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; Claudia Schurmann; Anne E Justice; Rebecca S Fine; Jonathan P Bradfield; Tõnu Esko; Ayush Giri; Mariaelisa Graff; Xiuqing Guo; Audrey E Hendricks; Tugce Karaderi; Adelheid Lempradl; Adam E Locke; Anubha Mahajan; Eirini Marouli; Suthesh Sivapalaratnam; Kristin L Young; Tamuno Alfred; Mary F Feitosa; Nicholas G D Masca; Alisa K Manning; Carolina Medina-Gomez; Poorva Mudgal; Maggie C Y Ng; Alex P Reiner; Sailaja Vedantam; Sara M Willems; Thomas W Winkler; Gonçalo Abecasis; Katja K Aben; Dewan S Alam; Sameer E Alharthi; Matthew Allison; Philippe Amouyel; Folkert W Asselbergs; Paul L Auer; Beverley Balkau; Lia E Bang; Inês Barroso; Lisa Bastarache; Marianne Benn; Sven Bergmann; Lawrence F Bielak; Matthias Blüher; Michael Boehnke; Heiner Boeing; Eric Boerwinkle; Fotios Drenos; CHD Exome+ Consortium

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, Claudia Schurmann, Anne E Justice, Rebecca S Fine, Jonathan P Bradfield, Tõnu Esko, Ayush Giri, Mariaelisa Graff, Xiuqing Guo, Audrey E Hendricks, Tugce Karaderi, Adelheid Lempradl, Adam E Locke, Anubha Mahajan, Eirini Marouli, Suthesh Sivapalaratnam, Kristin L Young, Tamuno AlfredMary F Feitosa, Nicholas G D Masca, Alisa K Manning, Carolina Medina-Gomez, Poorva Mudgal, Maggie C Y Ng, Alex P Reiner, Sailaja Vedantam, Sara M Willems, Thomas W Winkler, Gonçalo Abecasis, Katja K Aben, Dewan S Alam, Sameer E Alharthi, Matthew Allison, Philippe Amouyel, Folkert W Asselbergs, Paul L Auer, Beverley Balkau, Lia E Bang, Inês Barroso, Lisa Bastarache, Marianne Benn, Sven Bergmann, Lawrence F Bielak, Matthias Blüher, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Fotios Drenos, CHD Exome+ Consortium

Research output: Contribution to journal › Article (Academic Journal) › peer-review

278 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
Pages (from-to)	26-41
Number of pages	16
Journal	Nature Genetics
Volume	50
Issue number	1
Early online date	22 Dec 2017
DOIs	https://doi.org/10.1038/s41588-017-0011-x
Publication status	Published - Jan 2018

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UN SDGs

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

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278 Citations
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Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Turcot, V., CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium & MAGIC Investigators & Understanding Society Scientific Group, 16 Mar 2018, In: Nature Genetics. 50, 5, p. 765-766 2 p.
Research output: Contribution to journal › Comment/debate (Academic Journal) › peer-review
1 Citation (Scopus)

Cite this

Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., Bradfield, J. P., Esko, T., Giri, A., Graff, M., Guo, X., Hendricks, A. E., Karaderi, T., Lempradl, A., Locke, A. E., Mahajan, A., Marouli, E., Sivapalaratnam, S., Young, K. L., ... CHD Exome+ Consortium (2018). Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics, 50(1), 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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Turcot, V, Lu, Y, Highland, HM, Schurmann, C, Justice, AE, Fine, RS, Bradfield, JP, Esko, T, Giri, A, Graff, M, Guo, X, Hendricks, AE, Karaderi, T, Lempradl, A, Locke, AE, Mahajan, A, Marouli, E, Sivapalaratnam, S, Young, KL, Alfred, T, Feitosa, MF, Masca, NGD, Manning, AK, Medina-Gomez, C, Mudgal, P, Ng, MCY, Reiner, AP, Vedantam, S, Willems, SM, Winkler, TW, Abecasis, G, Aben, KK, Alam, DS, Alharthi, SE, Allison, M, Amouyel, P, Asselbergs, FW, Auer, PL, Balkau, B, Bang, LE, Barroso, I, Bastarache, L, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boehnke, M, Boeing, H, Boerwinkle, E, Drenos, F & CHD Exome+ Consortium 2018, 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity', Nature Genetics, vol. 50, no. 1, pp. 26-41. https://doi.org/10.1038/s41588-017-0011-x

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 - Schurmann, Claudia

AU - Justice, Anne E

AU - Fine, Rebecca S

AU - Bradfield, Jonathan P

AU - Esko, Tõnu

AU - Giri, Ayush

AU - Graff, Mariaelisa

AU - Guo, Xiuqing

AU - Hendricks, Audrey E

AU - Karaderi, Tugce

AU - Lempradl, Adelheid

AU - Locke, Adam E

AU - Mahajan, Anubha

AU - Marouli, Eirini

AU - Sivapalaratnam, Suthesh

AU - Young, Kristin L

AU - Alfred, Tamuno

AU - Feitosa, Mary F

AU - Masca, Nicholas G D

AU - Manning, Alisa K

AU - Medina-Gomez, Carolina

AU - Mudgal, Poorva

AU - Ng, Maggie C Y

AU - Reiner, Alex P

AU - Vedantam, Sailaja

AU - Willems, Sara M

AU - Winkler, Thomas W

AU - Abecasis, Gonçalo

AU - Aben, Katja K

AU - Alam, Dewan S

AU - Alharthi, Sameer E

AU - Allison, Matthew

AU - Amouyel, Philippe

AU - Asselbergs, Folkert W

AU - Auer, Paul L

AU - Balkau, Beverley

AU - Bang, Lia E

AU - Barroso, Inês

AU - Bastarache, Lisa

AU - Benn, Marianne

AU - Bergmann, Sven

AU - Bielak, Lawrence F

AU - Blüher, Matthias

AU - Boehnke, Michael

AU - Boeing, Heiner

AU - Boerwinkle, Eric

AU - Drenos, Fotios

AU - CHD Exome+ Consortium

PY - 2018/1

Y1 - 2018/1

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

U2 - 10.1038/s41588-017-0011-x

DO - 10.1038/s41588-017-0011-x

M3 - Article (Academic Journal)

C2 - 29273807

SN - 1061-4036

VL - 50

SP - 26

EP - 41

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

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UN SDGs

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

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