Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

Simple item page
dc.contributor.authorTurcot, Valerie
dc.contributor.authorLu, Yingchang
dc.contributor.authorHighland, Heather M.
dc.contributor.authorSchurmann, Claudia
dc.contributor.authorJustice, Anne E.
dc.contributor.authorFine, Rebecca S.
dc.contributor.authorLoos, Ruth J. F.
dc.date.accessioned2026-02-06T18:43:33Z
dc.date.issued2018
dc.departmentDoğu Akdeniz Üniversitesi
dc.description.abstractGenome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
dc.description.sponsorshipNHMRC Practitioner Fellowship [APP1103329]; NIH/NIDDK [K01DK107836]; Wellcome Trust Senior Investigator [WT098395, WT098381]; NIH Research Senior Investigator; European Research Council [SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC, 323195, 293574]; American Heart Association [13POST16500011, 13GRNT16490017]; NIH [R01DK089256, R01DK101855, K99HL130580, R01DK106621, HL094535, HL109946, R01DK075787, R01HD057194, U01HG007416, 1R01HL092577, R01HL128914, K24HL105780, R01DK110113, U01HG007417, R01DK107786, K23HL114724]; Doris Duke Medical Foundation; University of Michigan Internal Medicine Department, Division of Gastroenterology; University of Michigan Biological Sciences Scholars Program; Central Society for Clinical Research; Danish Diabetes Academy - Novo Nordisk Foundation; Finnish Foundation for Cardiovascular Research; Dekker scholarshipJunior Staff Member Netherlands Heart Foundation [2014T001]; UCL Hospitals NIHR Biomedical Research Centre; UK MRC [MC_UU_12013/1-9]; University of Queensland; QIMR Berghofer; Montreal Heart Institute Foundation; Canada Research Chair program; BMBF [01ER1206, 01ER1507m]; Max Planck Society; NHLBI [R01DK089256, R21HL121422]; Nuffield Department of Clinical Medicine Award; Clarendon Scholarship; NCI [R25CA94880, P30CA008748]; Research Council of Norway; University of Bergen; KG Jebsen Foundation; Helse Vest; Norwegian Diabetes Association; Established Investigator Award from the American Heart Association [13EIA14220013]; Foundation Leducq [14CVD01]; Doris Duke Charitable Foundation Clinical Scientist Development Award; ERC Advanced Principal Investigator award; NHMRC Fellowship [APP1042255]; Lundbeck Foundation; Benzon Foundation; Canadian Institutes of Health Research (CIHR); Leenaards Foundation; Swiss National Science Foundation [31003A-143914]; SystemsX.ch [51RTP0_151019]; UK Biobank resource [1251, 9072]; [R01HG008983]; [R21DA040177]; American Heart Association (AHA) [13GRNT16490017, 13POST16500011] Funding Source: American Heart Association (AHA); National Cancer Institute [P30CA008748] Funding Source: NIH RePORTER; National Heart Lung and Blood Institute [T32HL007055, R01HL109946, R01HL092577] Funding Source: NIH RePORTER; National Human Genome Research Institute [ZIAHG000024] Funding Source: NIH RePORTER; National Institute of Diabetes and Digestive and Kidney Diseases [R01DK093757, U01DK062370, P30DK063491, R01DK072193, P30DK020572, R01DK075787] Funding Source: NIH RePORTER; Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish; British Heart Foundation [RG/08/014/24067, RG/14/5/30893, RG/13/13/30194, CH/12/2/29428, SP/13/2/30111, RG/16/4/32218] Funding Source: researchfish; Cancer Research UK [16563] Funding Source: researchfish; Economic and Social Research Council [ES/S008349/1] Funding Source: researchfish; Lundbeck Foundation [R190-2014-3904, R16-2007-1691] Funding Source: researchfish; Medical Research Council [MR/M501633/2, MC_PC_13046, MC_PC_13048, MR/K007017/1, MC_UU_12015/7, HDR-2002, MR/L003120/1, G0600237, G0601966, G1001799, MR/L01341X/1, MR/M501633/1, MR/S003746/1, MC_CF023241, G9521010, MR/K026992/1, G0700704B, MR/P013880/1, MC_UU_12015/1, MC_UU_12015/2, MR/N01104X/2, MR/K006584/1, MC_PC_13040, MR/R023484/1, MC_PC_U127561128, MR/L01632X/1, MR/N01104X/1, MR/P02811X/1] Funding Source: researchfish; National Institute for Health Research [NF-SI-0617-10149, NF-SI-0512-10113, NF-SI-0616-10080, NF-SI-0515-10020, NF-SI-0611-10136, NF-SI-0617-10154, NF-SI-0512-10135, NF-SI-0611-10219, NF-SI-0611-10099, ACF-2016-19-005, NF-SI-0512-10165] Funding Source: researchfish; NNF Center for Basic Metabolic Research [Hansen Group, Grarup Group, Pers Group, Pedersen Group] Funding Source: researchfish; Novo Nordisk Fonden [NNF16OC0021496, NNF15OC0016108, NNF17OC0027492, NNF16OC0021254, NNF14OC0011039] Funding Source: researchfish; Steno Diabetes Center Copenhagen (SDCC) [SDCC 3. B Epidemiology] Funding Source: researchfish; Wellcome Trust [098395/Z/12/Z, 213422/Z/18/Z] Funding Source: researchfish; BBSRC [BB/F019394/1] Funding Source: UKRI; ESRC [ES/S008349/1] Funding Source: UKRI; GCRF [MR/P02811X/1] Funding Source: UKRI; MRC [MR/S003746/1, MR/R023484/1, MR/P013880/1, G0600237, MC_UU_12015/1, MC_PC_13048, MC_PC_13046, MR/L01632X/1, MR/L01341X/1, MR/N01104X/1, MR/N01104X/2, MC_PC_13040, G0601966, MR/M501633/1, G9521010, G1001799, MC_PC_U127561128, MC_UU_12015/2, MR/L003120/1, MR/K007017/1, MC_UU_12015/7, MR/M501633/2] Funding Source: UKRI
