The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts.
A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.
Lyon
Helen N
HN
Program in Genomics, Divisions of Genetics and Endocrinology, Children's Hospital, Boston, Massachusetts, USA. helen.lyon@childrens.harvard.edu
Emilsson
Valur
V
Hinney
Anke
A
Heid
Iris M
IM
Lasky-Su
Jessica
J
Zhu
Xiaofeng
X
Thorleifsson
Gudmar
G
Gunnarsdottir
Steinunn
S
Walters
G Bragi
GB
Thorsteinsdottir
Unnur
U
Kong
Augustine
A
Gulcher
Jeffrey
J
Nguyen
Thuy Trang
TT
Scherag
André
A
Pfeufer
Arne
A
Meitinger
Thomas
T
Brönner
Günter
G
Rief
Winfried
W
Soto-Quiros
Manuel E
ME
Avila
Lydiana
L
Klanderman
Barbara
B
Raby
Benjamin A
BA
Silverman
Edwin K
EK
Weiss
Scott T
ST
Laird
Nan
N
Ding
Xiao
X
Groop
Leif
L
Tuomi
Tiinamaija
T
Isomaa
Bo
B
Bengtsson
Kristina
K
Butler
Johannah L
JL
Cooper
Richard S
RS
Fox
Caroline S
CS
O'Donnell
Christopher J
CJ
Vollmert
Caren
C
Celedón
Juan C
JC
Wichmann
H Erich
HE
Hebebrand
Johannes
J
Stefansson
Kari
K
Lange
Christoph
C
Hirschhorn
Joel N
JN
D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002648:Child; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins