Cited by 732Genetic Associations and EpidemiologyGenetics and Physical PerformanceNutrition, Genetics, and Disease

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A common genetic variant is associated with adult and childhood obesity.

Herbert, Alan, Gerry, Norman P., McQueen, Matthew B., Heid, Iris M., Pfeufer, Arne, Illig, Thomas, Wichmann, H.-Erich, Meitinger, Thomas, Hunter, David, Hu, Frank B., Colditz, Graham, Hinney, Anke, Hebebrand, Johannes, Koberwitz, Kerstin, Zhu, Xiaofeng, Cooper, Richard, Ardlie, Kristin, Lyon, Helen, Hirschhorn, Joel N., Laird, Nan M., Lenburg, Marc E., Lange, Christoph, Christman, Michael F.·2006·Science

DOI 10.1126/science.1124779

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Abstract

Obesity is a heritable trait and a risk factor for many common diseases such as type 2 diabetes, heart disease, and hypertension. We used a dense whole-genome scan of DNA samples from the Framingham Heart Study participants to identify a common genetic variant near the INSIG2 gene associated with obesity. We have replicated the finding in four separate samples composed of individuals of Western European ancestry, African Americans, and children. The obesity-predisposing genotype is present in 10% of individuals. Our study suggests that common genetic polymorphisms are important determinants of obesity.

