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; Torben Jørgensen; 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, Torben Jørgensen, CHD Exome+ Consortium

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Journal	Nature Genetics
Volume	50
Issue number	1
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 - 2018

Bibliographical note

Publisher Corrections:
1.
In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article (doi: 10.1038/s41588-018-0082-3).
2.
In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article (doi: 10.1038/s41588-018-0050-y).
3.
In the HTML version of this article initially published, the author groups ‘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’, ‘The MAGIC Investigators’ and ‘Understanding Society Scientific Group’ appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article. (doi.:10.1038/s41588-019-0447-2 )

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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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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.",

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author = "Val{\'e}rie Turcot and Yingchang Lu and Highland, {Heather M} and Claudia Schurmann and Justice, {Anne E} and Fine, {Rebecca S} and Bradfield, {Jonathan P} and T{\~o}nu Esko and Ayush Giri and Mariaelisa Graff and Xiuqing Guo and Hendricks, {Audrey E} and Tugce Karaderi and Adelheid Lempradl and Locke, {Adam E} and Anubha Mahajan and Eirini Marouli and Suthesh Sivapalaratnam and Young, {Kristin L} and Tamuno Alfred and Feitosa, {Mary F} and Masca, {Nicholas G D} and Manning, {Alisa K} and Carolina Medina-Gomez and Poorva Mudgal and Ng, {Maggie C Y} and Reiner, {Alex P} and Sailaja Vedantam and Willems, {Sara M} and Winkler, {Thomas W} and Gon{\c c}alo Abecasis and Aben, {Katja K} and Alam, {Dewan S} and Alharthi, {Sameer E} and Matthew Allison and Philippe Amouyel and Asselbergs, {Folkert W} and Auer, {Paul L} and Beverley Balkau and Bang, {Lia E} and In{\^e}s Barroso and Lisa Bastarache and Marianne Benn and Sven Bergmann and Bielak, {Lawrence F} and Matthias Bl{\"u}her and Michael Boehnke and Heiner Boeing and Eric Boerwinkle and Torben J{\o}rgensen and {CHD Exome+ Consortium}",

note = "Publisher Corrections: 1. In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article (doi: 10.1038/s41588-018-0082-3). 2. In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article (doi: 10.1038/s41588-018-0050-y). 3. In the HTML version of this article initially published, the author groups {\textquoteleft}CHD Exome+ Consortium{\textquoteright}, {\textquoteleft}EPIC-CVD Consortium{\textquoteright}, {\textquoteleft}ExomeBP Consortium{\textquoteright}, {\textquoteleft}Global Lipids Genetic Consortium{\textquoteright}, {\textquoteleft}GoT2D Genes Consortium{\textquoteright}, {\textquoteleft}EPIC InterAct Consortium{\textquoteright}, {\textquoteleft}INTERVAL Study{\textquoteright}, {\textquoteleft}ReproGen Consortium{\textquoteright}, {\textquoteleft}T2D-Genes Consortium{\textquoteright}, {\textquoteleft}The MAGIC Investigators{\textquoteright} and {\textquoteleft}Understanding Society Scientific Group{\textquoteright} appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article. (doi.:10.1038/s41588-019-0447-2 )",

year = "2018",

doi = "10.1038/s41588-017-0011-x",

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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, Jørgensen, T & 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 - Jørgensen, Torben

AU - CHD Exome+ Consortium

N1 - Publisher Corrections: 1. In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article (doi: 10.1038/s41588-018-0082-3). 2. In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article (doi: 10.1038/s41588-018-0050-y). 3. In the HTML version of this article initially published, the author groups ‘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’, ‘The MAGIC Investigators’ and ‘Understanding Society Scientific Group’ appeared at the end of the author list but should have appeared earlier in the list, after author Krina T. Zondervan. The errors have been corrected in the HTML version of the article. (doi.: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 - http://www.scopus.com/inward/record.url?scp=85039153797&partnerID=8YFLogxK

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

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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