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; Lia E Bang; Marianne Benn; Jette Bork-Jensen; Ruth Frikke-Schmidt; Gorm B Jensen; Marit E Jørgensen; Torben Jørgensen; Pia R Kamstrup; Allan Linneberg; Sune F Nielsen; Børge G Nordestgaard; Tune H Pers; Betina H Thuesen; Anne Tybjaerg-Hansen; Anette Varbo; Henrik Vestergaard; 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, Lia E Bang, Marianne Benn, Jette Bork-Jensen, Ruth Frikke-Schmidt, Gorm B Jensen, Marit E Jørgensen, Torben Jørgensen, Pia R Kamstrup, Allan Linneberg, Sune F Nielsen, Børge G Nordestgaard, Tune H Pers, Betina H Thuesen, Anne Tybjaerg-Hansen, Anette Varbo, Henrik Vestergaard, CHD Exome+ Consortium

311 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
Udgave nummer	1
Sider (fra-til)	26-41
Antal sider	16
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-017-0011-x
Status	Udgivet - jan. 2018

Adgang til dokumentet

10.1038/s41588-017-0011-x

Citationsformater

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

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, Bang, LE , Benn, M, Bork-Jensen, J, Frikke-Schmidt, R, Jensen, GB, Jørgensen, ME, Jørgensen, T , Kamstrup, PR , Linneberg, A , Nielsen, SF , Nordestgaard, BG, Pers, TH, Thuesen, BH, Tybjaerg-Hansen, A, Varbo, A, Vestergaard, H & 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/s41588-017-0011-x

@article{039ee8af338e4013801834cb35b607d2,

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.",

keywords = "Journal Article",

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 Bang, {Lia E} and Marianne Benn and Jette Bork-Jensen and Ruth Frikke-Schmidt and Jensen, {Gorm B} and J{\o}rgensen, {Marit E} and Torben J{\o}rgensen and Kamstrup, {Pia R} and Allan Linneberg and Nielsen, {Sune F} and Nordestgaard, {B{\o}rge G} and Pers, {Tune H} and Thuesen, {Betina H} and Anne Tybjaerg-Hansen and Anette Varbo and Henrik Vestergaard and {CHD Exome+ Consortium}",

year = "2018",

month = jan,

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

language = "English",

volume = "50",

pages = "26--41",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

}

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 - Bang, Lia E

AU - Benn, Marianne

AU - Bork-Jensen, Jette

AU - Frikke-Schmidt, Ruth

AU - Jensen, Gorm B

AU - Jørgensen, Marit E

AU - Jørgensen, Torben

AU - Kamstrup, Pia R

AU - Linneberg, Allan

AU - Nielsen, Sune F

AU - Nordestgaard, Børge G

AU - Pers, Tune H

AU - Thuesen, Betina H

AU - Tybjaerg-Hansen, Anne

AU - Varbo, Anette

AU - Vestergaard, Henrik

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 - 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

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater