Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals

Zari Dastani; Marie-France Hivert; Nicholas Timpson; John R B Perry; Xin Yuan; Robert A Scott; Peter Henneman; Iris M Heid; Jorge R Kizer; Leo-Pekka Lyytikäinen; Christian Fuchsberger; Toshiko Tanaka; Andrew P Morris; Kerrin Small; Aaron Isaacs; Marian Beekman; Stefan Coassin; Kurt Lohman; Lu Qi; Stavroula Kanoni; James S Pankow; Hae-Won Uh; Ying Wu; Aurelian Bidulescu; Laura J Rasmussen-Torvik; Celia M T Greenwood; Martin Ladouceur; Jonna Grimsby; Alisa K Manning; Ching-Ti Liu; Jaspal Kooner; Vincent E Mooser; Peter Vollenweider; Karen A Kapur; John Chambers; Nicholas J Wareham; Claudia Langenberg; Rune Frants; Ko Willems-Vandijk; Ben A Oostra; Sara M Willems; Claudia Lamina; Thomas W Winkler; Niels Grarup; Torben Jørgensen; Thomas Sparsø; Torben Hansen; Oluf Pedersen; Fredrik Karpe; Kirsten O Kyvik; DIAGRAM+ Consortium

doi:10.1371/journal.pgen.1002607

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals

Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula KanoniJames S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Niels Grarup, Torben Jørgensen, Thomas Sparsø, Torben Hansen, Oluf Pedersen, Fredrik Karpe, Kirsten O Kyvik, DIAGRAM+ Consortium

291 Citationer (Scopus)

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10⁻⁸- 1.2 ×10⁻⁴³). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10⁻⁴). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10⁻³, n = 22,044), increased triglycerides (p = 2.6×10⁻¹⁴, n = 93,440), increased waist-to-hip ratio (p = 1.8×10⁻⁵, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10⁻³, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10⁻¹³, n = 96,748) and decreased BMI (p = 1.4×10⁻⁴, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Originalsprog	Engelsk
Tidsskrift	P L o S Genetics (Online)
Vol/bind	8
Udgave nummer	3
Sider (fra-til)	e1002607
ISSN	1553-7404
DOI	https://doi.org/10.1371/journal.pgen.1002607
Status	Udgivet - 29 mar. 2012

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Dastani, Z., Hivert, M-F., Timpson, N., Perry, J. R. B., Yuan, X., Scott, R. A., Henneman, P., Heid, I. M., Kizer, J. R., Lyytikäinen, L-P., Fuchsberger, C., Tanaka, T., Morris, A. P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., ... DIAGRAM+ Consortium (2012). Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. P L o S Genetics (Online), 8(3), e1002607. https://doi.org/10.1371/journal.pgen.1002607

Dastani, Z, Hivert, M-F, Timpson, N, Perry, JRB, Yuan, X, Scott, RA, Henneman, P, Heid, IM, Kizer, JR, Lyytikäinen, L-P, Fuchsberger, C, Tanaka, T, Morris, AP, Small, K, Isaacs, A, Beekman, M, Coassin, S, Lohman, K, Qi, L, Kanoni, S, Pankow, JS, Uh, H-W, Wu, Y, Bidulescu, A, Rasmussen-Torvik, LJ, Greenwood, CMT, Ladouceur, M, Grimsby, J, Manning, AK, Liu, C-T, Kooner, J, Mooser, VE, Vollenweider, P, Kapur, KA, Chambers, J, Wareham, NJ, Langenberg, C, Frants, R, Willems-Vandijk, K, Oostra, BA, Willems, SM, Lamina, C, Winkler, TW, Grarup, N, Jørgensen, T, Sparsø, T, Hansen, T , Pedersen, O, Karpe, F, Kyvik, KO & DIAGRAM+ Consortium 2012, 'Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals', P L o S Genetics (Online), bind 8, nr. 3, s. e1002607. https://doi.org/10.1371/journal.pgen.1002607

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title = "Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals",

abstract = "Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.",

author = "Zari Dastani and Marie-France Hivert and Nicholas Timpson and Perry, {John R B} and Xin Yuan and Scott, {Robert A} and Peter Henneman and Heid, {Iris M} and Kizer, {Jorge R} and Leo-Pekka Lyytik{\"a}inen and Christian Fuchsberger and Toshiko Tanaka and Morris, {Andrew P} and Kerrin Small and Aaron Isaacs and Marian Beekman and Stefan Coassin and Kurt Lohman and Lu Qi and Stavroula Kanoni and Pankow, {James S} and Hae-Won Uh and Ying Wu and Aurelian Bidulescu and Rasmussen-Torvik, {Laura J} and Greenwood, {Celia M T} and Martin Ladouceur and Jonna Grimsby and Manning, {Alisa K} and Ching-Ti Liu and Jaspal Kooner and Mooser, {Vincent E} and Peter Vollenweider and Kapur, {Karen A} and John Chambers and Wareham, {Nicholas J} and Claudia Langenberg and Rune Frants and Ko Willems-Vandijk and Oostra, {Ben A} and Willems, {Sara M} and Claudia Lamina and Winkler, {Thomas W} and Niels Grarup and Torben J{\o}rgensen and Thomas Spars{\o} and Torben Hansen and Oluf Pedersen and Fredrik Karpe and Kyvik, {Kirsten O} and {DIAGRAM+ Consortium}",

year = "2012",

month = mar,

day = "29",

doi = "10.1371/journal.pgen.1002607",

language = "English",

volume = "8",

pages = "e1002607",

journal = "P L o S Genetics",

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TY - JOUR

T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits

T2 - a multi-ethnic meta-analysis of 45,891 individuals

AU - Dastani, Zari

AU - Hivert, Marie-France

AU - Timpson, Nicholas

AU - Perry, John R B

AU - Yuan, Xin

AU - Scott, Robert A

AU - Henneman, Peter

AU - Heid, Iris M

AU - Kizer, Jorge R

AU - Lyytikäinen, Leo-Pekka

AU - Fuchsberger, Christian

AU - Tanaka, Toshiko

AU - Morris, Andrew P

AU - Small, Kerrin

AU - Isaacs, Aaron

AU - Beekman, Marian

AU - Coassin, Stefan

AU - Lohman, Kurt

AU - Qi, Lu

AU - Kanoni, Stavroula

AU - Pankow, James S

AU - Uh, Hae-Won

AU - Wu, Ying

AU - Bidulescu, Aurelian

AU - Rasmussen-Torvik, Laura J

AU - Greenwood, Celia M T

AU - Ladouceur, Martin

AU - Grimsby, Jonna

AU - Manning, Alisa K

AU - Liu, Ching-Ti

AU - Kooner, Jaspal

AU - Mooser, Vincent E

AU - Vollenweider, Peter

AU - Kapur, Karen A

AU - Chambers, John

AU - Wareham, Nicholas J

AU - Langenberg, Claudia

AU - Frants, Rune

AU - Willems-Vandijk, Ko

AU - Oostra, Ben A

AU - Willems, Sara M

AU - Lamina, Claudia

AU - Winkler, Thomas W

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Sparsø, Thomas

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Karpe, Fredrik

AU - Kyvik, Kirsten O

AU - DIAGRAM+ Consortium

PY - 2012/3/29

Y1 - 2012/3/29

N2 - Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

AB - Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

U2 - 10.1371/journal.pgen.1002607

DO - 10.1371/journal.pgen.1002607

M3 - Journal article

C2 - 22479202

SN - 1553-7390

VL - 8

SP - e1002607

JO - P L o S Genetics

JF - P L o S Genetics

IS - 3

ER -

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals

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