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Background
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“Additionally, SNPs near the human INSIG2 locus have been associated with obesity and lipid metabolism (Do et al., 2010; Herbert et al., 2006; Hotta et al., 2008; Kaulfers et al., 2015).”
Longitudinal analysis reveals transition barriers between dominant ecological states in the gut microbiome
Levy, R., Magis, A. T., Earls, J. C., Manor, O., Wilmanski, T. M., Lovejoy, J. C., Gibbons, S. M., Omenn, G. S., Hood, L., & Price, N. D. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922498117 · Cited by 70
“Furthermore, integrating molecular profiling into ongoing longitudinal cohort studies, such as the Framingham Heart Study, has been successful in identifying genomic drivers of diseases like obesity (4).”
Obesity Prevention
Dubé, L. (2010) · Elsevier eBooks · doi:10.1016/c2009-0-01687-0 · Cited by 74
Obesity and polymorphisms in genes regulating human adipose tissue
Dahlman, I. A., & Arner, P. (2007) · International Journal of Obesity · doi:10.1038/sj.ijo.0803657 · Cited by 71
Genetics of Childhood Obesity
Zhao, J., & Grant, S. F. A. (2011) · Journal of Obesity · doi:10.1155/2011/845148 · Cited by 75
“We have an ongoing GWAS of BMI variation in children so we are in position to query these SNPs in our dataset of in excess of 6,000 children with measures of BMI [99].”
BackgroundResultInfluential
Genetic Mapping at 3-Kilobase Resolution Reveals Inositol 1,4,5-Triphosphate Receptor 3 as a Risk Factor for Type 1 Diabetes in Sweden
Roach, J. C., Deutsch, K., Li, S., Siegel, A. F., Bekris, L. M., Einhaus, D., Sheridan, C. M., Glusman, G., Hood, L., Lernmark, Å., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/507876 · Cited by 70
Is Obesity Our Genetic Legacy?
Blakemore, A. I. F., & Froguel, P. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1676 · Cited by 71
“In addition to the studies reported previously, there are reports of association with the genes encoding b-catenin-like protein 1 (69), insulin-induced gene 2 (70) myotubularin-related protein-9 (71), ganglioside induced differentiation associated protein 1, and somastatin-receptor-2 (72), but these await independent…”
Result
Heritability of Response Inhibition in Children
Schachar, R. J., Forget‐Dubois, N., Dionne, G., Boivin, M., & Robaey, P. (2010) · Journal of the International Neuropsychological Society · doi:10.1017/s1355617710001463 · Cited by 72
“The approach has been successful in studies of cardiac disease and QT interval (Arking et al., 2006), obesity (Herbert et al., 2006), and fetal hemoglobin level (Menzel & Thein, 2009).”
Organized sport and physical activity participation and body mass index in children and youth: A longitudinal study
Cairney, J., & Veldhuizen, S. (2017) · Preventive Medicine Reports · doi:10.1016/j.pmedr.2017.04.005 · Cited by 69
“(Robertson et al., 1999) and genetics (e.g., Herbert et al., 2006).”
Background
Genetic Susceptibility to Peripheral Arterial Disease: A Dark Corner in Vascular Biology
Knowles, J. W., Assimes, T. L., Li, J. Z., Quertermous, T., & Cooke, J. P. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000282199.66398.8c · Cited by 68
Obesity and diabetes genes are associated with being born small for gestational age: Results from the Auckland Birthweight Collaborative study
Morgan, A. R., Thompson, J., Murphy, R., Black, P., Lam, W.-J., Ferguson, L. R., & Mitchell, E. A. (2010) · BMC Medical Genetics · doi:10.1186/1471-2350-11-125 · Cited by 70
“INSIG2 2 Obesity GWAS [68,69] rs7566605 10 kb upstream”
Background
Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4Rgenes to obesity in Mexican children
Mejía‐Benítez, A., Klünder‐Klünder, M., Yengo, L., Meyre, D., Aradillas-García, C., de la Cruz, E., Pérez-Luque, E. L., Malacara, J. M., Garay, M. E., Peralta‐Romero, J., et al. (2013) · BMC Medical Genetics · doi:10.1186/1471-2350-14-21 · Cited by 66
Is the Gene-Environment Interaction Paradigm Relevant to Genome-Wide Studies? The Case of Education and Body Mass Index
Boardman, J. D., Domingue, B. W., Blalock, C. L., Haberstick, B. C., Harris, K. M., & McQueen, M. B. (2013) · Demography · doi:10.1007/s13524-013-0259-4 · Cited by 65
“This model is comparable to the FBAT approach (Laird et al. 2000; Laird and Lange 2006), which has been successfully used to identify SNPs linked to obesity (Herbert et al. 2006).”
Challenges in reproducibility of genetic association studies: lessons learned from the obesity field
Li, A., & Meyre, D. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.82 · Cited by 68
Association of FTO With Obesity-Related Traits in the Cebu Longitudinal Health and Nutrition Survey (CLHNS) Cohort
Marvelle, A. F., Lange, L. A., Li, Q., Adair, L. S., & Mohlke, K. L. (2008) · Diabetes · doi:10.2337/db07-1700 · Cited by 63
