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.
Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. iris.heid@klinik.uni-regensburg.de
Iris M
IM
Heid
Cornelia
C
Huth
Ruth J F
RJ
Loos
Florian
F
Kronenberg
Vera
V
Adamkova
Sonia S
SS
Anand
Kristin
K
Ardlie
Heike
H
Biebermann
Peter
P
Bjerregaard
Heiner
H
Boeing
Claude
C
Bouchard
Marina
M
Ciullo
Jackie A
JA
Cooper
Dolores
D
Corella
Christian
C
Dina
James C
JC
Engert
Eva
E
Fisher
Francesc
F
Francès
Philippe
P
Froguel
Johannes
J
Hebebrand
Robert A
RA
Hegele
Anke
A
Hinney
Margret R
MR
Hoehe
Frank B
FB
Hu
Jaroslav A
JA
Hubacek
Steve E
SE
Humphries
Steven C
SC
Hunt
Thomas
T
Illig
Marjo-Riita
MR
Järvelin
Marika
M
Kaakinen
Barbara
B
Kollerits
Heiko
H
Krude
Jitender
J
Kumar
Leslie A
LA
Lange
Birgit
B
Langer
Shengxu
S
Li
Andreas
A
Luchner
Helen N
HN
Lyon
David
D
Meyre
Karen L
KL
Mohlke
Vincent
V
Mooser
Almut
A
Nebel
Thuy Trang
TT
Nguyen
Bernhard
B
Paulweber
Louis
L
Perusse
Lu
L
Qi
Tuomo
T
Rankinen
Dieter
D
Rosskopf
Stefan
S
Schreiber
Shantanu
S
Sengupta
Rossella
R
Sorice
Anita
A
Suk
Gudmar
G
Thorleifsson
Unnur
U
Thorsteinsdottir
Henry
H
Völzke
Karani S
KS
Vimaleswaran
Nicholas J
NJ
Wareham
Dawn
D
Waterworth
Salim
S
Yusuf
Cecilia
C
Lindgren
Mark I
MI
McCarthy
Christoph
C
Lange
Joel N
JN
Hirschhorn
Nan
N
Laird
H-Erich
HE
Wichmann
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