Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data

Nicholas J. Timpson; Cecilia M. Lindgren; Michael N. Weedon; Joshua Randall; Willem H. Ouwehand; David P. Strachan; N. William Rayner; Mark Walker; Graham A. Hitman; Alex S.F. Doney; Colin N.A. Palmer; Andrew D. Morris; Andrew T. Hattersley; Eleftheria Zeggini; Timothy M. Frayling; Mark I. McCarthy

doi:10.2337/db08-0906

Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data

Nicholas J. Timpson
, Cecilia M. Lindgren
, Michael N. Weedon
, Joshua Randall
, Willem H. Ouwehand
, David P. Strachan
, N. William Rayner
, Mark Walker
, Graham A. Hitman
, Alex S.F. Doney
, Colin N.A. Palmer
, Andrew D. Morris
, Andrew T. Hattersley
, Eleftheria Zeggini
, Timothy M. Frayling
, Mark I. McCarthy

Publikation: Beitrag in Fachzeitschrift › Artikel › Begutachtung

104 Zitate (Scopus)

Abstract

OBJECTIVE-This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome- wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS-We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into "obese" and "nonobese") according to median BMI (30.2 kg/m²). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS-In the "obese-type 2 diabetes" scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 × 10 ^-13), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the "nonobese" scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 × 10^-14). These patterns, confimed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: P_DIFF = 1.4 × 10^-7; TCF7L2: P_DIFF = 4.0 X 10^-6). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR _obese 1.08 [1.011.15]; RR_nonobese 1.18 [1.10-1.27]: _PdiFF = 0.04). CONCLUSIONS-This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.

Originalsprache	Englisch
Seiten (von - bis)	505-510
Seitenumfang	6
Fachzeitschrift	Diabetes
Jahrgang	58
Ausgabenummer	2
DOIs	https://doi.org/10.2337/db08-0906
Publikationsstatus	Veröffentlicht - Feb. 2009
Extern publiziert	Ja

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10.2337/db08-0906

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Timpson, N. J., Lindgren, C. M., Weedon, M. N., Randall, J., Ouwehand, W. H., Strachan, D. P., Rayner, N. W., Walker, M., Hitman, G. A., Doney, A. S. F., Palmer, C. N. A., Morris, A. D., Hattersley, A. T., Zeggini, E., Frayling, T. M., & McCarthy, M. I. (2009). Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes, 58(2), 505-510. https://doi.org/10.2337/db08-0906

@article{9d4f1bad2e904fb5b5f3a183b5096f80,

title = "Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data",

abstract = "OBJECTIVE-This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome- wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS-We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into {"}obese{"} and {"}nonobese{"}) according to median BMI (30.2 kg/m2). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS-In the {"}obese-type 2 diabetes{"} scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95\% CI 1.34-1.66], P = 1.3 × 10 -13), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the {"}nonobese{"} scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 × 10-14). These patterns, confimed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: PDIFF = 1.4 × 10-7; TCF7L2: PDIFF = 4.0 X 10-6). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR obese 1.08 [1.011.15]; RRnonobese 1.18 [1.10-1.27]: PdiFF = 0.04). CONCLUSIONS-This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.",

author = "Timpson, \{Nicholas J.\} and Lindgren, \{Cecilia M.\} and Weedon, \{Michael N.\} and Joshua Randall and Ouwehand, \{Willem H.\} and Strachan, \{David P.\} and Rayner, \{N. William\} and Mark Walker and Hitman, \{Graham A.\} and Doney, \{Alex S.F.\} and Palmer, \{Colin N.A.\} and Morris, \{Andrew D.\} and Hattersley, \{Andrew T.\} and Eleftheria Zeggini and Frayling, \{Timothy M.\} and McCarthy, \{Mark I.\}",

year = "2009",

month = feb,

doi = "10.2337/db08-0906",

language = "English",

volume = "58",

pages = "505--510",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "2",

}

Timpson, NJ, Lindgren, CM, Weedon, MN, Randall, J, Ouwehand, WH, Strachan, DP, Rayner, NW, Walker, M, Hitman, GA, Doney, ASF, Palmer, CNA, Morris, AD, Hattersley, AT, Zeggini, E, Frayling, TM & McCarthy, MI 2009, 'Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data', Diabetes, Jg. 58, Nr. 2, S. 505-510. https://doi.org/10.2337/db08-0906

TY - JOUR

T1 - Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data

AU - Timpson, Nicholas J.

AU - Lindgren, Cecilia M.

AU - Weedon, Michael N.

AU - Randall, Joshua

AU - Ouwehand, Willem H.

AU - Strachan, David P.

AU - Rayner, N. William

AU - Walker, Mark

AU - Hitman, Graham A.

AU - Doney, Alex S.F.

AU - Palmer, Colin N.A.

AU - Morris, Andrew D.

AU - Hattersley, Andrew T.

AU - Zeggini, Eleftheria

AU - Frayling, Timothy M.

AU - McCarthy, Mark I.

PY - 2009/2

Y1 - 2009/2

N2 - OBJECTIVE-This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome- wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS-We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into "obese" and "nonobese") according to median BMI (30.2 kg/m2). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS-In the "obese-type 2 diabetes" scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 × 10 -13), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the "nonobese" scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 × 10-14). These patterns, confimed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: PDIFF = 1.4 × 10-7; TCF7L2: PDIFF = 4.0 X 10-6). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR obese 1.08 [1.011.15]; RRnonobese 1.18 [1.10-1.27]: PdiFF = 0.04). CONCLUSIONS-This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.

AB - OBJECTIVE-This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome- wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS-We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into "obese" and "nonobese") according to median BMI (30.2 kg/m2). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS-In the "obese-type 2 diabetes" scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 × 10 -13), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the "nonobese" scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 × 10-14). These patterns, confimed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: PDIFF = 1.4 × 10-7; TCF7L2: PDIFF = 4.0 X 10-6). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone (RR obese 1.08 [1.011.15]; RRnonobese 1.18 [1.10-1.27]: PdiFF = 0.04). CONCLUSIONS-This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes.

UR - https://www.scopus.com/pages/publications/63249135474

U2 - 10.2337/db08-0906

DO - 10.2337/db08-0906

M3 - Article

C2 - 19056611

AN - SCOPUS:63249135474

SN - 0012-1797

VL - 58

SP - 505

EP - 510

JO - Diabetes

JF - Diabetes

IS - 2

ER -

Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data

Abstract

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