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

ABSTRACT: 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.

SUBMITTER: Ballantyne RL

PROVIDER: S-EPMC5181595 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Ballantyne Rachel L RL Zhang Xuan X Zhang Xuan X Nuñez Sara S Xue Chenyi C Zhao Wei W Reed Eric E Salaheen Danish D Foulkes Andrea S AS Li Mingyao M Reilly Muredach P MP

Human molecular genetics 20160610 14

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 linc ...[more]

PMID: 27288454

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Project description:ObjectiveTranscriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT (Genetic Investigation of Anthropometric Traits), UK Biobank, GLGC (Global Lipids Genetics Consortium), Cardiogram (Coronary Artery Disease Genome Wide Replication and Meta-Analysis), and DIAGRAM (Diabetes Genetics Replication and Meta-Analysis)/DIAMANTE (Diabetes Meta-Analysis of Trans-Ethnic Association Studies). These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation.ConclusionsThese findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.

Dataset Information

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

Publications

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

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