Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?
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.
Heid
Iris M
IM
Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. iris.heid@klinik.uni-regensburg.de
Huth
Cornelia
C
Loos
Ruth J F
RJ
Kronenberg
Florian
F
Adamkova
Vera
V
Anand
Sonia S
SS
Ardlie
Kristin
K
Biebermann
Heike
H
Bjerregaard
Peter
P
Boeing
Heiner
H
Bouchard
Claude
C
Ciullo
Marina
M
Cooper
Jackie A
JA
Corella
Dolores
D
Dina
Christian
C
Engert
James C
JC
Fisher
Eva
E
Francès
Francesc
F
Froguel
Philippe
P
Hebebrand
Johannes
J
Hegele
Robert A
RA
Hinney
Anke
A
Hoehe
Margret R
MR
Hu
Frank B
FB
Hubacek
Jaroslav A
JA
Humphries
Steve E
SE
Hunt
Steven C
SC
Illig
Thomas
T
Järvelin
Marjo-Riita
MR
Kaakinen
Marika
M
Kollerits
Barbara
B
Krude
Heiko
H
Kumar
Jitender
J
Lange
Leslie A
LA
Langer
Birgit
B
Li
Shengxu
S
Luchner
Andreas
A
Lyon
Helen N
HN
Meyre
David
D
Mohlke
Karen L
KL
Mooser
Vincent
V
Nebel
Almut
A
Nguyen
Thuy Trang
TT
Paulweber
Bernhard
B
Perusse
Louis
L
Qi
Lu
L
Rankinen
Tuomo
T
Rosskopf
Dieter
D
Schreiber
Stefan
S
Sengupta
Shantanu
S
Sorice
Rossella
R
Suk
Anita
A
Thorleifsson
Gudmar
G
Thorsteinsdottir
Unnur
U
Völzke
Henry
H
Vimaleswaran
Karani S
KS
Wareham
Nicholas J
NJ
Waterworth
Dawn
D
Yusuf
Salim
S
Lindgren
Cecilia
C
McCarthy
Mark I
MI
Lange
Christoph
C
Hirschhorn
Joel N
JN
Laird
Nan
N
Wichmann
H-Erich
HE
D000293:Adolescent; D000328:Adult; D005260:Female; D005828:Genetics, Population; D055106:Genome-Wide Association Study / Q000592:standards*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D012107:Research Design / Q000592:standards*; D055815:Young Adult
C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins