (P < 1 × 10<sup>-4</sup>) 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<sup>-10</sup>). We also identify 1870 sentinel trans-irQTLs (MAF ≥ 0.01, P < 1.5 × 10<sup>-13</sup>) 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.

Nature CommunicationsVol. 16(1)
Boston University (US), University of North Carolina at Chapel Hill (US), Tufts University (US), Boston Medical Center (US), National Institutes of Health (US), Children's Hospital of Philadelphia (US), University of Washington (US), Medical College of Wisconsin (US), University of Michigan (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Fred Hutch Cancer Center (US), National Heart, Lung, and Blood Institute (US), Framingham Heart Study (US), Boston Public Schools (US), National Institutes of Health Clinical Center (US), University of Manitoba (CA), University of Pennsylvania (US)
Jackson State University, Broad Institute, Mississippi State Department of Health, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute on Minority Health and Health Disparities, NHLBI Division of Intramural Research
Openalex Percentile: Top 11%
Genetic Associations and Epidemiology
1.82
DOIOpen Access PDFOpenAlex
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