title: The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts.
abstract: 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.
authors.affiliation: Program in Genomics, Divisions of Genetics and Endocrinology, Children's Hospital, Boston, Massachusetts, USA. helen.lyon@childrens.harvard.edu
authors.forename: Helen N
authors.initials: HN
authors.lastname: Lyon
authors.forename: Valur
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authors.lastname: Hinney
authors.forename: Iris M
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authors.forename: Steinunn
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authors.lastname: Kong
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authors.lastname: Gulcher
authors.forename: Thuy Trang
authors.initials: TT
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authors.lastname: Meitinger
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authors.lastname: Brönner
authors.forename: Winfried
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authors.lastname: Soto-Quiros
authors.forename: Lydiana
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authors.lastname: Avila
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authors.lastname: Klanderman
authors.forename: Benjamin A
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authors.lastname: Raby
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Scott T
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authors.lastname: Weiss
authors.forename: Nan
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authors.lastname: Laird
authors.forename: Xiao
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authors.lastname: Ding
authors.forename: Leif
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authors.lastname: Groop
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Bo
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authors.lastname: Isomaa
authors.forename: Kristina
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authors.lastname: Bengtsson
authors.forename: Johannah L
authors.initials: JL
authors.lastname: Butler
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Caren
authors.initials: C
authors.lastname: Vollmert
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.forename: H Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Christoph
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authors.lastname: Lange
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: 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
chemical_list: C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins