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

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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. / Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Bang, Lia E; Benn, Marianne; Kamstrup, Pia R; Bork-Jensen, Jette; Frikke-Schmidt, Ruth; Gjesing, Anette P; Grarup, Niels; Hansen, Torben; Have, Christian Theil; Jørgensen, Torben; Nielsen, Sune F.; Linneberg, Allan René; Pedersen, Oluf; Pers, Tune H; Vestergaard, Henrik; Nordestgaard, Børge; Tybjærg-Hansen, Anne; Varbo, Anette; CHD Exome+ Consortium; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetics Consortium; GoT2D Genes Consortium; EPIC-InterAct Consortium; INTERVAL Study; ReproGen Consortium; T2D-Genes Consortium; The MAGIC Investigators; Understanding Society Scientific Group; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth J F.

In: Nature Genetics, Vol. 50, 2018, p. 26-41.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Turcot, V, Lu, Y, Highland, HM, Bang, LE, Benn, M, Kamstrup, PR, Bork-Jensen, J, Frikke-Schmidt, R, Gjesing, AP, Grarup, N, Hansen, T, Have, CT, Jørgensen, T, Nielsen, SF, Linneberg, AR, Pedersen, O, Pers, TH, Vestergaard, H, Nordestgaard, B, Tybjærg-Hansen, A, Varbo, A, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetics Consortium, GoT2D Genes Consortium, EPIC-InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, The MAGIC Investigators, Understanding Society Scientific Group, Lindgren, CM, Hirschhorn, JN & Loos, RJF 2018, 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity', Nature Genetics, vol. 50, pp. 26-41. https://doi.org/10.1038/s41588-017-0011-x

APA

Turcot, V., Lu, Y., Highland, H. M., Bang, L. E., Benn, M., Kamstrup, P. R., ... Loos, R. J. F. (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 50, 26-41. https://doi.org/10.1038/s41588-017-0011-x

Vancouver

Turcot V, Lu Y, Highland HM, Bang LE, Benn M, Kamstrup PR et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics. 2018;50:26-41. https://doi.org/10.1038/s41588-017-0011-x

Author

Turcot, Valérie ; Lu, Yingchang ; Highland, Heather M ; Bang, Lia E ; Benn, Marianne ; Kamstrup, Pia R ; Bork-Jensen, Jette ; Frikke-Schmidt, Ruth ; Gjesing, Anette P ; Grarup, Niels ; Hansen, Torben ; Have, Christian Theil ; Jørgensen, Torben ; Nielsen, Sune F. ; Linneberg, Allan René ; Pedersen, Oluf ; Pers, Tune H ; Vestergaard, Henrik ; Nordestgaard, Børge ; Tybjærg-Hansen, Anne ; Varbo, Anette ; CHD Exome+ Consortium ; EPIC-CVD Consortium ; ExomeBP Consortium ; Global Lipids Genetics Consortium ; GoT2D Genes Consortium ; EPIC-InterAct Consortium ; INTERVAL Study ; ReproGen Consortium ; T2D-Genes Consortium ; The MAGIC Investigators ; Understanding Society Scientific Group ; Lindgren, Cecilia M ; Hirschhorn, Joel N ; Loos, Ruth J F. / Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. In: Nature Genetics. 2018 ; Vol. 50. pp. 26-41.

Bibtex

@article{86d8ceb9ed7246209801c3e4b213e336,
title = "Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity",
abstract = "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 ~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 ~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.",
keywords = "Journal Article",
author = "Val{\'e}rie Turcot and Yingchang Lu and Highland, {Heather M} and Bang, {Lia E} and Marianne Benn and Kamstrup, {Pia R} and Jette Bork-Jensen and Ruth Frikke-Schmidt and Gjesing, {Anette P} and Niels Grarup and Torben Hansen and Have, {Christian Theil} and Torben J{\o}rgensen and Nielsen, {Sune F.} and Linneberg, {Allan Ren{\'e}} and Oluf Pedersen and Pers, {Tune H} and Henrik Vestergaard and B{\o}rge Nordestgaard and Anne Tybj{\ae}rg-Hansen and Anette Varbo and {CHD Exome+ Consortium} and {EPIC-CVD Consortium} and {ExomeBP Consortium} and {Global Lipids Genetics Consortium} and {GoT2D Genes Consortium} and {EPIC-InterAct Consortium} and {INTERVAL Study} and {ReproGen Consortium} and {T2D-Genes Consortium} and {The MAGIC Investigators} and {Understanding Society Scientific Group} and Lindgren, {Cecilia M} and Hirschhorn, {Joel N} and Loos, {Ruth J F}",
note = "Publisher correction: https://doi.org/10.1038/s41588-019-0447-2",
year = "2018",
doi = "10.1038/s41588-017-0011-x",
language = "English",
volume = "50",
pages = "26--41",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

AU - Turcot, Valérie

AU - Lu, Yingchang

AU - Highland, Heather M

AU - Bang, Lia E

AU - Benn, Marianne

AU - Kamstrup, Pia R

AU - Bork-Jensen, Jette

AU - Frikke-Schmidt, Ruth

AU - Gjesing, Anette P

AU - Grarup, Niels

AU - Hansen, Torben

AU - Have, Christian Theil

AU - Jørgensen, Torben

AU - Nielsen, Sune F.

AU - Linneberg, Allan René

AU - Pedersen, Oluf

AU - Pers, Tune H

AU - Vestergaard, Henrik

AU - Nordestgaard, Børge

AU - Tybjærg-Hansen, Anne

AU - Varbo, Anette

AU - CHD Exome+ Consortium

AU - EPIC-CVD Consortium

AU - ExomeBP Consortium

AU - Global Lipids Genetics Consortium

AU - GoT2D Genes Consortium

AU - EPIC-InterAct Consortium

AU - INTERVAL Study

AU - ReproGen Consortium

AU - T2D-Genes Consortium

AU - The MAGIC Investigators

AU - Understanding Society Scientific Group

AU - Lindgren, Cecilia M

AU - Hirschhorn, Joel N

AU - Loos, Ruth J F

N1 - Publisher correction: https://doi.org/10.1038/s41588-019-0447-2

PY - 2018

Y1 - 2018

N2 - 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 ~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 ~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.

AB - 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 ~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 ~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.

KW - Journal Article

UR - https://www.nature.com/articles/s41588-018-0082-3

U2 - 10.1038/s41588-017-0011-x

DO - 10.1038/s41588-017-0011-x

M3 - Journal article

C2 - 29273807

VL - 50

SP - 26

EP - 41

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

ER -

ID: 189198227