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 Aulchenko; David 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

doi:10.1371/journal.pgen.1000768

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 language	English (US)
Article number	e1000768
Journal	PLoS genetics
Volume	5
Issue number	12
DOIs	https://doi.org/10.1371/journal.pgen.1000768
State	Published - Dec 2009

ASJC Scopus subject areas

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

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10.1371/journal.pgen.1000768

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Brent Richards, J., Waterworth, D., O'Rahilly, S., Hivert, M. F., Loos, R. J. F., Perry, J. R. B., Tanaka, T., Timpson, N. J., Semple, R. K., Soranzo, N., Song, K., Rocha, N., Grundberg, E., Dupuis, J., Florez, J. C., Langenberg, C., Prokopenko, I., Saxena, R., Sladek, R., ... Spector, T. D. (2009). A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS genetics, 5(12), Article e1000768. https://doi.org/10.1371/journal.pgen.1000768

Brent Richards, J, Waterworth, D, O'Rahilly, S, Hivert, MF, Loos, RJF, Perry, JRB, Tanaka, T, Timpson, NJ, Semple, RK, Soranzo, N, Song, K, Rocha, N, Grundberg, E, Dupuis, J, Florez, JC, Langenberg, C, Prokopenko, I, Saxena, R, Sladek, R, Aulchenko, Y, Evans, D, Waeber, G, Erdmann, J, Burnett, MS, Sattar, N, Devaney, J, Willenborg, C, Hingorani, A, Witteman, JCM, Vollenweider, P, Glaser, B, Hengstenberg, C, Ferrucci, L, Melzer, D, Stark, K, Deanfield, J, Winogradow, J, Grassl, M, Hall, AS, Egan, JM, Thompson, JR, Ricketts, SL, König, IR, Reinhard, W, Grundy, SM, Wichmann, HE, Barter, P, Mahley, R, Kesaniemi, YA, Rader, DJ, Reilly, MP, Epstein, SE, Stewart, AFR, Van Duijn, CM, Schunkert, H, Burling, K, Deloukas, P, Pastinen, T, Samani, NJ, McPherson, R, Smith, GD, Frayling, TM, Wareham, NJ, Meigs, JB, Mooser, V & Spector, TD 2009, 'A genome-wide association study reveals variants in ARL15 that influence adiponectin levels', PLoS genetics, vol. 5, no. 12, e1000768. https://doi.org/10.1371/journal.pgen.1000768

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title = "A genome-wide association study reveals variants in ARL15 that influence adiponectin levels",

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.",

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

year = "2009",

month = dec,

doi = "10.1371/journal.pgen.1000768",

language = "English (US)",

volume = "5",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

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T1 - A genome-wide association study reveals variants in ARL15 that influence adiponectin levels

AU - Brent Richards, J.

AU - Waterworth, Dawn

AU - O'Rahilly, Stephen

AU - Hivert, Marie France

AU - Loos, Ruth J F

AU - Perry, John R B

AU - Tanaka, Toshiko

AU - Timpson, Nicholas John

AU - Semple, Robert K.

AU - Soranzo, Nicole

AU - Song, Kijoung

AU - Rocha, Nuno

AU - Grundberg, Elin

AU - Dupuis, Josée

AU - Florez, Jose C.

AU - Langenberg, Claudia

AU - Prokopenko, Inga

AU - Saxena, Richa

AU - Sladek, Robert

AU - Aulchenko, Yurii

AU - Evans, David

AU - Waeber, Gerard

AU - Erdmann, Jeanette

AU - Burnett, Mary Susan

AU - Sattar, Naveed

AU - Devaney, Joseph

AU - Willenborg, Christina

AU - Hingorani, Aroon

AU - Witteman, Jaquelin C M

AU - Vollenweider, Peter

AU - Glaser, Beate

AU - Hengstenberg, Christian

AU - Ferrucci, Luigi

AU - Melzer, David

AU - Stark, Klaus

AU - Deanfield, John

AU - Winogradow, Janina

AU - Grassl, Martina

AU - Hall, Alistair S.

AU - Egan, Josephine M.

AU - Thompson, John R.

AU - Ricketts, Sally L.

AU - König, Inke R.

AU - Reinhard, Wibke

AU - Grundy, Scott M

AU - Wichmann, H. Erich

AU - Barter, Phil

AU - Mahley, Robert

AU - Kesaniemi, Y. Antero

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Epstein, Stephen E.

AU - Stewart, Alexandre F R

AU - Van Duijn, Cornelia M.

AU - Schunkert, Heribert

AU - Burling, Keith

AU - Deloukas, Panos

AU - Pastinen, Tomi

AU - Samani, Nilesh J.

AU - McPherson, Ruth

AU - Smith, George Davey

AU - Frayling, Timothy M.

AU - Wareham, Nicholas J.

AU - Meigs, James B.

AU - Mooser, Vincent

AU - Spector, Tim D.

PY - 2009/12

Y1 - 2009/12

N2 - 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.

AB - 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.

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JO - PLoS genetics

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ER -

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

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