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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Background
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BackgroundMethodInfluential
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Common SNPs in FTO Gene Are Associated with Obesity Related Anthropometric Traits in an Island Population from the Eastern Adriatic Coast of Croatia
Zhang, G., Karns, R. A., Narančić, N. S., Sun, G., Cheng, H., Missoni, S., Duraković, Z., Rudan, P., Chakraborty, R., & Deka, R. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010375 · Cited by 35
MC4R variants rs12970134 and rs17782313 are associated with obese polycystic ovary syndrome patients in the Western region of Saudi Arabia
Batarfi, A. A., Filimban, N., Bajouh, O. S., Dallol, A., Chaudhary, A., & Bakhashab, S. (2019) · BMC Medical Genetics · doi:10.1186/s12881-019-0876-x · Cited by 34
Association study of polymorphisms in Insulin Induced Gene 2 (INSIG2) with antipsychotic‐induced weight gain in European and African‐American schizophrenia patients
Tiwari, A. K., Zai, C. C. H., Meltzer, H. Y., Lieberman, J. A., Müller, D. J., & Kennedy, J. L. (2010) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.1111 · Cited by 34
“We also included the polymorphism rs7566605 located 10 kb upstream of the INSIG2 gene associated with BMI and various other indices of obesity (Herbert et al., 2006; Lyon et al., 2007).”
Genetic Variation and Effects on Human Eating Behavior
de Krom, M., Bauer, F., Collier, D. A., Adan, R. A. H., & la Fleur, S. E. (2009) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-080508-141124 · Cited by 34
INSIG2 gene polymorphism is associated with increased subcutaneous fat in women and poor response to resistance training in men
Suer, F. E., Gordish‐Dressman, H., Clarkson, P. M., Thompson, P. D., Angelopoulos, T. J., Gordon, P. M., Moyna, N. M., Pescatello, L. S., Visich, P. S., Zoeller, R. F., et al. (2008) · BMC Medical Genetics · doi:10.1186/1471-2350-9-117 · Cited by 34
“[4] conducted a genome-wide association study to identify genetic loci (single nucleotide polymorphisms; SNPs) contributing to obesity using BMI as the primary phenotype.”
BackgroundInfluential
A Whole Genome Linkage Scan Identifies Multiple Chromosomal Regions Influencing Adiposity‐Related Traits among Samoans
Dai, F., Sun, G., Åberg, K. A., Keighley, E. D., Indugula, S. R., Roberts, S. T., Smelser, D. T., Viali, S., Li, J., Deka, R., et al. (2008) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2008.00462.x · Cited by 34
“…and 780 Annals of Human Genetics (2008) 72,780–792 C© 2008 The Authors Journal compilation C© 2008 Blackwell Publishing Ltd/University College London genetic variants associated with obesity and related traits (Bell et al. 2005, Rankinen et al. 2006, Herbert et al. 2006, Frayling et al. 2007).”
Background
The association of breakfast consumption habit, snacking behavior and body mass index among university students
Isa, K. A. M., & Masuri, M. G. (2011) · American Journal of Food and Nutrition · doi:10.5251/ajfn.2011.1.2.55.60 · Cited by 32
Comparison of the Health Benefits of Different Eras of Japanese Foods : Lipid and Carbohydrate Metabolism Focused Research
Honma, T., Kitano, Y., Kijima, R., Jibu, Y., Kawakami, Y., Tsuduki, T., Nakagawa, K., & Miyazawa, T. (2013) · NIPPON SHOKUHIN KOGYO GAKKAISHI · doi:10.3136/nskkk.60.541 · Cited by 33
A Survey on Machine and Deep Learning Models for Childhood and Adolescent Obesity
Siddiqui, H., Rattani, A., Woods, N. K., Cure, L., Lewis, R. K., Twomey, J. M., Smith‐Campbell, B., & Hill, T. J. (2021) · IEEE Access · doi:10.1109/access.2021.3131128 · Cited by 37
“Lot of research has been done to study the causal effect of genetics in relation to obesity [50], [51].”
Bivariate Linkage Study of Proximal Hip Geometry and Body Size Indices: The Framingham Study
Karasik, D., Dupuis, J., Cupples, L. A., Beck, T., Mahaney, M. C., Havill, L. M., Kiel, D. P., & Demissie, S. (2007) · Calcified Tissue International · doi:10.1007/s00223-007-9052-y · Cited by 33
“Height and body mass index (BMI) are also under genetic influence [23, 24].”
Background
Multistage Sampling for Genetic Studies
Elston, R. C., Lin, D., & Gang, Z. (2007) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.8.080706.092357 · Cited by 33
“(58) for a single-stage familybased association study and was applied to a genome-wide family-based association study with 100,000 SNPs (18).”