“Variants in FTO and INSIG2, identified through GWA studies, were also genotyped (2, 8).”
Background
Efficient Association Mapping of Quantitative Trait Loci with Selective Genotyping
Huang, B. E., & Lin, D. Y. (2007) · The American Journal of Human Genetics · doi:10.1086/512727 · Cited by 64
A Systems Biology Approach to Drug Discovery
Zhu, J., Zhang, B., & Schadt, E. E. (2008) · Advances in genetics · doi:10.1016/s0065-2660(07)00421-x · Cited by 63
Genetic risk sum score comprised of common polygenic variation is associated with body mass index
Peterson, R. E., MAES, H. H. M., Holmans, P., Sanders, A. R., Levinson, D. F., Shi, J., Kendler, K. S., Gejman, P. V., & Webb, B. T. (2010) · Human Genetics · doi:10.1007/s00439-010-0917-1 · Cited by 64
“The first common single nucleotide polymorphisms (SNPs) associated with BMI and common obesity were in the fat mass and obesity-associated (FTO) gene and near melanocortin 4 receptor (MC4R) and have been widely replicated (Frayling et al. 2007; Dina et al. 2007; Herbert et al. 2006; Scuteri et al. 2007; Hinney et al.…”
Background
Association of Variants of the Interleukin-23 Receptor Gene With Susceptibility to Pediatric Crohn’s Disease
Baldassano, R. N., Bradfield, J. P., Monos, D. S., Kim, C. E., Glessner, J., Casalunovo, T., Frackelton, E. C., Otieno, F. G., Kanterakis, S., Shaner, J. L., et al. (2007) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2007.04.024 · Cited by 63
Atherosclerosis
Miller, D. T., Ridker, P. M., Libby, P., & Kwiatkowski, D. J. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.12.045 · Cited by 64
The genome revolution and its role in understanding complex diseases
Hofker, M. H., Fu, J., & Wijmenga, C. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.002 · Cited by 65
Progress in the genetics of common obesity: size matters
Li, S., & Loos, R. J. F. (2008) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3282f6a7f3 · Cited by 58
Meta-analysis of genome-wide association studies for circulating phylloquinone concentrations
Dashti, H. S., Shea, M. K., Smith, C. E., Tanaka, T., Hruby, A., Richardson, K., Wang, T. J., Nalls, M. A., Guo, X., Liu, Y., et al. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.093146 · Cited by 61
INSIG-2 promoter polymorphism and obesity related phenotypes: association study in 1428 members of 248 families
Hall, D. H., Rahman, T., Avery, P. J., & Keavney, B. D. (2006) · BMC Medical Genetics · doi:10.1186/1471-2350-7-83 · Cited by 61
“31, which is in good agreement with the Caucasian populations genotyped in the study by Herbert et al [5].”
BackgroundResultInfluential
Studies of Metabolic Phenotypic Correlates of 15 Obesity Associated Gene Variants
Sandholt, C. H., Vestmar, M. A., Bille, D. S., Borglykke, A., Almind, K., Hansen, L., Sandbæk, A., Lauritzen, T., Witte, D. R., Jørgensen, T., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023531 · Cited by 62
“Several GWAS of body mass index (BMI) and/or obesity have been performed, and the first wave resulted in the suggestion of SNPs in/ near the INSIG2 [4], FTO [5], PFKP [6], and CTNNBL1 [7] genes, however, only SNPs in the FTO locus were convincingly replicated in other GWAS [6,8] and independent replication studies [9–…”
Result
Gene–gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics
Liou, Y.-J., Bai, Y. M., Lin, E., Chen, J.-Y., Chen, T.-T., Hong, C.-J., & Tsai, S.-J. (2010) · The Pharmacogenomics Journal · doi:10.1038/tpj.2010.74 · Cited by 60
“, in a genome-wide association study, demonstrated a genetic variant (rs7566605) situated 10-kb upstream of the transcription start site of INSIG2 was associated with obesity that was replicated by several replication studies, though not by all”
Background
Influence of common variants near INSIG2, in FTO, and near MC4R genes on overweight and the metabolic profile in adolescence: the TRAILS (TRacking Adolescents’ Individual Lives Survey) Study
Liem, E. T., Vonk, J. M., Pieter, J. J. S., van der Steege, G., Oosterom, E., Stolk, R. P., & Snieder, H. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28186 · Cited by 59
“Although it was shown that variation near INSIG2 predicted the amount of weight loss during treatment of obese children and adolescents (8), the association between the variant near INSIG2 and overweight was not conﬁrmed by other 1 From the Departments of Pediatrics–Beatrix Children’s Hospital (ETL and PJJS), Epidemio…”
BackgroundMethodInfluential
Identifying genetic interactions in genome‐wide data using Bayesian networks
Jiang, X., Barmada, M. M., & Visweswaran, S. (2010) · Genetic Epidemiology · doi:10.1002/gepi.20514 · Cited by 60
“Often, the data from such studies are analyzed with single-locus methods [Coon et al., 2007; Herbert et al., 2006; Lambert et al., 2009; Reiman et al., 2007].”
Method
