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

Turcot, Valerie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tonu; 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 GD; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie CY; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Goncalo; 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, Ines; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blueher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Boeger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der I; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; Bakker, Paul IW; Groot, Mark CH; Mutsert, Renee; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; Heijer, Martin; Hollander, Anneke I; Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dube, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Joergen; Grant, Struan FA; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Oyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna MM; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Hakan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jorgensen, Marit E; Jorgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, Rene S; Kahonen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltan; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimaki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindstrom, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken S; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikainen, Leo-Pekka; Mannisto, Satu; Marenne, Gaelle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Mueller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njolstad, Pal R; Nordestgaard, Borge G; Nyholt, Dale R; O'Connel, Jeffrey R; O'Donoghue, Michelle L; Loohuis, Loes M Olde; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John RB; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva RB; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renstrom, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert V; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Toenjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, Andre G; Uusitupa, Matti; Laan, Sander W; Duijn, Cornelia M; Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Edwards, Digna R Velez; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Voelker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth JF

doi:10.1038/s41588-017-0011-x

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Author(s)

Turcot, Valerie

Lu, Yingchang

Highland, Heather M

Schurmann, Claudia

Justice, Anne E

Fine, Rebecca S

Bradfield, Jonathan P

Esko, Tonu

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 GD

Manning, Alisa K

Medina-Gomez, Carolina

Mudgal, Poorva

Ng, Maggie CY

Reiner, Alex P

Vedantam, Sailaja

Willems, Sara M

Winkler, Thomas W

Abecasis, Goncalo

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, Ines

Bastarache, Lisa

Benn, Marianne

Bergmann, Sven

Bielak, Lawrence F

Blueher, Matthias

Boehnke, Michael

Boeing, Heiner

Boerwinkle, Eric

Boeger, Carsten A

Bork-Jensen, Jette

Bots, Michiel L

Bottinger, Erwin P

Bowden, Donald W

Brandslund, Ivan

Breen, Gerome

Brilliant, Murray H

Broer, Linda

Brumat, Marco

Burt, Amber A

Butterworth, Adam S

Campbell, Peter T

Cappellani, Stefania

Carey, David J

Catamo, Eulalia

