A functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci

Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiat...

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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 5253 - 15
Hlavní autoři:	Joslin, Amelia C., Sobreira, Débora R., Hansen, Grace T., Sakabe, Noboru J., Aneas, Ivy, Montefiori, Lindsey E., Farris, Kathryn M., Gu, Jing, Lehman, Donna M., Ober, Carole, He, Xin, Nóbrega, Marcelo A.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 06.09.2021 Nature Publishing Group Nature Portfolio
Témata:	13/100 38/109 38/47 38/91 45/43 45/77 49/22 49/31 49/90 631/208/191 631/208/200 631/208/212/177 692/699/2743/393 Adipocytes Adipocytes - cytology Adipocytes - physiology Annotations Arrhythmias, Cardiac - genetics Arrhythmias, Cardiac - pathology Chromatin Differentiation (biology) Enhancer Elements, Genetic Gene expression Gene loci Genes Genetic Diseases, X-Linked - genetics Genetic Diseases, X-Linked - pathology Genetic Pleiotropy Genome-wide association studies Genome-Wide Association Study Genomics Gigantism - genetics Gigantism - pathology Heart Defects, Congenital - genetics Heart Defects, Congenital - pathology Humanities and Social Sciences Humans Hypothalamus Hypothalamus - physiology Intellectual Disability - genetics Intellectual Disability - pathology MAP Kinase Kinase 5 - genetics multidisciplinary Neurons - cytology Neurons - physiology Obesity Obesity - genetics Pleiotropy Polymorphism, Single Nucleotide Protein Kinases - genetics Quantitative Trait Loci Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics Science Science (multidisciplinary) Transcription Factors - genetics Transcriptome
ISSN:	2041-1723, 2041-1723
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Popis
Shrnutí:	Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS. Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-25614-3