Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: Does heterogeneity of estimates relate to study design?

Iris M. Heid, Cornelia Huth, Ruth J F Loos, Florian Kronenberg, Vera Adamkova, Sonia S. Anand, Kristin Ardlie, Heike Biebermann, Peter Bjerregaard, Heiner Boeing, Claude Bouchard, Marina Ciullo, Jackie A. Cooper, Dolores Corella, Christian Dina, James C. Engert, Eva Fisher, Francec Francè, Philippe Froguel, Johannes HebebrandRobert A. Hegele, Anke Hinney, Margret R. Hoehe, Frank B. Hu, Jaroslav A. Hubacek, Steve E. Humphries, Steven Hunt, Thomas Illig, Marjo Riita Järvelin, Marika Kaakinen, Barbara Kollerits, Heiko Krude, Jitender Kumar, Leslie A. Lange, Birgit Langer, Shengxu Li, Andreas Luchner, Helen N. Lyon, David Meyre, Karen L. Mohlke, Vincent Mooser, Almut Nebel, Thuy Trang Nguyen, Bernhard Paulweber, Louis Perusse, Lu Qi, Tuomo Rankinen, Dieter Rosskopf, Stefan Schreiber, Shantanu Sengupta, Rossella Sorice, Anita Suk, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Henry Völzke, Karani S. Vimaleswaran, Nicholas J. Wareham, Dawn Waterworth, Salim Yusuf, Cecilia Lindgren, Mark I. McCarthy, Christoph Lange, Joel N. Hirschhorn, Nan Laird, H. Erich Wichmann

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (pvalue = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs maymask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

Original languageEnglish
Article numbere1000694
JournalPLoS Genetics
Volume5
Issue number10
DOIs
Publication statusPublished - Oct 2009
Externally publishedYes

Fingerprint

obesity
meta-analysis
Meta-Analysis
Obesity
experimental design
Population
polymorphism
odds ratio
genotype
Odds Ratio
Genotype
health status
Genome-Wide Association Study
Genetic Association Studies
Health Status
genome
statistics
genetic polymorphism
gene

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Heid, I. M., Huth, C., Loos, R. J. F., Kronenberg, F., Adamkova, V., Anand, S. S., ... Wichmann, H. E. (2009). Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: Does heterogeneity of estimates relate to study design? PLoS Genetics, 5(10), [e1000694]. https://doi.org/10.1371/journal.pgen.1000694

Meta-analysis of the INSIG2 association with obesity including 74,345 individuals : Does heterogeneity of estimates relate to study design? / Heid, Iris M.; Huth, Cornelia; Loos, Ruth J F; Kronenberg, Florian; Adamkova, Vera; Anand, Sonia S.; Ardlie, Kristin; Biebermann, Heike; Bjerregaard, Peter; Boeing, Heiner; Bouchard, Claude; Ciullo, Marina; Cooper, Jackie A.; Corella, Dolores; Dina, Christian; Engert, James C.; Fisher, Eva; Francè, Francec; Froguel, Philippe; Hebebrand, Johannes; Hegele, Robert A.; Hinney, Anke; Hoehe, Margret R.; Hu, Frank B.; Hubacek, Jaroslav A.; Humphries, Steve E.; Hunt, Steven; Illig, Thomas; Järvelin, Marjo Riita; Kaakinen, Marika; Kollerits, Barbara; Krude, Heiko; Kumar, Jitender; Lange, Leslie A.; Langer, Birgit; Li, Shengxu; Luchner, Andreas; Lyon, Helen N.; Meyre, David; Mohlke, Karen L.; Mooser, Vincent; Nebel, Almut; Nguyen, Thuy Trang; Paulweber, Bernhard; Perusse, Louis; Qi, Lu; Rankinen, Tuomo; Rosskopf, Dieter; Schreiber, Stefan; Sengupta, Shantanu; Sorice, Rossella; Suk, Anita; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Völzke, Henry; Vimaleswaran, Karani S.; Wareham, Nicholas J.; Waterworth, Dawn; Yusuf, Salim; Lindgren, Cecilia; McCarthy, Mark I.; Lange, Christoph; Hirschhorn, Joel N.; Laird, Nan; Wichmann, H. Erich.

