Journal
NATURE GENETICS
Volume 50, Issue 1, Pages 26-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-017-0011-x
Keywords
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Categories
Funding
- NHMRC 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]
- BBSRC [BB/F019394/1] Funding Source: UKRI
- ESRC [ES/S008349/1] Funding Source: UKRI
- MRC [MR/N01104X/2, MC_UU_12015/2, MR/L01632X/1, G0600237, MR/S003746/1, MR/M501633/2, MR/L003120/1, MC_UU_12015/1, MR/K007017/1, MR/P013880/1, MC_PC_U127561128, MR/L01341X/1, G0601966, MR/N01104X/1, MR/P02811X/1, G1001799, G9521010] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- British Heart Foundation [RG/13/13/30194, RG/16/4/32218, SP/13/2/30111, RG/14/5/30893, RG/08/014/24067] 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 [MC_CF023241, MR/K026992/1, MR/P02811X/1, MC_PC_13040, MC_PC_U127561128, MR/L003120/1, MC_UU_12015/2, MR/M501633/1, MR/K006584/1, HDR-2002, MC_UU_12015/1, G0601966, G0600237, MR/L01341X/1, MC_PC_13048, MR/N01104X/1, G0700704B, MR/K007017/1, G9521010, MR/L01632X/1, MR/N01104X/2, MR/P013880/1, MR/M501633/2, G1001799, MC_PC_13046] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10219, NF-SI-0512-10165, NF-SI-0512-10135, NF-SI-0611-10136, NF-SI-0512-10113, NF-SI-0515-10020, NF-SI-0611-10099, NF-SI-0617-10149, NF-SI-0617-10154, NF-SI-0616-10080] Funding Source: researchfish
- NNF Center for Basic Metabolic Research [Grarup Group, Pers Group, Pedersen Group, Hansen Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF16OC0021496, NNF15OC0016108, NNF16OC0021254, NNF14OC0011039, NNF17OC0027492] Funding Source: researchfish
- Wellcome Trust [098395/Z/12/Z, 213422/Z/18/Z] Funding Source: researchfish
- Steno Diabetes Center Copenhagen (SDCC) [SDCC 3. B Epidemiology] Funding Source: researchfish
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [R01HD073342, R01HD057194] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [P30CA008748, R25CA094880, T32CA009156] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [KL2TR001109, UL1TR001881] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K23HL114724, R21HL121422, R01HL109946, R01HL128914, R00HL130580, R01HL092577, K99HL130580, K99HL094535, T32HL007055, R00HL094535, K24HL105780, R01HL117078, R01HL057818] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U01HG007417, R01HG008983, F31HG009850, U01HG007416, ZIAHG000024] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK101855, R01DK075787, P30DK020572, R01DK106236, P30DK063491, R01DK106621, R01DK089256, R01DK110113, U01DK062370, R01DK107786, K01DK107836, R01DK072193, R01DK093757, R01DK107904] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM096911] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS033335] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R21DA040177] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD018522] Funding Source: NIH RePORTER
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Genome-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.
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