A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

JB Richards; D Waterworth; S O'Rahilly; MF Hivert; RJF Loos; JRB Perry; T Tanaka; NJ Timpson; RK Semple; N Soranzo; K Song; N Rocha; E Grundberg; J Dupuis; JC Florez; C Langenberg; I Prokopenko; R Saxena; R Sladek; Yuriy Aulchenko; D Evans; G Waeber; J Erdmann; MS Burnett; N Sattar; J Devaney; C Willenborg; A Hingorani; JCM Witteman; P Vollenweider; B Glaser; C Hengstenberg; L Ferrucci; D Melzer; K Stark; J Deanfield; J Winogradow; M Grassl; AS Hall; JM Egan; JR Thompson; SL Ricketts; IR Konig; W Reinhard; S Grundy; HE Wichmann; P Barter; R Mahley; YA Kesaniemi; DJ Rader; MP Reilly; SE Epstein; AFR Stewart; Cornelia Duijn; H Schunkert; K Burling; P Deloukas; T Pastinen; NJ Samani; R McPherson; GD Smith; TM Frayling; NJ Wareham; JB Meigs; V Mooser; TD Spector

doi:10.1371/journal.pgen.1000768

A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

JB Richards, D Waterworth, S O'Rahilly, MF Hivert, RJF Loos, JRB Perry, T Tanaka, NJ Timpson, RK Semple, N Soranzo, K Song, N Rocha, E Grundberg, J Dupuis, JC Florez, C Langenberg, I Prokopenko, R Saxena, R Sladek, Yuriy AulchenkoD Evans, G Waeber, J Erdmann, MS Burnett, N Sattar, J Devaney, C Willenborg, A Hingorani, JCM Witteman, P Vollenweider, B Glaser, C Hengstenberg, L Ferrucci, D Melzer, K Stark, J Deanfield, J Winogradow, M Grassl, AS Hall, JM Egan, JR Thompson, SL Ricketts, IR Konig, W Reinhard, S Grundy, HE Wichmann, P Barter, R Mahley, YA Kesaniemi, DJ Rader, MP Reilly, SE Epstein, AFR Stewart, Cornelia Duijn, H Schunkert, K Burling, P Deloukas, T Pastinen, NJ Samani, R McPherson, GD Smith, TM Frayling, NJ Wareham, JB Meigs, V Mooser, TD 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 <= 5x10(-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 = 9.2x10(-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 = 8.5610 26, 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.

Original language	Undefined/Unknown
Journal	PLoS Genetics (print)
Volume	5
Issue number	12
DOIs	https://doi.org/10.1371/journal.pgen.1000768
Publication status	Published - 2009

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Richards, JB., 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., ... Spector, TD. (2009). A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels. PLoS Genetics (print), 5(12). 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 <= 5x10(-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 = 9.2x10(-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 = 8.5610 26, 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 = "JB Richards and D Waterworth and S O'Rahilly and MF Hivert and RJF Loos and JRB Perry and T Tanaka and NJ Timpson and RK Semple and N Soranzo and K Song and N Rocha and E Grundberg and J Dupuis and JC Florez and C Langenberg and I Prokopenko and R Saxena and R Sladek and Yuriy Aulchenko and D Evans and G Waeber and J Erdmann and MS Burnett and N Sattar and J Devaney and C Willenborg and A Hingorani and JCM Witteman and P Vollenweider and B Glaser and C Hengstenberg and L Ferrucci and D Melzer and K Stark and J Deanfield and J Winogradow and M Grassl and AS Hall and JM Egan and JR Thompson and SL Ricketts and IR Konig and W Reinhard and S Grundy and HE Wichmann and P Barter and R Mahley and YA Kesaniemi and DJ Rader and MP Reilly and SE Epstein and AFR Stewart and Cornelia Duijn and H Schunkert and K Burling and P Deloukas and T Pastinen and NJ Samani and R McPherson and GD Smith and TM Frayling and NJ Wareham and JB Meigs and V Mooser and TD Spector",

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

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Richards, JB, 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, Konig, IR, Reinhard, W, Grundy, S, Wichmann, HE, Barter, P, Mahley, R, Kesaniemi, YA, Rader, DJ, Reilly, MP, Epstein, SE, Stewart, AFR, Duijn, C, 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 (print), vol. 5, no. 12. 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, JB

AU - Waterworth, D

AU - O'Rahilly, S

AU - Hivert, MF

AU - Loos, RJF

AU - Perry, JRB

AU - Tanaka, T

AU - Timpson, NJ

AU - Semple, RK

AU - Soranzo, N

AU - Song, K

AU - Rocha, N

AU - Grundberg, E

AU - Dupuis, J

AU - Florez, JC

AU - Langenberg, C

AU - Prokopenko, I

AU - Saxena, R

AU - Sladek, R

AU - Aulchenko, Yuriy

AU - Evans, D

AU - Waeber, G

AU - Erdmann, J

AU - Burnett, MS

AU - Sattar, N

AU - Devaney, J

AU - Willenborg, C

AU - Hingorani, A

AU - Witteman, JCM

AU - Vollenweider, P

AU - Glaser, B

AU - Hengstenberg, C

AU - Ferrucci, L

AU - Melzer, D

AU - Stark, K

AU - Deanfield, J

AU - Winogradow, J

AU - Grassl, M

AU - Hall, AS

AU - Egan, JM

AU - Thompson, JR

AU - Ricketts, SL

AU - Konig, IR

AU - Reinhard, W

AU - Grundy, S

AU - Wichmann, HE

AU - Barter, P

AU - Mahley, R

AU - Kesaniemi, YA

AU - Rader, DJ

AU - Reilly, MP

AU - Epstein, SE

AU - Stewart, AFR

AU - Duijn, Cornelia

AU - Schunkert, H

AU - Burling, K

AU - Deloukas, P

AU - Pastinen, T

AU - Samani, NJ

AU - McPherson, R

AU - Smith, GD

AU - Frayling, TM

AU - Wareham, NJ

AU - Meigs, JB

AU - Mooser, V

AU - Spector, TD

PY - 2009

Y1 - 2009

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 <= 5x10(-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 = 9.2x10(-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 = 8.5610 26, 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 <= 5x10(-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 = 9.2x10(-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 = 8.5610 26, 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

VL - 5

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 12

ER -