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

Valérie Turcot; Yingchang Lu; Heather M Highland; Lia E Bang; Marianne Benn; Pia R Kamstrup; Jette Bork-Jensen; Ruth Frikke-Schmidt; Anette P Gjesing; Niels Grarup; Torben Hansen; Christian Theil Have; Torben Jørgensen; Sune F. Nielsen; Allan René Linneberg; Oluf Pedersen; Tune H Pers; Henrik Vestergaard; Børge Nordestgaard; Anne Tybjærg-Hansen; Anette Varbo; 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; Cecilia M Lindgren; Joel N Hirschhorn; Ruth J F Loos

doi:10.1038/s41588-017-0011-x

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

Valérie Turcot, Yingchang Lu, Heather M Highland, Lia E Bang, Marianne Benn, Pia R Kamstrup, Jette Bork-Jensen, Ruth Frikke-Schmidt, Anette P Gjesing, Niels Grarup, Torben Hansen, Christian Theil Have, Torben Jørgensen, Sune F. Nielsen, Allan René Linneberg, Oluf Pedersen, Tune H Pers, Henrik Vestergaard, Børge Nordestgaard, Anne Tybjærg-HansenAnette Varbo, 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, Cecilia M Lindgren, Joel N Hirschhorn, Ruth J F Loos

128 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	50
Sider (fra-til)	26-41
Antal sider	16
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-017-0011-x
Status	Udgivet - 1 jan. 2018

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Turcot, V., Lu, Y., Highland, H. M., Bang, L. E., Benn, M., Kamstrup, P. R., Bork-Jensen, J., Frikke-Schmidt, R., Gjesing, A. P., Grarup, N., Hansen, T., Have, C. T., Jørgensen, T., Nielsen, S. F., Linneberg, A. R., Pedersen, O., Pers, T. H., Vestergaard, H., Nordestgaard, B., ... 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

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, bind 50, s. 26-41. https://doi.org/10.1038/s41588-017-0011-x

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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.",

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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}",

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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

PY - 2018/1/1

Y1 - 2018/1/1

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

SN - 1061-4036

VL - 50

SP - 26

EP - 41

JO - Nature: New biology

JF - Nature: New biology

ER -

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

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