Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
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Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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The SH2B1 gene locus is an obesity risk allele in human populations.
“genome-wide scans have identified the SH2B1 gene locus as an obesity risk allele in human populations (195).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [195]
Variants at the four BMI loci have also been associated with childhood BMI.
“Variants at these four loci have also been associated with childhood BMI18–20”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [20]
Four novel loci for menarche were previously identified by GWA studies for adult BMI: rs9939609 (in/near FTO, P=3.1×10−8), rs633715 (SEC16B, P=2.1×10−8), rs2002675 (TRA2B, ETV5, P=1.2×10−9) and rs2947411 (TMEM18, P=1.7×10−8).
“Four novel loci for menarche were previously identified by GWA studies for adult BMI18–20; these were rs9939609 (in/near FTO, P=3.1×10−8), rs633715 (SEC16B, P=2.1×10−8), rs2002675 (TRA2B, ETV5, P=1.2×10−9) and rs2947411 (TMEM18, P=1.7×10−8).”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [20]
rs3101336 tags a CNV near the NEGR1 gene locus, which has been previously associated with body mass index.
“This SNP tags a CNV near to the NEGR1 gene locus, which has been previously associated with body mass index20.”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [20]
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Self-citation
- Authors
- the GIANT Consortium
- Venue
- Nature Genetics
- Published
- 2008-12-14
- Volume
- 41
- Issue
- 1
- Pages
- 25-34
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2695662
- OpenAlex
- W2129150286
- Cited by
- 1,720
- References
- 50
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 35 · 2023: 47 · 2022: 56 · 2021: 67 · 2020: 65 · 2019: 66 · 2018: 54 · 2017: 93 · 2016: 88 · 2015: 107 · 2014: 129 · 2013: 183 · 2012: 163
- FWCI
- 99.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
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- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- IRIS (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
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- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- UNC Libraries
- Funders
- American Diabetes Association
- Richard and Susan Smith Family Foundation
- GlaxoSmithKline
- Division of Cancer Prevention, National Cancer Institute
- Wellcome Trust (068545/Z/02), 076467, G0000934, 077011, 077016, 079557, 068545, 201413, 090532, 089061, 076467/Z05/z, 082390, HEALTH-F4-2007-201413, 076113)
- Sarnoff Cardiovascular Research Foundation
- Folkhälsanin Tutkimussäätiö
- National Institute for Health and Care Research (G0000934, NF-SI-0508-10082)
- British Heart Foundation (FS/05/061/19501, 068545/Z/02, G0000934)
- Diabetes UK
- University of Southampton
- King's College London
- University of Bristol (076467, 076467/Z/05/Z)
- ZonMw
- Academy of Finland (124243, 118065)
- Erasmus Medisch Centrum
- Suomen Kulttuurirahasto
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (19501, 175.010.2005.011)
- Vetenskapsrådet
- Samfundet Folkhälsan
- National Institutes of Health (5r01ca049449-18, G0000934, n01hg065403-000, NO1-AG-1–2109, 6r01hl087679-03, 5rl1mh083268-05, 068545/Z/02, CA-49449, N01‐HG‐65403, CA67262, CA 87969, DK062370)
- Medical Research Council (076467, 076467/Z/05/Z, 068545/Z/02, G0000934, G0601261)
- Münchner Zentrum für Gesundheitswissenschaften
- National Institute on Aging (N01-AG-12109, NO1-AG-1-2109, G0000934)
- National Heart, Lung, and Blood Institute (HL-087679, U01HL084729, HL-084729, R01 HL087679)
- National Institute of Mental Health (RL1-MH083268, 1RL1MH083268)
- National Human Genome Research Institute (Z01HG000024, 01-HG-65403, HG02651, R01HG002651, N01 HG065403)
- National Cancer Institute (CA-49449, R01CA065725, CA-87969, 5UO1CA098233, U01CA067262, CA67262, P01CA087969, R01‐CA049449, CA 65725, CA50385, U01CA098233, R01CA050385, U01CA049449, R01CA067262)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK075787, T32-DK07191, DK-072193, R01DK072193, U01DK062370, R56DK062370, K23DK067288, F32DK079466, K23DK080145, R01DK029867, DK-062370, R01DK075787, R01DK062370, T32DK007191)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- body mass index, obesity, genome-wide association study, genetic loci, FTO, melanocortin-4 receptor, TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, NEGR1, central nervous system, dietary intake, body weight regulation, monogenic obesity, candidate causal variants
- MeSH terms
- Alleles, Anthropometry, Body Weight, Central Nervous System, Humans, Obesity, Meta-Analysis as Topic, Cohort Studies, Body Mass Index, Gene Dosage, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study
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