Caulfield, Mark J

Chambers, John C

Chasman, Daniel I

Chen, Yii-Der I

Chowdhury, Rajiv

Christensen, Cramer

Chu, Audrey Y

Cocca, Massimiliano

Collins, Francis S

Cook, James P

Corley, Janie

Galbany, Jordi Corominas

Cox, Amanda J

Crosslin, David S

Cuellar-Partida, Gabriel

D'Eustacchio, Angela

Danesh, John

Davies, Gail

Bakker, Paul IW

Groot, Mark CH

Mutsert, Renee

Deary, Ian J

Dedoussis, George

Demerath, Ellen W

Heijer, Martin

Hollander, Anneke I

Ruijter, Hester M

Dennis, Joe G

Denny, Josh C

Angelantonio, Emanuele

Drenos, Fotios

Du, Mengmeng

Dube, Marie-Pierre

Dunning, Alison M

Easton, Douglas F

Edwards, Todd L

Ellinghaus, David

Ellinor, Patrick T

Elliott, Paul

Evangelou, Evangelos

Farmaki, Aliki-Eleni

Farooqi, I Sadaf

Faul, Jessica D

Fauser, Sascha

Feng, Shuang

Ferrannini, Ele

Ferrieres, Jean

Florez, Jose C

Ford, Ian

Fornage, Myriam

Franco, Oscar H

Franke, Andre

Franks, Paul W

Friedrich, Nele

Frikke-Schmidt, Ruth

Galesloot, Tessel E

Gan, Wei

Gandin, Ilaria

Gasparini, Paolo

Gibson, Jane

Giedraitis, Vilmantas

Gjesing, Anette P

Gordon-Larsen, Penny

Gorski, Mathias

Grabe, Hans-Joergen

Grant, Struan FA

Grarup, Niels

Griffiths, Helen L

Grove, Megan L

Gudnason, Vilmundur

Gustafsson, Stefan

Haessler, Jeff

Hakonarson, Hakon

Hammerschlag, Anke R

Hansen, Torben

Harris, Kathleen Mullan

Harris, Tamara B

Hattersley, Andrew T

Have, Christian T

Hayward, Caroline

He, Liang

Heard-Costa, Nancy L

Heath, Andrew C

Heid, Iris M

Helgeland, Oyvind

Hernesniemi, Jussi

Hewitt, Alex W

Holmen, Oddgeir L

Hovingh, G Kees

Howson, Joanna MM

Hu, Yao

Huang, Paul L

Huffman, Jennifer E

Ikram, M Arfan

Ingelsson, Erik

Jackson, Anne U

Jansson, Jan-Hakan

Jarvik, Gail P

Jensen, Gorm B

Jia, Yucheng

Johansson, Stefan

Jorgensen, Marit E

Jorgensen, Torben

Jukema, J Wouter

Kahali, Bratati

Kahn, Rene S

Kahonen, Mika

Kamstrup, Pia R

Kanoni, Stavroula

Kaprio, Jaakko

Karaleftheri, Maria

Kardia, Sharon LR

Karpe, Fredrik

Kathiresan, Sekar

Kee, Frank

Kiemeney, Lambertus A

Kim, Eric

Kitajima, Hidetoshi

Komulainen, Pirjo

Kooner, Jaspal S

Kooperberg, Charles

Korhonen, Tellervo

Kovacs, Peter

Kuivaniemi, Helena

Kutalik, Zoltan

Kuulasmaa, Kari

Kuusisto, Johanna

Laakso, Markku

Lakka, Timo A

Lamparter, David

Lange, Ethan M

Lange, Leslie A

Langenberg, Claudia

Larson, Eric B

Lee, Nanette R

Lehtimaki, Terho

Lewis, Cora E

Li, Huaixing

Li, Jin

Li-Gao, Ruifang

Lin, Honghuang

Lin, Keng-Hung

Lin, Li-An

Lin, Xu

Lind, Lars

Lindstrom, Jaana

Linneberg, Allan

Liu, Ching-Ti

Liu, Dajiang J

Liu, Yongmei

Lo, Ken S

Lophatananon, Artitaya

Lotery, Andrew J

Loukola, Anu

Luan, Jian'an

Lubitz, Steven A

Lyytikainen, Leo-Pekka

Mannisto, Satu

Marenne, Gaelle

Mazul, Angela L

McCarthy, Mark I

McKean-Cowdin, Roberta

Medland, Sarah E

Meidtner, Karina

Milani, Lili

Mistry, Vanisha

Mitchell, Paul

Mohlke, Karen L

Moilanen, Leena

Moitry, Marie

Montgomery, Grant W

Mook-Kanamori, Dennis O

Moore, Carmel

Mori, Trevor A

Morris, Andrew D

Morris, Andrew P

Mueller-Nurasyid, Martina

Munroe, Patricia B

Nalls, Mike A

Narisu, Narisu

Nelson, Christopher P

Neville, Matt

Nielsen, Sune F

Nikus, Kjell

Njolstad, Pal R

Nordestgaard, Borge G

Nyholt, Dale R

O'Connel, Jeffrey R

O'Donoghue, Michelle L

