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 Grundy; H-Erich Wichmann; Phil Barter; Robert Mahley; Y Antero Kesaniemi; George Davey Smith; GIANT Consortium

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 Grundy, H-Erich Wichmann, Phil Barter, Robert Mahley, Y Antero Kesaniemi, George Davey Smith, GIANT Consortium

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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<or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P<or =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 = 9.2x10(-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 = 2.9x10(-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 = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-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.

Translated title of the contribution	A genome-wide association study reveals variants in ARL15 that influence adiponectin levels
Original language	English
Pages (from-to)	e1000768
Number of pages	1
Journal	PLoS Genetics
Volume	5
Issue number	12
DOIs	https://doi.org/10.1371/journal.pgen.1000768
Publication status	Published - Dec 2009

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Richards, J. B., 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., ... GIANT Consortium (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

@article{85785a8269524833ab143bd1717c3c99,

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<or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P<or =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 = 9.2x10(-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 = 2.9x10(-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 = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-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 = "Richards, {J Brent} and Dawn Waterworth and Stephen O'Rahilly and Marie-France Hivert 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 Mary-Susan Burnett 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 Scott Grundy and H-Erich Wichmann and Phil Barter and Robert Mahley and Kesaniemi, {Y Antero} and {Davey Smith}, George and {GIANT Consortium}",

year = "2009",

month = dec,

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

language = "English",

volume = "5",

pages = "e1000768",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science",

number = "12",

}

Richards, JB, Waterworth, D, O'Rahilly, S, Hivert, M-F, 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, M-S, 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, S, Wichmann, H-E, Barter, P, Mahley, R, Kesaniemi, YA, Davey Smith, G & GIANT Consortium 2009, 'A genome-wide association study reveals variants in ARL15 that influence adiponectin levels', PLoS Genetics, vol. 5, no. 12, pp. e1000768. https://doi.org/10.1371/journal.pgen.1000768

TY - JOUR

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

AU - Richards, J Brent

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

AU - Wichmann, H-Erich

AU - Barter, Phil

AU - Mahley, Robert

AU - Kesaniemi, Y Antero

AU - Davey Smith, George

AU - GIANT Consortium

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<or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P<or =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 = 9.2x10(-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 = 2.9x10(-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 = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-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<or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P<or =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 = 9.2x10(-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 = 2.9x10(-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 = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-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.

U2 - 10.1371/journal.pgen.1000768

DO - 10.1371/journal.pgen.1000768

M3 - Article (Academic Journal)

C2 - 20011104

SN - 1553-7404

VL - 5

SP - e1000768

JO - PLoS Genetics

JF - PLoS Genetics

IS - 12

ER -

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

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