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

• Published in: Human molecular genetics Vol. 25; no. 14; pp. 3125 - 3141
• Main Authors: Ballantyne, Rachel L, Zhang, Xuan, Nuñez, Sara, Xue, Chenyi, Zhao, Wei, Reed, Eric, Salaheen, Danish, Foulkes, Andrea S, Li, Mingyao, Reilly, Muredach P
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.07.2016
• Subjects: Adipocytes - metabolism; Alleles; Association Studies; Genome, Human; Genome-Wide Association Study; Humans; Linkage Disequilibrium; Myocardial Infarction - genetics; Myocardial Infarction - physiopathology; Pakistan; Polymorphism, Single Nucleotide; RNA, Long Noncoding - genetics; Sequence Analysis, RNA; Waist-Hip Ratio
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw154

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 ∼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.