Heterozygous rare genetic variants in non-syndromic early-onset obesity
Serra‐Juhé, C., Martos‐Moreno, G. Á., de Pieri, F. B., Flores, R., Chowen, J. A., Jurado, L. A. P., & Argente, J. (2019) · International Journal of Obesity · doi:10.1038/s41366-019-0357-5 · Cited by 64
Gene-Gene and Gene-Environmental Interactions of Childhood Asthma: A Multifactor Dimension Reduction Approach
Su, M., Tung, K., Liang, P., Tsai, C., Kuo, N.-W., & Lee, Y. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030694 · Cited by 60
“SNP rs7566605 in INSIG2 gene is a common genetic variant associated with obesity [29].”
BackgroundInfluential
Advances in systems biology are enhancing our understanding of disease and moving us closer to novel disease treatments
Schadt, E. E., Zhang, B., & Zhu, J. (2009) · Genetica · doi:10.1007/s10709-009-9359-x · Cited by 57
“…(Edwards et al. 2005; Haines et al. 2005; Klein et al. 2005), heart disease (Helgadottir et al. 2007; McPherson et al. 2007), host control of HIV-1(Fellay et al. 2007), type I and II diabetes (Grant et al. 2006; Sladek et al. 2007), and obesity (Herbert et al. 2006), to name just a few.”
Background
Non-Replication of Genome-Wide Based Associations between Common Variants in INSIG2 and PFKP and Obesity in Studies of 18,014 Danes
Andreasen, C. H., Mogensen, M. S., Borch‐Johnsen, K., Sandbæk, A., Lauritzen, T., Sørensen, T. I. A., Hansen, L., Almind, K., Jørgensen, T., Pedersen, O. B., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002872 · Cited by 58
“The rs7566605 located 10 kb upstream of the insulin induced gene 2 (INSIG2), was the first common obesityrelated gene variant to be identified through a GWA approach, including 694 individuals [1].”
Background
Effects of BDNF, T3, and corticosterone on expression of the hypothalamic obesity gene network in vivo and in vitro
Byerly, M. S., Simon, J., Bihan-Duval, É. L., Duclos, M. J. M. J., Cogburn, L. A., & Porter, T. E. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90813.2008 · Cited by 57
“This allows for dissociation of food intake from development of adiposity, since both genetic and environmental factors contribute to energy homeostasis (18).”
Background
Genome‐wide Linkage Scan for the Metabolic Syndrome: The GENNID Study
Edwards, K. L., Hutter, C. M., Wan, J. Y., Kim, H., & Monks, S. A. (2008) · Obesity · doi:10.1038/oby.2008.236 · Cited by 56
FTO predicts weight regain in the Look AHEAD clinical trial
AHEAD, T. G. S. O. L., McCaffery, J. M., Papandonatos, G. D., Huggins, G. S., Peter, I., Kahn, S. E., Knowler, W. C., Evans-Hudnall, G. L., Lipkin, E. W., Kitabchi, A. E., et al. (2013) · International Journal of Obesity · doi:10.1038/ijo.2013.54 · Cited by 56
Genetics of obesity
Martínez-Hernández, A., Enríquez, L. H. G., Moreno-Aliaga, M. J., & Martí, A. (2007) · Public Health Nutrition · doi:10.1017/s1368980007000626 · Cited by 59
“Gene chips containing 500 000 SNPs are already available allowing the identiﬁcation of possible mutations in known and unknown genes related to obesity 41 .”
Study Designs for Genome‐Wide Association Studies
Kraft, P. L., & Cox, D. G. (2008) · Advances in genetics · doi:10.1016/s0065-2660(07)00417-8 · Cited by 55
Genetic contributors to obesity
McPherson, R. (2007) · Canadian Journal of Cardiology · doi:10.1016/s0828-282x(07)71002-4 · Cited by 59
Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study
van den Berg, S. W., Dollé, M. E. T., Imholz, S., van der A, D. L., Slot, R. V. ‘., Wijmenga, C., Verschuren, W. M. M., Strien, C., Siezen, C. L. E., Hoebee, B., et al. (2009) · International Journal of Obesity · doi:10.1038/ijo.2009.152 · Cited by 53
INSIG2 gene rs7566605 polymorphism is associated with severe obesity in Japanese
Hotta, K., Nakamura, M., Nakata, Y., Matsuo, T., Kamohara, S., Kotani, K., Komatsu, R., Itoh, N., Mineo, I., Wada, J., et al. (2008) · Journal of Human Genetics · doi:10.1007/s10038-008-0317-8 · Cited by 54
“An association between rs7566605 in the upstream region of the INSIG2 gene and obesity was also found in several Caucasian and Hispanic American populations (Herbert et al. 2006; Hall et al. 2006; Lyon et al. 2007; Liu et al. 2008).”
BackgroundResultInfluential
Regulation of Hepatic Insig-2 by the Farnesoid X Receptor
Hubbert, M. L., Zhang, Y., Lee, F. Y., & Edwards, P. A. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0089 · Cited by 55
Admixture Mapping Provides Evidence of Association of the VNN1 Gene with Hypertension
Zhu, X., & Cooper, R. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001244 · Cited by 55
“Genome-wide association studies based on 100,000 or more SNPs are now technically feasible [9,10] and initial results with macular degeneration, obesity, type 1 and type 2 diabetes, prostate cancer and multiple sclerosis, among others, suggest promise for this method [11–19].”
Result

