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

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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
Issue number10
Publication statusPublished - Oct 2009
Externally publishedYes


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., Ardlie, K., Biebermann, H., Bjerregaard, P., Boeing, H., Bouchard, C., Ciullo, M., Cooper, J. A., Corella, D., Dina, C., Engert, J. C., Fisher, E., Francè, F., Froguel, P., ... 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].