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 Citations (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.

Original language	English
Journal	Nature Genetics
Volume	50
Pages (from-to)	26-41
Number of pages	16
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-017-0011-x
Publication status	Published - 1 Jan 2018

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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, vol. 50, pp. 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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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 Genetics

JF - Nature Genetics

ER -

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

Abstract

Keywords

UN SDGs

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