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Long intergenic noncoding RNAs (lincRNAs) play important roles in disease, but the vast majority of these transcripts remain uncharacterized. A team led by researchers from Duke University defined a set of 54,944 human lincRNAs by drawing on four publicly available lincRNA datasets, and annotated ~2.5 million single-nucleotide polymorphisms from each of 15 cardiometabolic genome-wide association study datasets into these lincRNAs. They identified hundreds of lincRNAs with at least one trait-associated SNP: 898 SNPs in 343 unique lincRNAs at 5% false discovery rate, and 469 SNPs in 146 unique lincRNAs meeting Bonferroni-corrected P <0.05. An additional 64 trait-associated lincRNAs were identified using a class-level testing strategy at Bonferroni-corrected P <0.05. To better understand the genomic context and prioritize trait-associated lincRNAs, the team examined the pattern of linkage disequilibrium between SNPs in the lincRNAs and SNPs that met genome-wide-significance in the region (±500 kb of lincRNAs). A subset of the lincRNA-trait association findings was replicated in independent GWAS data from the Pakistan Risk of Myocardial Infarction Study (PROMIS) study. For trait-associated lincRNAs, they also investigated synteny and conservation relative to mouse, expression patterns in five cardiometabolic-relevant tissues, and allele-specific expression in RNA sequencing data for adipose tissue and leukocytes. Finally, they revealed a functional role in human adipocytes for linc-NFE2L3-1, which is expressed in adipose and is associated with waist-hip ratio adjusted for BMI. This comprehensive profile of trait-associated lincRNAs provides novel insights into disease mechanism and serves as a launching point for interrogation of the biology of specific lincRNAs in cardiometabolic disease.
Linc-NFE2L3-1, a lincRNA harboring obesity-associated GWAS SNPs, modulates human adipocyte metabolism
GWAS SNPs associated with WHRadjBMI, and LD heat map at linc-NFE2L3-1 locus.
