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 t...

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Vydáno v:Nature communications Ročník 16; číslo 1; s. 10615 - 15
Hlavní autoři: Liu, Chunyu, Joehanes, Roby, Ma, Jiantao, Xie, Jiuyong, Yang, Jian, Wang, Mengyao, Huan, Tianxiao, Hwang, Shih-Jen, Wen, Jia, Sun, Quan, Demirkale, Cumhur Y., Heard-Costa, Nancy L., Orchard, Peter, Carson, April P., Haessler, Jeffrey W., Raffield, Laura M., Reiner, Alex P., Franceschini, Nora, Auer, Paul L., Kooperberg, Charles, Li, Yun, O’Connor, George, Murabito, Joanne M., Munson, Peter, Levy, Daniel
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 22.11.2025
Nature Publishing Group
Nature Portfolio
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ISSN:2041-1723, 2041-1723
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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. Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.
AbstractList 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.
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 ) across 4,971 genes. Among 11,425 sentinel cis-irQTLs, 72% replicate (P < 1 × 10 ) 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 ). We also identify 1870 sentinel trans-irQTLs (MAF ≥ 0.01, P < 1.5 × 10 ) 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.
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.Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.
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. Here the authors use a genome-wide approach to identify genetic variants associated with RNA isoform variation, uncovering new links between transcriptional regulation and complex traits. The findings can advance understanding of disease mechanisms.
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.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.
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 Orchard, Peter
Munson, Peter
Li, Yun
Hwang, Shih-Jen
Huan, Tianxiao
Sun, Quan
Franceschini, Nora
Raffield, Laura M.
Heard-Costa, Nancy L.
Wen, Jia
Auer, Paul L.
Joehanes, Roby
Ma, Jiantao
O’Connor, George
Kooperberg, Charles
Murabito, Joanne M.
Liu, Chunyu
Demirkale, Cumhur Y.
Haessler, Jeffrey W.
Yang, Jian
Levy, Daniel
Wang, Mengyao
Carson, April P.
Xie, Jiuyong
Reiner, Alex P.
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Snippet We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In Framingham...
Abstract We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In...
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SubjectTerms 38
49/23
631/208/1792
631/208/205
692/499
692/699/75
Blood pressure
Body mass index
Diabetes
DNA methylation
Female
Gene expression
Gene Expression Profiling
Gene Frequency
Gene regulation
Gene sequencing
Genes
Genetic diversity
Genetic variance
Genome, Human
Genome-wide association studies
Genome-Wide Association Study
Genotype & phenotype
Health promotion
Heart
High density lipoprotein
Humanities and Social Sciences
Humans
Hypertension
Isoforms
Male
Middle Aged
multidisciplinary
Polymorphism, Single Nucleotide
Protein Isoforms - genetics
Proteins
Quantitative trait loci
Quantitative Trait Loci - genetics
Regulatory mechanisms (biology)
Science
Science (multidisciplinary)
Transcriptome - genetics
Transcriptomes
Whole Genome Sequencing
Womens health
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Title Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation
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