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INFERNO: inferring the molecular mechanisms of noncoding genetic variants.

TitleINFERNO: inferring the molecular mechanisms of noncoding genetic variants.
Publication TypeJournal Article
Year of Publication2018
AuthorsAmlie-Wolf A, Tang M, Mlynarski EE, Kuksa PP, Valladares O, Katanić Ž, Tsuang D, Brown CD, Schellenberg GD, San Wang L-
JournalNucleic Acids Res
Date Published2018 09 28
KeywordsAdaptive Immunity, Case-Control Studies, Enhancer Elements, Genetic, Female, Genetic Markers, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Internet, Linkage Disequilibrium, Male, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA, Long Noncoding, Schizophrenia, Software

The majority of variants identified by genome-wide association studies (GWAS) reside in the noncoding genome, affecting regulatory elements including transcriptional enhancers. However, characterizing their effects requires the integration of GWAS results with context-specific regulatory activity and linkage disequilibrium annotations to identify causal variants underlying noncoding association signals and the regulatory elements, tissue contexts, and target genes they affect. We propose INFERNO, a novel method which integrates hundreds of functional genomics datasets spanning enhancer activity, transcription factor binding sites, and expression quantitative trait loci with GWAS summary statistics. INFERNO includes novel statistical methods to quantify empirical enrichments of tissue-specific enhancer overlap and to identify co-regulatory networks of dysregulated long noncoding RNAs (lncRNAs). We applied INFERNO to two large GWAS studies. For schizophrenia (36,989 cases, 113,075 controls), INFERNO identified putatively causal variants affecting brain enhancers for known schizophrenia-related genes. For inflammatory bowel disease (IBD) (12,882 cases, 21,770 controls), INFERNO found enrichments of immune and digestive enhancers and lncRNAs involved in regulation of the adaptive immune response. In summary, INFERNO comprehensively infers the molecular mechanisms of causal noncoding variants, providing a sensitive hypothesis generation method for post-GWAS analysis. The software is available as an open source pipeline and a web server.

Pubmed Link
Alternate JournalNucleic Acids Res.
PubMed ID30113658
PubMed Central IDPMC6158604
Grant ListR01 GM099962 / GM / NIGMS NIH HHS / United States
T32 AG000255 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
U54 AG052427 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
RF1 AG055477 / AG / NIA NIH HHS / United States
U54 NS100693 / NS / NINDS NIH HHS / United States

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