dc.description.sponsorshipA.P.R. was supported by R01DK089256. A.W.H. is supported by an NHMRC Practitioner Fellowship (APP1103329). A.K.M. received funding from NIH/NIDDK K01DK107836. A.T.H. is a Wellcome Trust Senior Investigator (WT098395) and an NIH Research Senior Investigator. A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (WT098017). A.R.W. is supported by the European Research Council (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). A.U.J. is supported by the American Heart Association (13POST16500011) and the NIH (R01DK089256, R01DK101855, K99HL130580). B.K. and E.K.S. were supported by the Doris Duke Medical Foundation, the NIH (R01DK106621), the University of Michigan Internal Medicine Department, Division of Gastroenterology, the University of Michigan Biological Sciences Scholars Program and the Central Society for Clinical Research. C.J.W. is supported by the NIH (HL094535, HL109946). D.J.L. is supported by R01HG008983 and R21DA040177. D.R.W. is supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. V. Salomaa has been supported by the Finnish Foundation for Cardiovascular Research. F.W.A. is supported by Dekker scholarshipJunior Staff Member 2014T001 Netherlands Heart Foundation and the UCL Hospitals NIHR Biomedical Research Centre. F.D. is supported by the UK MRC (MC_UU_12013/1-9). G.C.-P. received scholarship support from the University of Queensland and QIMR Berghofer. G.L. is funded by the Montreal Heart Institute Foundation and the Canada Research Chair program. H.Y. and T.M.F. are supported by the European Research Council (323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). I.M.H. is supported by BMBF (01ER1206) and BMBF (01ER1507m), the NIH and the Max Planck Society. J. Haessler was supported by NHLBI R21HL121422. J.N.H. is supported by NIH R01DK075787. K.E.N. was supported by the NIH (R01DK089256, R01HD057194, U01HG007416, R01DK101855) and the American Heart Association (13GRNT16490017). M.A.R. is supported by the Nuffield Department of Clinical Medicine Award, Clarendon Scholarship. M.I.M. is a Wellcome Trust Senior Investigator (WT098381) and an NIH Research Senior Investigator. M.D. is supported by the NCI (R25CA94880, P30CA008748). P.R.N. is supported by the European Research Council (AdG; 293574), the Research Council of Norway, the University of Bergen, the KG Jebsen Foundation and the Helse Vest, Norwegian Diabetes Association. P.T.E. is supported by the NIH (1R01HL092577, R01HL128914, K24HL105780), by an Established Investigator Award from the American Heart Association (13EIA14220013) and by the Foundation Leducq (14CVD01). P.L.A. was supported by NHLBI R21HL121422 and R01DK089256. P.L.H. is supported by the NIH (NS33335, HL57818). R.S.F. is supported by the NIH (T32GM096911). R.J.F.L. is supported by the NIH (R01DK110113, U01HG007417, R01DK101855, R01DK107786). S.A.L. is supported by the NIH (K23HL114724) and a Doris Duke Charitable Foundation Clinical Scientist Development Award. T.D.S. holds an ERC Advanced Principal Investigator award. T.A.M. is supported by an NHMRC Fellowship (APP1042255). T.H.P. received Lundbeck Foundation and Benzon Foundation support. V.T. is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). Z.K. is supported by the Leenaards Foundation, the Swiss National Science Foundation (31003A-143914) and SystemsX.ch (51RTP0_151019). Part of this work was conducted using the UK Biobank resource (project numbers 1251 and 9072). A full list of acknowledgments appears in the Supplementary Note.
dc.identifier.doi10.1038/s41588-017-0011-x
dc.identifier.endpage+
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.issue1
dc.identifier.orcid0000-0002-1733-263X
dc.identifier.orcid0000-0002-0275-9905
dc.identifier.orcid0000-0002-2467-0231
dc.identifier.orcid0000-0001-6225-8240
dc.identifier.orcid0000-0002-2555-4427
dc.identifier.orcid0000-0002-5436-8658
dc.identifier.orcid0000-0002-0703-0742
dc.identifier.pmid29273807
dc.identifier.scopus2-s2.0-85039153797
dc.identifier.scopusqualityQ1
dc.identifier.startpage26
dc.identifier.urihttps://doi.org/10.1038/s41588-017-0011-x
dc.identifier.urihttps://hdl.handle.net/11129/13675
dc.identifier.volume50
dc.identifier.wosWOS:000423157400007
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakPubMed
dc.indekslendigikaynakScopus
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.ispartofNature Genetics
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WoS_20260204
dc.subjectGenome-Wide Association
dc.subjectMelanocortin-4 Receptor Gene
dc.subjectDonepezil 23 Mg
dc.subjectFrameshift Mutation
dc.subjectGlucose-Homeostasis
dc.subjectHypothalamic Ampk
dc.subjectCoding Variants
dc.subjectBlood-Pressure
dc.subjectRare
dc.subjectLoci
dc.titleProtein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
dc.typeArticle

Files

Collections

WoS Indexed Publications Collection
PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu