Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences

Autoři: Cassandra N. Spracklen aff001;  Apoorva K. Iyengar aff001;  Swarooparani Vadlamudi aff001;  Chelsea K. Raulerson aff001;  Anne U. Jackson aff003;  Sarah M. Brotman aff001;  Ying Wu aff001;  Maren E. Cannon aff001;  James P. Davis aff001;  Aaron T. Crain aff001;  Kevin W. Currin aff001;  Hannah J. Perrin aff001;  Narisu Narisu aff004;  Heather M. Stringham aff003;  Christian Fuchsberger aff003;  Adam E. Locke aff003;  Ryan P. Welch aff003;  Johanna K. Kuusisto aff007;  Päivi Pajukanta aff008;  Laura J. Scott aff003;  Yun Li aff001;  Francis S. Collins aff004;  Michael Boehnke aff003;  Markku Laakso aff007;  Karen L. Mohlke aff001
Působiště autorů: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America aff001;  Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, Massachusetts, United States of America aff002;  Department of Biostatistics and Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, Michigan, United States of America aff003;  National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff004;  Center for Biomedicine, European Academy of Bolzano/Bozen, University of Lübeck, Bolzano/Bozen, Italy aff005;  McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America aff006;  Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland aff007;  Department of Human Genetics, University of California, Los Angeles, California, United States of America aff008;  Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America aff009
Vyšlo v časopise: Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009019
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009019


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.

Klíčová slova:

Adiponectin – Alleles – DNA transcription – Genetic loci – Genome-wide association studies – Genomic signal processing – Haplotypes – Introns


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