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 - Psaty, Bruce M
AU - Tracy, Russell P
AU - Brody, Jennifer
AU - Chen, Ida
AU - Viikari, Jorma
AU - Kähönen, Mika
AU - Vogelzangs, Nicole
AU - DIAGRAM+ Consortium
PY - 2012
Y1 - 2012
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.
KW - Adiponectin/blood
KW - African Americans
KW - Asian Continental Ancestry Group
KW - Cholesterol, HDL/genetics
KW - Diabetes Mellitus, Type 2/genetics
KW - European Continental Ancestry Group
KW - Female
KW - Gene Expression
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Glucose Tolerance Test
KW - Humans
KW - Insulin Resistance/genetics
KW - Male
KW - Metabolic Networks and Pathways
KW - Polymorphism, Single Nucleotide
KW - Waist-Hip Ratio
U2 - 10.1371/journal.pgen.1002607
DO - 10.1371/journal.pgen.1002607
M3 - Article
C2 - 22479202
SN - 1553-7390
VL - 8
SP - e1002607
JO - Plos Genetics
JF - Plos Genetics
IS - 3
ER -