%0 Journal Article %J Nature Genetics %D 2019 %T Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. %A Liu, Mengzhen %A Jiang, Yu %A Wedow, Robbee %A Li, Yue %A Brazel, David M %A Chen, Fang %A Datta, Gargi %A Davila-Velderrain, Jose %A McGuire, Daniel %A Tian, Chao %A Zhan, Xiaowei %A Choquet, Hélène %A Docherty, Anna R %A Jessica Faul %A Foerster, Johanna R %A Fritsche, Lars G %A Gabrielsen, Maiken Elvestad %A Gordon, Scott D %A Jeffrey Haessler %A Jouke-Jan Hottenga %A Huang, Hongyan %A Jang, Seon-Kyeong %A Philip R Jansen %A Ling, Yueh %A Mägi, Reedik %A Matoba, Nana %A McMahon, George %A Mulas, Antonella %A Orrù, Valeria %A Palviainen, Teemu %A Anita Pandit %A Reginsson, Gunnar W %A Skogholt, Anne Heidi %A Smith, Jennifer A %A Taylor, Amy E %A Turman, Constance %A Gonneke Willemsen %A Young, Hannah %A Young, Kendra A %A Zajac, Gregory J M %A Zhao, Wei %A Zhou, Wei %A Bjornsdottir, Gyda %A Boardman, Jason D %A Boehnke, Michael %A Dorret I Boomsma %A Chen, Chu %A Francesco Cucca %A Davies, Gareth E %A Charles B Eaton %A Ehringer, Marissa A %A Tõnu Esko %A Fiorillo, Edoardo %A Gillespie, Nathan A %A Gudbjartsson, Daniel F %A Haller, Toomas %A Kathleen Mullan Harris %A Andrew C Heath %A Hewitt, John K %A Hickie, Ian B %A Hokanson, John E %A Hopfer, Christian J %A Hunter, David J %A Iacono, William G %A Johnson, Eric O %A Kamatani, Yoichiro %A Sharon L R Kardia %A Matthew C Keller %A Kellis, Manolis %A Charles Kooperberg %A Kraft, Peter %A Krauter, Kenneth S %A Laakso, Markku %A Penelope A Lind %A Loukola, Anu %A Lutz, Sharon M %A Pamela A F Madden %A Nicholas G Martin %A McGue, Matt %A Matthew B McQueen %A Sarah E Medland %A Andres Metspalu %A Mohlke, Karen L %A Nielsen, Jonas B %A Okada, Yukinori %A Peters, Ulrike %A Tinca J Polderman %A Posthuma, Danielle %A Reiner, Alexander P %A Rice, John P %A Rimm, Eric %A Rose, Richard J %A Runarsdottir, Valgerdur %A Stallings, Michael C %A Stančáková, Alena %A Stefansson, Hreinn %A Thai, Khanh K %A Hilary A Tindle %A Tyrfingsson, Thorarinn %A Wall, Tamara L %A David R Weir %A Weisner, Constance %A Whitfield, John B %A Winsvold, Bendik Slagsvold %A Yin, Jie %A Zuccolo, Luisa %A Laura Bierut %A Hveem, Kristian %A Lee, James J %A Munafò, Marcus R %A Saccone, Nancy L %A Willer, Cristen J %A Marilyn C Cornelis %A David, Sean P %A Hinds, David A %A Jorgenson, Eric %A Kaprio, Jaakko %A Stitzel, Jerry A %A Stefansson, Kari %A Thorgeirsson, Thorgeir E %A Gonçalo R Abecasis %A Liu, Dajiang J %A Scott Vrieze %K Alcohol Drinking %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Phenotype %K Risk %K Smoking %K Tobacco %K Tobacco Use Disorder %X

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

%B Nature Genetics %V 51 %P 237-244 %G eng %N 2 %R 10.1038/s41588-018-0307-5 %0 Journal Article %J Nat Genet %D 2018 %T Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. %A Turcot, Valérie %A Lu, Yingchang %A Highland, Heather M %A Schurmann, Claudia %A Justice, Anne E %A Fine, Rebecca S %A Bradfield, Jonathan P %A Tõnu Esko %A Giri, Ayush %A Graff, Mariaelisa %A Guo, Xiuqing %A Hendricks, Audrey E %A Karaderi, Tugce %A Lempradl, Adelheid %A Locke, Adam E %A Mahajan, Anubha %A Marouli, Eirini %A Sivapalaratnam, Suthesh %A Young, Kristin L %A Alfred, Tamuno %A Feitosa, Mary F %A Masca, Nicholas G D %A Alisa Manning %A Medina-Gomez, Carolina %A Mudgal, Poorva %A Ng, Maggie C Y %A Reiner, Alex P %A Vedantam, Sailaja %A Willems, Sara M %A Thomas W Winkler %A Gonçalo R Abecasis %A Aben, Katja K %A Alam, Dewan S %A Alharthi, Sameer E %A Matthew A. Allison %A Amouyel, Philippe %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Bang, Lia E %A Barroso, Inês %A Bastarache, Lisa %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boehnke, Michael %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bork-Jensen, Jette %A Bots, Michiel L %A Erwin P Bottinger %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Brumat, Marco %A Burt, Amber A %A Adam S Butterworth %A Campbell, Peter T %A Cappellani, Stefania %A Carey, David J %A Catamo, Eulalia %A Caulfield, Mark J %A Chambers, John C %A Daniel I Chasman %A Yii-Der I Chen %A Chowdhury, Rajiv %A Cramer Christensen %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Jordi Corominas Galbany %A Cox, Amanda J %A Crosslin, David S %A Cuellar-Partida, Gabriel %A D'Eustacchio, Angela %A Danesh, John %A Gail Davies %A Bakker, Paul I W %A Groot, Mark C H %A Mutsert, Renée %A Ian J Deary %A George Dedoussis %A Ellen W