Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?

Title: Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?
Author(s): 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
Frances, F
Froguel, P
Hebebrand, J
Hegele, RA
Hinney, A
Hoehe, MR
Hu, FB
Hubacek, JA
Humphries, SE
Hunt, SC
Illig, T
Jarvelin, M-R
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
Voelzke, H
Vimaleswaran, KS
Wareham, NJ
Waterworth, D
Yusuf, S
Lindgren, C
McCarthy, MI
Lange, C
Hirschhorn, JN
Laird, N
Wichmann, H-E
Item Type: Journal Article
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 (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≥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 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.
Publication Date: 23-Oct-2009
Date of Acceptance: 22-Sep-2009
ISSN: 1553-7390
Publisher: Public Library of Science
Journal / Book Title: PLOS Genetics
Volume: 5
Issue: 10
Copyright Statement: © 2009 Heid et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: G0600331
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Genetics, Population
Genome-Wide Association Study
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Middle Aged
Polymorphism, Genetic
Research Design
Young Adult
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Genetics, Population
Polymorphism, Genetic
Research Design
Middle Aged
Genome-Wide Association Study
Young Adult
Developmental Biology
0604 Genetics
Publication Status: Published
Article Number: ARTN e1000694
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care

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