Method
Calibration of credibility of agnostic genome‐wide associations
Ioannidis, J. P. A. (2008) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30721 · Cited by 33
“…disease [Maraganore et al., 2005; Elbaz et al., 2006]; the INSIG2neighboring variant that was proposed to be associated with obesity risk [Herbert et al., 2006; Dina et al., 2007; Loos et al., 2007; Rosskopf et al., 2007]; and even some of the gene variants (such as EXT2-ALX4 variants)…”
Background
Single nucleotide polymorphisms in obesity-related genes and all-cause and cause-specific mortality: a prospective cohort study
Gallicchio, L. M., Chang, H. H., Christo, D. K., Thuita, L. W., Huang, H. Y., Strickland, P. T., Ruczinski, I., Clipp, S. L., & Helzlsouer, K. J. (2009) · BMC Medical Genetics · doi:10.1186/1471-2350-10-103 · Cited by 32
“Lyon HN, Emilsson V, Hinney A, Heid IM, Lasky-Su J, Zhu X, Thorleifsson G, Gunnarsdottir S, Walters GB, Thorsteinsdottir U, et al.: The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts.”
Result
Functional Genomic Architecture of Predisposition to Voluntary Exercise in Mice: Expression QTL in the Brain
Kelly, S. A., Nehrenberg, D. L., Hua, K., Garland, T., & Pomp, D. (2012) · Genetics · doi:10.1534/genetics.112.140509 · Cited by 33
“Insig2 has been implicated in the functional regulation of lipid and cholesterol metabolism, positively (Herbert et al. 2006; Lyon et al. 2007) and negatively (Dina et al. 2007) associated with human obesity, associated with cholesterol biosynthesis, and characterized as a strong candidate…”
Background
The A-allele of the common FTO gene variant rs9939609 complicates weight maintenance in severe obese patients
Woehning, A., Schultz, J.-H., Roeder, E., Moeltner, A., Isermann, B., Nawroth, P., Wolfrum, C., & Rudofsky, G. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.14 · Cited by 32
Using Linkage Analysis to Identify Quantitative Trait Loci for Sleep Apnea in Relationship to Body Mass Index
Larkin, E. K., Patel, S. R., Elston, R. C., Gray‐McGuire, C., Zhu, X., & Redline, S. S. (2008) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2008.00472.x · Cited by 33
“Also, several genome-wide association studies of obesity have identified genes that were not observed in this study, including fat mass and obesity associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), catenin β-like 1 CTNNBL1 and phosphofructokinase, platelet (PFKP) (Herbert et al., 2006;…”
Background
New insights into the genetics of body weight
Dina, C. (2008) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e328303e5e6 · Cited by 32
Gastric inhibitory polypeptide receptor: association analyses for obesity of several polymorphisms in large study groups
Vogel, C. I., Scherag, A., Brönner, G., Nguyen, T. T., Wang, H.-J., Grallert, H., Bornhorst, A., Rosskopf, D., Völzke, H., Reinehr, T., et al. (2009) · BMC Medical Genetics · doi:10.1186/1471-2350-10-19 · Cited by 30
Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma
Wang, Y., Tong, C., Wang, Z., Wang, Z., Mauger, D. T., Tantisira, K. G., Israel, E., Szefler, S. J., Chinchilli, V. M., Boushey, H. A., et al. (2015) · The Pharmacogenomics Journal · doi:10.1038/tpj.2014.83 · Cited by 31
Association of the Common Genetic Variant Upstream of INSIG2 Gene with Obesity Related Phenotypes in Chinese Children and Adolescents
Wang, H., Zhang, H., ZHANG, S.-W., Pan, Y., & Ma, J. (2008) · Biomedical and Environmental Sciences · doi:10.1016/s0895-3988(09)60013-1 · Cited by 31
Obesity
Capel, F. (2007) · CRC Press eBooks · doi:10.3109/9781420020137 · Cited by 31
Adaptive Two-Stage Analysis of Genetic Association in Case-Control Designs
Zheng, G., Song, K. S., & Elston, R. C. (2007) · Human Heredity · doi:10.1159/000099830 · Cited by 30
Gene × Environment Interactions in Obesity: The State of the Evidence
Ahmad, S., Varga, T. V., & Franks, P. W. (2013) · Human Heredity · doi:10.1159/000351070 · Cited by 31
Obesity and genomics: role of technology in unraveling the complex genetic architecture of obesity
Apalasamy, Y. D., & Mohamed, Z. (2015) · Human Genetics · doi:10.1007/s00439-015-1533-x · Cited by 35
Genetics of type 2 diabetes mellitus and obesity—a review
Jafar‐Mohammadi, B., & McCarthy, M. I. (2008) · Annals of Medicine · doi:10.1080/07853890701670421 · Cited by 31
“In a low-density scan initiated in the Framingham cohort, Herbert and colleagues published evidence that variation at the INSIG2 gene may be responsible for a modest increase in the risk of obesity (76).”