Demerath %A Heijer, Martin %A Anneke I den Hollander %A Hester M den Ruijter %A Joe G Dennis %A Denny, Josh C %A Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dubé, Marie-Pierre %A Dunning, Alison M %A Easton, Douglas F %A Edwards, Todd L %A Ellinghaus, David %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Farooqi, I Sadaf %A Jessica Faul %A Fauser, Sascha %A Feng, Shuang %A Ferrannini, Ele %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Myriam Fornage %A Franco, Oscar H %A Franke, Andre %A Franks, Paul W %A Friedrich, Nele %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Paolo P. Gasparini %A Gibson, Jane %A Giedraitis, Vilmantas %A Gjesing, Anette P %A Gordon-Larsen, Penny %A Gorski, Mathias %A Hans-Jörgen Grabe %A Grant, Struan F A %A Grarup, Niels %A Griffiths, Helen L %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Jeffrey Haessler %A Hakonarson, Hakon %A Anke R Hammerschlag %A Hansen, Torben %A Tamara B Harris %A Andrew T Hattersley %A Have, Christian T %A Caroline Hayward %A He, Liang %A Heard-Costa, Nancy L %A Andrew C Heath %A Iris M Heid %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Oddgeir L Holmen %A Hovingh, G Kees %A Howson, Joanna M M %A Hu, Yao %A Huang, Paul L %A Huffman, Jennifer E %A Mohammed Arfan Ikram %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jia, Yucheng %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Sharon L R Kardia %A Karpe, Fredrik %A Kathiresan, Sekar %A Kee, Frank %A Lambertus A Kiemeney %A Eric S Kim %A Kitajima, Hidetoshi %A Komulainen, Pirjo %A Kooner, Jaspal S %A Charles Kooperberg %A Korhonen, Tellervo %A Kovacs, Peter %A Kuivaniemi, Helena %A Kutalik, Zoltán %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lamparter, David %A Lange, Ethan M %A Leslie A Lange %A Langenberg, Claudia %A Eric B Larson %A Lee, Nanette R %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Keng-Hung %A Lin, Li-An %A Lin, Xu %A Lars Lind %A Lindström, Jaana %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Dajiang J %A Yongmei Liu %A Ken Sin Lo %A Lophatananon, Artitaya %A Lotery, Andrew J %A Loukola, Anu %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Männistö, Satu %A Marenne, Gaëlle %A Mazul, Angela L %A McCarthy, Mark I %A McKean-Cowdin, Roberta %A Sarah E Medland %A Meidtner, Karina %A Lili Milani %A Mistry, Vanisha %A Mitchell, Paul %A Mohlke, Karen L %A Moilanen, Leena %A Moitry, Marie %A Grant W Montgomery %A Dennis O Mook-Kanamori %A Moore, Carmel %A Mori, Trevor A %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Michael A Nalls %A Narisu, Narisu %A Nelson, Christopher P %A Neville, Matt %A Sune Fallgaard Nielsen %A Nikus, Kjell %A Njølstad, Pål R %A Børge G Nordestgaard %A Nyholt, Dale R %A Jeff O'Connell %A O'Donoghue, Michelle L %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Palmer, Nicholette D %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Markus Perola %A Perry, James A %A Perry, John R B %A Pers, Tune H %A Person, Thomas N %A Peters, Annette %A Petersen, Eva R B %A Peyser, Patricia A %A Pirie, Ailith %A Polasek, Ozren %A Tinca J Polderman %A Puolijoki, Hannu %A Olli T Raitakari %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Renstrom, Frida %A Rheinberger, Myriam %A Ridker, Paul M %A Rioux, John D %A Rivas, Manuel A %A Roberts, David J %A Neil R Robertson %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Veikko Salomaa %A Nilesh J Samani %A Sapkota, Yadav %A Sattar, Naveed %A Schoen, Robert E %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Svati H Shah %A Sheu, Wayne H-H %A Sim, Xueling %A Slater, Andrew J %A Small, Kerrin S %A Albert Vernon Smith %A Southam, Lorraine %A Timothy Spector %A Elizabeth K Speliotes %A John M Starr %A Stefansson, Kari %A Steinthorsdottir, Valgerdur %A Kathleen E Stirrups %A Strauch, Konstantin %A Heather M Stringham %A Stumvoll, Michael %A Sun, Liang %A Surendran, Praveen %A Swift, Amy J %A Tada, Hayato %A Tansey, Katherine E %A Tardif, Jean-Claude %A Kent D Taylor %A Teumer, Alexander %A Thompson, Deborah J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A André G Uitterlinden %A Uusitupa, Matti %A Laan, Sander W %A Duijn, Cornelia M %A Leeuwen, Nienke %A van Setten, Jessica %A Vanhala, Mauno %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Digna R Velez Edwards %A Vermeulen, Sita H %A Veronesi, Giovanni %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Völker, Uwe %A Vuckovic, Dragana %A Wagenknecht, Lynne E %A Walker, