A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Copyright policy )https://repository.ubn.ru.nl/handle/2066/282335 , 11368/3039144 , 1871.1/d89d90c9-762d-41a8-8b69-014aa7e6f202 , 11370/3b6f69e0-7150-4bd9-877b-94de360066bb , 1887/3479845 , 20.500.14243/419435 , 2066/282335 , 11388/296424 , 10576/42514 , 10668/21878 , 1983/5b8d5f84-7a3a-4e95-9f06-f5e23349c04c , 20.500.11820/38770c60-7b76-49f8-aa4b-5a0491cd1018 , 1959.13/1479920
https://repository.ubn.ru.nl/handle/2066/282335 , 11368/3039144 , 1871.1/d89d90c9-762d-41a8-8b69-014aa7e6f202 , 11370/3b6f69e0-7150-4bd9-877b-94de360066bb , 1887/3479845 , 20.500.14243/419435 , 2066/282335 , 11388/296424 , 10576/42514 , 10668/21878 , 1983/5b8d5f84-7a3a-4e95-9f06-f5e23349c04c , 20.500.11820/38770c60-7b76-49f8-aa4b-5a0491cd1018 , 1959.13/1479920
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
AbstractA major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.
- University of Edinburgh United Kingdom
- University of Illinois at Urbana Champaign United States
- University of Gothenburg Sweden
- Osaka University Japan
- Tohoku University Japan
post-GWAS, LOCI, genetic analysis, VARIANTS, lipid blood level, genetic risk, ANNOTATION, whole exome sequencing, Cromatina, functional genomic, genetics, Aetiology, Genome-Wide Association Study*, Genetics & Heredity, Chromatin/genetics, Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience, CHOLESTEROL, Genomics, Lipids, Chromatin, complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization; Chromatin; Genomics; Humans; Lipids; Genome-Wide Association Study; Polymorphism, Single Nucleotide, name=Genetics(clinical), complex trait, Lípidos, complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization., Single Nucleotide/genetics, single cell RNA seq, /dk/atira/pure/subjectarea/asjc/1300/1311, 572, /dk/atira/pure/subjectarea/asjc/2700/2716; name=Genetics(clinical), phenotype, name=Genetics, 610, INTEGRATIVE ANALYSIS, ta3111, Article, 576, lipid, Genetics, genomics, Humans, human, Polymorphism, binding site, Complex traits, lipid biology, Lipids/genetics, genetic variation, Urology - Radboud University Medical Center, chemical structure, cholesterol metabolism, chromatin, Human Genetics - Radboud University Medical Center, transcriptome, Polimorfismo de nucleótido simple, Medizin, Medical and Health Sciences, INTEGRATIVE ANALYSIS ; WIDE ASSOCIATION ; 3D GENOME ; VARIANTS ; CHOLESTEROL ; ANNOTATION ; OBESITY ; COMMON ; LOCI ; EXPRESSION, Lipids / genetics, single nucleotide polymorphism, binding affinity, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, 3D GENOME, transcription factor, variant prioritization, Chromatin/genetics; Genome-Wide Association Study; Genomics; Humans; Lipids/genetics; Polymorphism, Single Nucleotide/genetics; complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization, Global Lipids Genetics Consortium, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, retinoid X receptor alpha, fine-mapping, OBESITY, Estudio de asociación del Genoma, ddc:570, triacylglycerol, functional genomics, Biotechnology, Health Evidence - Radboud University Medical Center, EXPRESSION, Genómica, regulatory mechanism, complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization, Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences, gene frequency, Polymorphism, Single Nucleotide, adipogenesis, complex traits, Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences, post-genome-wide association studies (GWASs), /dk/atira/pure/subjectarea/asjc/1300/1311; name=Genetics, COMMON, genome-wide association study, Human Genome, Million Veterans Program, /dk/atira/pure/subjectarea/asjc/2700/2716, Single Nucleotide* / genetics, Wnt signaling, 3111, cell differentiation, Chromatin / genetics, gene expression, Institut für Ernährungswissenschaft, 3111 Biomedicine, untranslated RNA, Genome-Wide Association Study
post-GWAS, LOCI, genetic analysis, VARIANTS, lipid blood level, genetic risk, ANNOTATION, whole exome sequencing, Cromatina, functional genomic, genetics, Aetiology, Genome-Wide Association Study*, Genetics & Heredity, Chromatin/genetics, Radboudumc 12: Sensory disorders DCMN: Donders Center for Medical Neuroscience, CHOLESTEROL, Genomics, Lipids, Chromatin, complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization; Chromatin; Genomics; Humans; Lipids; Genome-Wide Association Study; Polymorphism, Single Nucleotide, name=Genetics(clinical), complex trait, Lípidos, complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization., Single Nucleotide/genetics, single cell RNA seq, /dk/atira/pure/subjectarea/asjc/1300/1311, 572, /dk/atira/pure/subjectarea/asjc/2700/2716; name=Genetics(clinical), phenotype, name=Genetics, 610, INTEGRATIVE ANALYSIS, ta3111, Article, 576, lipid, Genetics, genomics, Humans, human, Polymorphism, binding site, Complex traits, lipid biology, Lipids/genetics, genetic variation, Urology - Radboud University Medical Center, chemical structure, cholesterol metabolism, chromatin, Human Genetics - Radboud University Medical Center, transcriptome, Polimorfismo de nucleótido simple, Medizin, Medical and Health Sciences, INTEGRATIVE ANALYSIS ; WIDE ASSOCIATION ; 3D GENOME ; VARIANTS ; CHOLESTEROL ; ANNOTATION ; OBESITY ; COMMON ; LOCI ; EXPRESSION, Lipids / genetics, single nucleotide polymorphism, binding affinity, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, 3D GENOME, transcription factor, variant prioritization, Chromatin/genetics; Genome-Wide Association Study; Genomics; Humans; Lipids/genetics; Polymorphism, Single Nucleotide/genetics; complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization, Global Lipids Genetics Consortium, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, retinoid X receptor alpha, fine-mapping, OBESITY, Estudio de asociación del Genoma, ddc:570, triacylglycerol, functional genomics, Biotechnology, Health Evidence - Radboud University Medical Center, EXPRESSION, Genómica, regulatory mechanism, complex traits; fine-mapping; functional genomics; lipid biology; post-GWAS; regulatory mechanism; variant prioritization, Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences, gene frequency, Polymorphism, Single Nucleotide, adipogenesis, complex traits, Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences, post-genome-wide association studies (GWASs), /dk/atira/pure/subjectarea/asjc/1300/1311; name=Genetics, COMMON, genome-wide association study, Human Genome, Million Veterans Program, /dk/atira/pure/subjectarea/asjc/2700/2716, Single Nucleotide* / genetics, Wnt signaling, 3111, cell differentiation, Chromatin / genetics, gene expression, Institut für Ernährungswissenschaft, 3111 Biomedicine, untranslated RNA, Genome-Wide Association Study
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