Loohuis, Loes M Olde

Ophoff, Roel A

Owen, Katharine R

Packard, Chris J

Padmanabhan, Sandosh

Palmer, Colin NA

Palmer, Nicholette D

Pasterkamp, Gerard

Patel, Aniruddh P

Pattie, Alison

Pedersen, Oluf

Peissig, Peggy L

Peloso, Gina M

Pennell, Craig E

Perola, Markus

Perry, James A

Perry, John RB

Pers, Tune H

Person, Thomas N

Peters, Annette

Petersen, Eva RB

Peyser, Patricia A

Pirie, Ailith

Polasek, Ozren

Polderman, Tinca J

Puolijoki, Hannu

Raitakari, Olli T

Rasheed, Asif

Rauramaa, Rainer

Reilly, Dermot F

Renstrom, Frida

Rheinberger, Myriam

Ridker, Paul M

Rioux, John D

Rivas, Manuel A

Roberts, David J

Robertson, Neil R

Robino, Antonietta

Rolandsson, Olov

Rudan, Igor

Ruth, Katherine S

Saleheen, Danish

Salomaa, Veikko

Samani, Nilesh J

Sapkota, Yadav

Sattar, Naveed

Schoen, Robert E

Schreiner, Pamela J

Schulze, Matthias B

Scott, Robert A

Segura-Lepe, Marcelo P

Shah, Svati H

Sheu, Wayne H-H

Sim, Xueling

Slater, Andrew J

Small, Kerrin S

Smith, Albert V

Southam, Lorraine

Spector, Timothy D

Speliotes, Elizabeth K

Starr, John M

Stefansson, Kari

Steinthorsdottir, Valgerdur

Stirrups, Kathleen E

Strauch, Konstantin

Stringham, Heather M

Stumvoll, Michael

Sun, Liang

Surendran, Praveen

Swift, Amy J

Tada, Hayato

Tansey, Katherine E

Tardif, Jean-Claude

Taylor, Kent D

Teumer, Alexander

Thompson, Deborah J

Thorleifsson, Gudmar

Thorsteinsdottir, Unnur

Thuesen, Betina H

Toenjes, Anke

Tromp, Gerard

Trompet, Stella

Tsafantakis, Emmanouil

Tuomilehto, Jaakko

Tybjaerg-Hansen, Anne

Tyrer, Jonathan P

Uher, Rudolf

Uitterlinden, Andre G

Uusitupa, Matti

Laan, Sander W

Duijn, Cornelia M

Leeuwen, Nienke

van Setten, Jessica

Vanhala, Mauno

Varbo, Anette

Varga, Tibor V

Varma, Rohit

Edwards, Digna R Velez

Vermeulen, Sita H

Veronesi, Giovanni

Vestergaard, Henrik

Vitart, Veronique

Vogt, Thomas F

Voelker, Uwe

Vuckovic, Dragana

Wagenknecht, Lynne E

Walker, Mark

Wallentin, Lars

Wang, Feijie

Wang, Carol A

Wang, Shuai

Wang, Yiqin

Ware, Erin B

Wareham, Nicholas J

Warren, Helen R

Waterworth, Dawn M

Wessel, Jennifer

White, Harvey D

Willer, Cristen J

Wilson, James G

Witte, Daniel R

Wood, Andrew R

Wu, Ying

Yaghootkar, Hanieh

Yao, Jie

Yao, Pang

Yerges-Armstrong, Laura M

Young, Robin

Zeggini, Eleftheria

Zhan, Xiaowei

Zhang, Weihua

Zhao, Jing Hua

Zhao, Wei

Zhou, Wei

Zondervan, Krina T

Rotter, Jerome I

Pospisilik, John A

Rivadeneira, Fernando

Borecki, Ingrid B

Deloukas, Panos

Frayling, Timothy M

Lettre, Guillaume

North, Kari E

Lindgren, Cecilia M

Hirschhorn, Joel N

Loos, Ruth JF

Griffith University Author(s)

Cox, Amanda J.

Year published

2018

Metadata

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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 ...
View more >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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Journal Title

Nature Genetics

Volume

DOI

https://doi.org/10.1038/s41588-017-0011-x

Copyright Statement

© 2018 Nature Publishing Group. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal website for access to the definitive, published version.

Subject

Biological sciences

Biomedical and clinical sciences

Publication URI

http://hdl.handle.net/10072/377154

Collection

Journal articles