Authors: Herbert, A., Gerry, N. P., McQueen, M. B., Heid, I. M., Pfeufer, A., Illig, T., Wichmann, H.-E., Meitinger, T., Hunter, D., Hu, F. B., Colditz, G., Hinney, A., Hebebrand, J., Koberwitz, K., Zhu, X., Cooper, R., Ardlie, K., Lyon, H., Hirschhorn, J. N., Laird, N. M., Lenburg, M. E., Lange, C., & Christman, M. F.
Affiliations: Boston University (US)
Corresponding author: Herbert, Alan
Christman, Michael F.
ORCID: Herbert, Alan
McQueen, Matthew B.
Heid, Iris M.
Wichmann, H.-Erich
Meitinger, Thomas
Hu, Frank B.
Colditz, Graham
Hinney, Anke
Hebebrand, Johannes
Zhu, Xiaofeng
Cooper, Richard
Ardlie, Kristin
Hirschhorn, Joel N.
Laird, Nan M.
Lenburg, Marc E.
Lange, Christoph
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2006-04-14
Volume: 312
Issue: 5771
Pages: 279-283
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1124779
OpenAlex: W2149512324
Cited by: 732
References: 32
Citations by year: 2026: 2 · 2025: 5 · 2024: 2 · 2023: 10 · 2022: 8 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 2 · 2017: 17 · 2016: 19 · 2015: 28 · 2014: 30 · 2013: 37 · 2012: 39
FWCI: 75.55
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Civil War Book Review (submittedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Site cant be reached (submittedVersion)
Funders: National Heart, Lung, and Blood Institute (R01 HL54485, U01HL065899, R01HL066289, R01HL66289, R01HL074166, U01 HL65899)
National Institute of Mental Health (R01MH59532, R01MH059532)
National Cancer Institute (CA-87969, P01CA087969)
National Institute of General Medical Sciences (R01GM046877)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK046200, K23DK067288, P30 DK-46200)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060726)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords: obesity, genetic association, INSIG2, childhood obesity, adult obesity, type 2 diabetes risk, whole genome scan, Framingham Heart Study, African Americans
MeSH terms: Adult, Alleles, Black or African American, Child, Europe, Female, Gene Frequency, Genes, Recessive, Genotype, Haplotypes, Humans, Male, Membrane Proteins, Models, Genetic, Obesity, Genetic Variation, Cohort Studies, Linkage Disequilibrium, Body Mass Index, Case-Control Studies, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, White People, Intracellular Signaling Peptides and Proteins

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A common genetic variant is associated with adult and childhood obesity.

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