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 & 31 andre 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, Ivan Brandslund, Cramer Christensen, Gorm B Jensen, Marit E Jørgensen, Betina H Thuesen, CHD Exome+ Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftNature Genetics
Vol/bind50
Udgave nummer1
Sider (fra-til)26-41
ISSN1061-4036
DOI
StatusUdgivet - 2018

Fingeraftryk

Energy Metabolism
Body Mass Index
Genome-Wide Association Study
Proteins
Adipocytes
Mutation

Citer dette

Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., ... 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/s41588-018-0050-y
Turcot, Valérie ; Lu, Yingchang ; Highland, Heather M ; Schurmann, Claudia ; Justice, Anne E ; Fine, Rebecca S ; Bradfield, Jonathan P ; Esko, Tõnu ; Giri, Ayush ; Graff, Mariaelisa ; Guo, Xiuqing ; Hendricks, Audrey E ; Karaderi, Tugce ; Lempradl, Adelheid ; Locke, Adam E ; Mahajan, Anubha ; Marouli, Eirini ; Sivapalaratnam, Suthesh ; Young, Kristin L ; Alfred, Tamuno ; Feitosa, Mary F ; Masca, Nicholas G D ; Manning, Alisa K ; Medina-Gomez, Carolina ; Mudgal, Poorva ; Ng, Maggie C Y ; Reiner, Alex P ; Vedantam, Sailaja ; Willems, Sara M ; Winkler, Thomas W ; Abecasis, Gonçalo ; Aben, Katja K ; Alam, Dewan S ; Alharthi, Sameer E ; Allison, Matthew ; Amouyel, Philippe ; Asselbergs, Folkert W ; Auer, Paul L ; Balkau, Beverley ; Bang, Lia E ; Barroso, Inês ; Bastarache, Lisa ; Benn, Marianne ; Bergmann, Sven ; Bielak, Lawrence F ; Brandslund, Ivan ; Christensen, Cramer ; Jensen, Gorm B ; Jørgensen, Marit E ; Thuesen, Betina H ; CHD Exome+ Consortium. / Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. I: Nature Genetics. 2018 ; Bind 50, Nr. 1. s. 26-41.
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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 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{\cc}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 Ivan Brandslund and Cramer Christensen and Jensen, {Gorm B} and J{\o}rgensen, {Marit E} and Thuesen, {Betina H} and {CHD Exome+ Consortium}",
note = "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.",
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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, Brandslund, I, Christensen, C, Jensen, GB, Jørgensen, ME, Thuesen, BH & CHD Exome+ Consortium 2018, 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity', Nature Genetics, bind 50, nr. 1, s. 26-41. https://doi.org/10.1038/s41588-018-0050-y

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

I: Nature Genetics, Bind 50, Nr. 1, 2018, s. 26-41.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - Brandslund, Ivan

AU - Christensen, Cramer

AU - Jensen, Gorm B

AU - Jørgensen, Marit E

AU - Thuesen, Betina H

AU - CHD Exome+ Consortium

N1 - 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.

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

U2 - 10.1038/s41588-018-0050-y

DO - 10.1038/s41588-018-0050-y

M3 - Journal article

VL - 50

SP - 26

EP - 41

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -