Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation

Liling L. Warren; Li Li; Matthew R. Nelson; Margaret G. Ehm; Judong Shen; Dana J. Fraser; Jennifer L. Aponte; Keith L. Nangle; Andrew J. Slater; Peter M. Woollard; Matt D. Hall; Simon D. Topp; Xin Yuan; Lon R. Cardon; Stephanie L. Chissoe; Vincent Mooser; Andrew D. Morris; Colin N. A. Palmer; John R. Perry; Timothy M. Frayling; John C. Whittaker; Dawn M. Waterworth

doi:10.2337/db11-0985

Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation

Liling L. Warren, Li Li, Matthew R. Nelson, Margaret G. Ehm, Judong Shen, Dana J. Fraser, Jennifer L. Aponte, Keith L. Nangle, Andrew J. Slater, Peter M. Woollard, Matt D. Hall, Simon D. Topp, Xin Yuan, Lon R. Cardon, Stephanie L. Chissoe, Vincent Mooser, Andrew D. Morris, Colin N. A. Palmer, John R. Perry, Timothy M. FraylingJohn C. Whittaker, Dawn M. Waterworth

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Abstract

Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g., odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted. Diabetes 61:1297-1301, 2012

Original language	English
Pages (from-to)	1297-1301
Number of pages	5
Journal	Diabetes
Volume	61
Issue number	5
DOIs	https://doi.org/10.2337/db11-0985
Publication status	Published - May 2012

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Warren, L. L., Li, L., Nelson, M. R., Ehm, M. G., Shen, J., Fraser, D. J., Aponte, J. L., Nangle, K. L., Slater, A. J., Woollard, P. M., Hall, M. D., Topp, S. D., Yuan, X., Cardon, L. R., Chissoe, S. L., Mooser, V., Morris, A. D., Palmer, C. N. A., Perry, J. R., ... Waterworth, D. M. (2012). Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation. Diabetes, 61(5), 1297-1301. https://doi.org/10.2337/db11-0985

@article{aaf61ad148a44abd8baa35980b078615,

title = "Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation",

abstract = "Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g., odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted. Diabetes 61:1297-1301, 2012",

author = "Warren, {Liling L.} and Li Li and Nelson, {Matthew R.} and Ehm, {Margaret G.} and Judong Shen and Fraser, {Dana J.} and Aponte, {Jennifer L.} and Nangle, {Keith L.} and Slater, {Andrew J.} and Woollard, {Peter M.} and Hall, {Matt D.} and Topp, {Simon D.} and Xin Yuan and Cardon, {Lon R.} and Chissoe, {Stephanie L.} and Vincent Mooser and Morris, {Andrew D.} and Palmer, {Colin N. A.} and Perry, {John R.} and Frayling, {Timothy M.} and Whittaker, {John C.} and Waterworth, {Dawn M.}",

year = "2012",

month = may,

doi = "10.2337/db11-0985",

language = "English",

volume = "61",

pages = "1297--1301",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "5",

}

Warren, LL, Li, L, Nelson, MR, Ehm, MG, Shen, J, Fraser, DJ, Aponte, JL, Nangle, KL, Slater, AJ, Woollard, PM, Hall, MD, Topp, SD, Yuan, X, Cardon, LR, Chissoe, SL, Mooser, V, Morris, AD, Palmer, CNA, Perry, JR, Frayling, TM, Whittaker, JC & Waterworth, DM 2012, 'Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation', Diabetes, vol. 61, no. 5, pp. 1297-1301. https://doi.org/10.2337/db11-0985

TY - JOUR

T1 - Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation

AU - Warren, Liling L.

AU - Li, Li

AU - Nelson, Matthew R.

AU - Ehm, Margaret G.

AU - Shen, Judong

AU - Fraser, Dana J.

AU - Aponte, Jennifer L.

AU - Nangle, Keith L.

AU - Slater, Andrew J.

AU - Woollard, Peter M.

AU - Hall, Matt D.

AU - Topp, Simon D.

AU - Yuan, Xin

AU - Cardon, Lon R.

AU - Chissoe, Stephanie L.

AU - Mooser, Vincent

AU - Morris, Andrew D.

AU - Palmer, Colin N. A.

AU - Perry, John R.

AU - Frayling, Timothy M.

AU - Whittaker, John C.

AU - Waterworth, Dawn M.

PY - 2012/5

Y1 - 2012/5

N2 - Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g., odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted. Diabetes 61:1297-1301, 2012

AB - Increased adiponectin levels have been shown to be associated with a lower risk of type 2 diabetes. To understand the relations between genetic variation at the adiponectin-encoding gene, ADIPOQ, and adiponectin levels, and subsequently its role in disease, we conducted a deep resequencing experiment of ADIPOQ in 14,002 subjects, including 12,514 Europeans, 594 African Americans, and 567 Indian Asians. We identified 296 single nucleotide polymorphisms (SNPs), including 30 amino acid changes, and carried out association analyses in a subset of 3,665 subjects from two independent studies. We confirmed multiple genome-wide association study findings and identified a novel association between a low-frequency SNP (rs17366653) and adiponectin levels (P = 2.2E-17). We show that seven SNPs exert independent effects on adiponectin levels. Together, they explained 6% of adiponectin variation in our samples. We subsequently assessed association between these SNPs and type 2 diabetes in the Genetics of Diabetes Audit and Research in Tayside Scotland (GO-DARTS) study, comprised of 5,145 case and 6,374 control subjects. No evidence of association with type 2 diabetes was found, but we were also unable to exclude the possibility of substantial effects (e.g., odds ratio 95% CI for rs7366653 [0.91-1.58]). Further investigation by large-scale and well-powered Mendelian randomization studies is warranted. Diabetes 61:1297-1301, 2012

U2 - 10.2337/db11-0985

DO - 10.2337/db11-0985

M3 - Article

C2 - 22403302

SN - 0012-1797

VL - 61

SP - 1297

EP - 1301

JO - Diabetes

JF - Diabetes

IS - 5

ER -

Deep Resequencing Unveils Genetic Architecture of ADIPOQ and Identifies a Novel Low-Frequency Variant Strongly Associated With Adiponectin Variation

Abstract

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