title: Controversial association results for INSIG2 on body mass index may be explained by interactions with age and with MC4R.
abstract: Among the single-nucleotide polymorphisms (SNPs) previously reported to be associated with body mass index (BMI) and obesity, we focus on a common risk variant rs7566605 upstream of the insulin-induced gene 2 (INSIG2) gene and a rare protective variant rs2229616 on the melanocortin-4 receptor (MC4R) gene. INSIG2 is involved in adipogenesis and MC4R effects hormonal appetite control in response to the amount of adipose tissue. The influence of rs2229616 (MC4R) on BMI and obesity has been confirmed repeatedly and insight into the underlying mechanism provided. However, a main effect of rs7566605 (INSIG2) is under debate because of inconsistent replications of association. Interaction of rs7566605 with age may offer an explanation. SNP-age and SNP-SNP interaction models were tested on independent individuals from three population-based longitudinal cohorts, restricting the analysis to an observed age of 25-74 years. KORA S3/F3, KORA S4/F4 (Augsburg, Germany, 1994-2005, 1999-2008), and Framingham-Offspring data (Framingham, USA, 1971-2001) were analysed, with a total sample size of N=6926 in the joint analysis. The effect of interaction between rs7566605 and age on BMI and obesity status is significant and consistent across studies. This new evidence for rs7566605 (INSIG2) complements previous research. In addition, the interaction effect of rs7566605 with the MC4R variant rs2229616 on BMI was observed. This effect size was three times larger than that in a previously reported single-locus main effect of rs2229616. This leads to the conclusion that SNP-age or SNP-SNP interactions can mask genetic effects for complex diseases if left unaccounted for.
authors: Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany.
authors: Dörthe
authors: D
authors: Malzahn
authors: 1] Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology and Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Neuherberg, Germany [3] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors: Martina
authors: M
authors: Müller-Nurasyid
authors: 1] Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
authors: Iris M
authors: IM
authors: Heid
authors: 1] Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-University, Munich, Germany [3] Klinikum Großhadern, Munich, Germany.
authors: H-Erich
authors: HE
authors: Wichmann
authors: Department of Genetic Epidemiology, University Medical Center, Georg-August-University, Göttingen, Germany.
authors: Heike
authors: H
authors: Bickeböller
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C470072:MC4R protein, human; D008565:Membrane Proteins; D044105:Receptor, Melanocortin, Type 4