In: PLoS Genetics, Vol. 5, No. 10, e1000694, 10.2009.

Research output: Contribution to journalArticle

Heid, IM, Huth, C, Loos, RJF, Kronenberg, F, Adamkova, V, Anand, SS, Ardlie, K, Biebermann, H, Bjerregaard, P, Boeing, H, Bouchard, C, Ciullo, M, Cooper, JA, Corella, D, Dina, C, Engert, JC, Fisher, E, Francè, F, Froguel, P, Hebebrand, J, Hegele, RA, Hinney, A, Hoehe, MR, Hu, FB, Hubacek, JA, Humphries, SE, Hunt, S, Illig, T, Järvelin, MR, Kaakinen, M, Kollerits, B, Krude, H, Kumar, J, Lange, LA, Langer, B, Li, S, Luchner, A, Lyon, HN, Meyre, D, Mohlke, KL, Mooser, V, Nebel, A, Nguyen, TT, Paulweber, B, Perusse, L, Qi, L, Rankinen, T, Rosskopf, D, Schreiber, S, Sengupta, S, Sorice, R, Suk, A, Thorleifsson, G, Thorsteinsdottir, U, Völzke, H, Vimaleswaran, KS, Wareham, NJ, Waterworth, D, Yusuf, S, Lindgren, C, McCarthy, MI, Lange, C, Hirschhorn, JN, Laird, N & Wichmann, HE 2009, 'Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: Does heterogeneity of estimates relate to study design?', PLoS Genetics, vol. 5, no. 10, e1000694. https://doi.org/10.1371/journal.pgen.1000694
Heid, Iris M. ; Huth, Cornelia ; Loos, Ruth J F ; Kronenberg, Florian ; Adamkova, Vera ; Anand, Sonia S. ; Ardlie, Kristin ; Biebermann, Heike ; Bjerregaard, Peter ; Boeing, Heiner ; Bouchard, Claude ; Ciullo, Marina ; Cooper, Jackie A. ; Corella, Dolores ; Dina, Christian ; Engert, James C. ; Fisher, Eva ; Francè, Francec ; Froguel, Philippe ; Hebebrand, Johannes ; Hegele, Robert A. ; Hinney, Anke ; Hoehe, Margret R. ; Hu, Frank B. ; Hubacek, Jaroslav A. ; Humphries, Steve E. ; Hunt, Steven ; Illig, Thomas ; Järvelin, Marjo Riita ; Kaakinen, Marika ; Kollerits, Barbara ; Krude, Heiko ; Kumar, Jitender ; Lange, Leslie A. ; Langer, Birgit ; Li, Shengxu ; Luchner, Andreas ; Lyon, Helen N. ; Meyre, David ; Mohlke, Karen L. ; Mooser, Vincent ; Nebel, Almut ; Nguyen, Thuy Trang ; Paulweber, Bernhard ; Perusse, Louis ; Qi, Lu ; Rankinen, Tuomo ; Rosskopf, Dieter ; Schreiber, Stefan ; Sengupta, Shantanu ; Sorice, Rossella ; Suk, Anita ; Thorleifsson, Gudmar ; Thorsteinsdottir, Unnur ; Völzke, Henry ; Vimaleswaran, Karani S. ; Wareham, Nicholas J. ; Waterworth, Dawn ; Yusuf, Salim ; Lindgren, Cecilia ; McCarthy, Mark I. ; Lange, Christoph ; Hirschhorn, Joel N. ; Laird, Nan ; Wichmann, H. Erich. / Meta-analysis of the INSIG2 association with obesity including 74,345 individuals : Does heterogeneity of estimates relate to study design?. In: PLoS Genetics. 2009 ; Vol. 5, No. 10.
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title = "Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: Does heterogeneity of estimates relate to study design?",
abstract = "The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41{\%} (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11{\%} (p-value = 0.33) and an OR of 1.10 (pvalue = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4{\%} to 12.5{\%}, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs maymask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.",
author = "Heid, {Iris M.} and Cornelia Huth and Loos, {Ruth J F} and Florian Kronenberg and Vera Adamkova and Anand, {Sonia S.} and Kristin Ardlie and Heike Biebermann and Peter Bjerregaard and Heiner Boeing and Claude Bouchard and Marina Ciullo and Cooper, {Jackie A.} and Dolores Corella and Christian Dina and Engert, {James C.} and Eva Fisher and Francec Franc{\`e} and Philippe Froguel and Johannes Hebebrand and Hegele, {Robert A.} and Anke Hinney and Hoehe, {Margret R.} and Hu, {Frank B.} and Hubacek, {Jaroslav A.} and Humphries, {Steve E.} and Steven Hunt and Thomas Illig and J{\"a}rvelin, {Marjo Riita} and Marika Kaakinen and Barbara Kollerits and Heiko Krude and Jitender Kumar and Lange, {Leslie A.} and Birgit Langer and Shengxu Li and Andreas Luchner and Lyon, {Helen N.} and David Meyre and Mohlke, {Karen L.} and Vincent Mooser and Almut Nebel and Nguyen, {Thuy Trang} and Bernhard Paulweber and Louis Perusse and Lu Qi and Tuomo Rankinen and Dieter Rosskopf and Stefan Schreiber and Shantanu Sengupta and Rossella Sorice and Anita Suk and Gudmar Thorleifsson and Unnur Thorsteinsdottir and Henry V{\"o}lzke and Vimaleswaran, {Karani S.} and Wareham, {Nicholas J.} and Dawn Waterworth and Salim Yusuf and Cecilia Lindgren and McCarthy, {Mark I.} and Christoph Lange and Hirschhorn, {Joel N.} and Nan Laird and Wichmann, {H. Erich}",
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T1 - Meta-analysis of the INSIG2 association with obesity including 74,345 individuals

