Genome-wide interrogation reveals hundreds of long intergenic noncoding RNAs that associate with cardiometabolic traits

Long intergenic noncoding RNAs (lincRNAs) play important roles in disease, but the vast majority of these transcripts remain uncharacterized. We defined a set of 54 944 human lincRNAs by drawing on four publicly available lincRNA datasets, and annotated similar to 2.5 million single nucleotide polymorphisms (SNPs) from each of 15 cardiometabolic genome-wide association study datasets into these lincRNAs. We 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, we 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 Genome-wide association studies data from the Pakistan Risk of Myocardial Infarction Study study. For trait-associated lincRNAs, we 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, we 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.