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
Témata:	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
ISSN:	2041-1723, 2041-1723
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-025-64336-8