T2 - Does heterogeneity of estimates relate to study design?

AU - Heid, Iris M.

AU - Huth, Cornelia

AU - Loos, Ruth J F

AU - Kronenberg, Florian

AU - Adamkova, Vera

AU - Anand, Sonia S.

AU - Ardlie, Kristin

AU - Biebermann, Heike

AU - Bjerregaard, Peter

AU - Boeing, Heiner

AU - Bouchard, Claude

AU - Ciullo, Marina

AU - Cooper, Jackie A.

AU - Corella, Dolores

AU - Dina, Christian

AU - Engert, James C.

AU - Fisher, Eva

AU - Francè, Francec

AU - Froguel, Philippe

AU - Hebebrand, Johannes

AU - Hegele, Robert A.

AU - Hinney, Anke

AU - Hoehe, Margret R.

AU - Hu, Frank B.

AU - Hubacek, Jaroslav A.

AU - Humphries, Steve E.

AU - Hunt, Steven

AU - Illig, Thomas

AU - Järvelin, Marjo Riita

AU - Kaakinen, Marika

AU - Kollerits, Barbara

AU - Krude, Heiko

AU - Kumar, Jitender

AU - Lange, Leslie A.

AU - Langer, Birgit

AU - Li, Shengxu

AU - Luchner, Andreas

AU - Lyon, Helen N.

AU - Meyre, David

AU - Mohlke, Karen L.

AU - Mooser, Vincent

AU - Nebel, Almut

AU - Nguyen, Thuy Trang

AU - Paulweber, Bernhard

AU - Perusse, Louis

AU - Qi, Lu

AU - Rankinen, Tuomo

AU - Rosskopf, Dieter

AU - Schreiber, Stefan

AU - Sengupta, Shantanu

AU - Sorice, Rossella

AU - Suk, Anita

AU - Thorleifsson, Gudmar

AU - Thorsteinsdottir, Unnur

AU - Völzke, Henry

AU - Vimaleswaran, Karani S.

AU - Wareham, Nicholas J.

AU - Waterworth, Dawn

AU - Yusuf, Salim

AU - Lindgren, Cecilia

AU - McCarthy, Mark I.

AU - Lange, Christoph

AU - Hirschhorn, Joel N.

AU - Laird, Nan

AU - Wichmann, H. Erich

PY - 2009/10

Y1 - 2009/10

N2 - The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (pvalue = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs maymask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

AB - The INSIG2 rs7566605 polymorphism was identified for obesity (BMI≥30 kg/m2) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I2 measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I2 measure of 11% (p-value = 0.33) and an OR of 1.10 (pvalue = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI≥32.5, 35.0, 37.5, 40.0 kg/m2 versus BMI<25 kg/m2) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs maymask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

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