Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences
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Spracklen, C.N, et al. Adiponectin Gwas Loci Harboring Extensive Allelic Heterogeneity Exhibit Distinct Molecular Consequences. Public Library of Science, 2020. https://doi.org/10.17615/4xxe-xj37APA
Spracklen, C., Iyengar, A., Vadlamudi, S., Raulerson, C., Jackson, A., Brotman, S., Wu, Y., Cannon, M., Davis, J., Crain, A., Currin, K., Perrin, H., Narisu, N., Stringham, H., Fuchsberger, C., Locke, A., Welch, R., Kuusisto, J., Pajukanta, P., Scott, L., Li, Y., Collins, F., Boehnke, M., Laakso, M., & Mohlke, K. (2020). Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. Public Library of Science. https://doi.org/10.17615/4xxe-xj37Chicago
Spracklen, C.N., A.K Iyengar, S Vadlamudi, C.K Raulerson, A.U Jackson, S.M Brotman, Y Wu et al. 2020. Adiponectin Gwas Loci Harboring Extensive Allelic Heterogeneity Exhibit Distinct Molecular Consequences. Public Library of Science. https://doi.org/10.17615/4xxe-xj37- Creator
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Spracklen, C.N.
- Affiliation: School of Medicine, Department of Genetics
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Iyengar, A.K.
- Affiliation: School of Medicine, Department of Genetics
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Vadlamudi, S.
- Affiliation: School of Medicine, Department of Genetics
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Raulerson, C.K.
- Affiliation: School of Medicine, Department of Genetics
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Jackson, A.U.
- Other Affiliation: University of Michigan
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Brotman, S.M.
- Affiliation: School of Medicine, Department of Genetics
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Wu, Y.
- Affiliation: School of Medicine, Department of Genetics
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Cannon, M.E.
- Affiliation: School of Medicine, Department of Genetics
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Davis, J.P.
- Affiliation: School of Medicine, Department of Genetics
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Crain, A.T.
- Affiliation: School of Medicine, Department of Genetics
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Currin, K.W.
- Affiliation: School of Medicine, Department of Genetics
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Perrin, H.J.
- Affiliation: School of Medicine, Department of Genetics
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Narisu, N.
- Other Affiliation: National Institutes of Health
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Stringham, H.M.
- Other Affiliation: University of Michigan
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Fuchsberger, C.
- Other Affiliation: University of Michigan
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Locke, A.E.
- Other Affiliation: University of Michigan
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Welch, R.P.
- Other Affiliation: University of Michigan
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Kuusisto, J.K.
- Other Affiliation: University of Eastern Finland
- Pajukanta, P.
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Scott, L.J.
- Other Affiliation: University of Michigan
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Li, Y.
- Affiliation: School of Medicine, Department of Genetics
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Collins, F.S.
- Other Affiliation: National Institutes of Health
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Boehnke, M.
- Other Affiliation: University of Michigan
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Laakso, M.
- Other Affiliation: University of Eastern Finland
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Mohlke, K.L.
- Affiliation: School of Medicine, Department of Genetics
- Abstract
- Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.
- Date of publication
- 2020
- Keyword
- Metabolic Syndrome
- Male
- Quantitative Trait Loci
- Genome-Wide Association Study
- Adipose Tissue
- Adiponectin
- Gene Frequency
- Genetic Predisposition to Disease
- Cadherins
- Regulatory Sequences, Nucleic Acid
- Polymorphism, Single Nucleotide
- Phenotype
- Alleles
- Insulin Receptor Substrate Proteins
- Humans
- DNA-Binding Proteins
- Transcription Factors
- DOI
- Identifier
- https://dx.doi.org/10.1371/JOURNAL.PGEN.1009019
- PMID 32915782
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 3.0 United States
- Journal title
- PLoS Genetics
- Journal volume
- 16
- Journal issue
- 9
- Language
- English
- Version
- Publisher
- ISSN
- 1553-7390
- Publisher
- Public Library of Science
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