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

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., Francès, F., Froguel, P., Hebebrand, J., Hegele, R. A., Hinney, A., Hoehe, M. R., Hu, F. B., Hubacek, J. A., Humphries, S. E., Hunt, S. C., Illig, T., Järvelin, M.-R., Kaakinen, M., Kollerits, B., Krude, H., Kumar, J., Lange, L. A., Langer, B., Li, S., Luchner, A., Lyon, H. N., Meyre, D., Mohlke, K. L., Mooser, V., Nebel, A., Nguyen, T. T., 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, K. S. ORCID: https://orcid.org/0000-0002-8485-8930, Wareham, N. J., Waterworth, D., Yusuf, S., Lindgren, C., McCarthy, M. I., Lange, C., Hirschhorn, J. N., Laird, N. and 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. ISSN 1553-7404 doi: 10.1371/journal.pgen.1000694

Abstract/Summary

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) 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 I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 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> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) 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 may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/34663
Item Type	Article
Refereed	Yes
Divisions	No Reading authors. Back catalogue items Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Chemistry, Food and Pharmacy > Department of Food and Nutritional Sciences > Human Nutrition Research Group
Publisher	Public Library of Science
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