Method
Screening and Replication using the Same Data Set: Testing Strategies for Family-Based Studies in which All Probands Are Affected
Murphy, A., Weiss, S. T., & Lange, C. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000197 · Cited by 30
“establish genome-wide significance within one data set. They usually identify only a handful of SNPs (typically fewer than 20) which are then genotyped in other studies in order to generalize the significant findings”
Identifying the Genotype Behind the Phenotype: A Role Model Found in VKORC1 and its Association with Warfarin Dosing
Crawford, D. C., Ritchie, M. D., & Rieder, M. J. (2007) · Pharmacogenomics · doi:10.2217/14622416.8.5.487 · Cited by 30
Fine‐mapping of Obesity‐related Quantitative Trait Loci in an F9/10 Advanced Intercross Line
Fawcett, G. L., Jarvis, J. P., Roseman, C. C., Wang, B., Wolf, J. B., & Cheverud, J. M. (2009) · Obesity · doi:10.1038/oby.2009.411 · Cited by 30
“Genes such as INSIG2 (15) are controversial and may exhibit nonadditive, epistatic effects on fat deposition.”
Background
Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test
Lasky-Su, J., Banaschewski, T., Buitelaar, J., Franke, B., Brookes, K., Sonuga-Barke, E., Ebstein, R., Eisenberg, J., Gill, M., Manor, I., et al. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.03.006 · Cited by 29
Association Analyses Between Type 2 Diabetes Genes and Obesity Traits in Pigs
Du, Z., Fan, B., Zhao, X., Amoako, R., & Rothschild, M. F. (2008) · Obesity · doi:10.1038/oby.2008.557 · Cited by 29
Effects of theFTOGene on Lifestyle Intervention Studies in Children
Rendo‐Urteaga, T., Moleres, A., & del Moral, A. M. (2009) · Obesity Facts · doi:10.1159/000262296 · Cited by 27
Polymorphisms of INSIG2, MC4R, and LEP Are Associated With Obesity- and Metabolic-Related Traits in Schizophrenic Patients
Kuo, P., Kao, C., Chen, P., Chen, C.-H., Tsai, Y.-S., Lu, M., & Huang, M. (2011) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e318234ee84 · Cited by 29
“A single nucleotide polymorphism (SNP) (rs7566605) at 10 kb upstream of the transcription site of INSIG2 was significantly associated with BMI.(19) In addition, the animal experiment demonstrated that overexpression of this gene causes a reduction in plasma triglyceride (TG) levels.”
BackgroundResultInfluential
Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment
Teoh, S. L., & Das, S. (2016) · Tumor Biology · doi:10.1007/s13277-016-5357-7 · Cited by 29
“Framingham Heart Study participants, a common genetic variant located 10 kb upstream of the transcription start site of INSIG2 gene was identified to be associated with obesity [90].”
Background
The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications
Say, Y.-H. (2017) · Journal of PHYSIOLOGICAL ANTHROPOLOGY · doi:10.1186/s40101-017-0142-x · Cited by 29
Genetics of Human Obesity
Fisler, J. S., & Warden, C. H. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-391884-0.00023-8 · Cited by 29
A latent class model for obesity
Greene, W. H., Harris, M. N., Hollingsworth, B. P., & Maitra, P. (2014) · Economics Letters · doi:10.1016/j.econlet.2014.01.004 · Cited by 28
Dog obesity – The need for identifying predisposing genetic markers
Switonski, M., & Mankowska, M. (2013) · Research in Veterinary Science · doi:10.1016/j.rvsc.2013.08.015 · Cited by 28
Pharmacogenetic Correlates of Antipsychotic-Induced Weight Gain in the Chinese Population
Luo, C., Liu, J., Wang, X., Mao, X., Zhou, H., & Liu, Z. (2019) · Neuroscience Bulletin · doi:10.1007/s12264-018-0323-6 · Cited by 31
“The rs7566605 SNP of INSIG2 was suggested to be associated with obesity [118], but the first study of an association of rs7566605 with AIWG yielded a negative result with CATIE samples [119].”
Result
A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort
Luo, M., Sainsbury, J., Tuff, J. F., Lacap, P. A., Yuan, X.-Y., Hirbod, T., Kimani, J., Wachihi, C., Ramdahin, S., Bielawny, T., et al. (2012) · Journal of Virology · doi:10.1128/jvi.01499-12 · Cited by 27
“Genome-wide SNP (single-nucleotide polymorphism) analysis allows for an unbiased identification of genetic factors that influence complex traits, and high-throughput technologies have allowed for tremendous progress in this field (3, 8, 18, 31).”
Background

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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