A genome-wide association study reveals variants in ARL15 that influence adiponectin levels

J. Brent Richards, Dawn Waterworth, Stephen O'Rahilly, Marie France Hivert, Ruth J F Loos, John R B Perry, Toshiko Tanaka, Nicholas John Timpson, Robert K. Semple, Nicole Soranzo, Kijoung Song, Nuno Rocha, Elin Grundberg, Josée Dupuis, Jose C. Florez, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Robert Sladek, Yurii AulchenkoDavid Evans, Gerard Waeber, Jeanette Erdmann, Mary Susan Burnett, Naveed Sattar, Joseph Devaney, Christina Willenborg, Aroon Hingorani, Jaquelin C M Witteman, Peter Vollenweider, Beate Glaser, Christian Hengstenberg, Luigi Ferrucci, David Melzer, Klaus Stark, John Deanfield, Janina Winogradow, Martina Grassl, Alistair S. Hall, Josephine M. Egan, John R. Thompson, Sally L. Ricketts, Inke R. König, Wibke Reinhard, Scott M Grundy, H. Erich Wichmann, Phil Barter, Robert Mahley, Y. Antero Kesaniemi, Daniel J. Rader, Muredach P. Reilly, Stephen E. Epstein, Alexandre F R Stewart, Cornelia M. Van Duijn, Heribert Schunkert, Keith Burling, Panos Deloukas, Tomi Pastinen, Nilesh J. Samani, Ruth McPherson, George Davey Smith, Timothy M. Frayling, Nicholas J. Wareham, James B. Meigs, Vincent Mooser, Tim D. Spector

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Abstract

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10-8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10-19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10-8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10-6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10-3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

Original languageEnglish (US)
Article numbere1000768
JournalPLoS Genetics
Volume5
Issue number12
DOIs
Publication statusPublished - Dec 2009

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ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Brent Richards, J., Waterworth, D., O'Rahilly, S., Hivert, M. F., Loos, R. J. F., Perry, J. R. B., ... Spector, T. D. (2009). A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genetics, 5(12), [e1000768]. https://doi.org/10.1371/journal.pgen.1000768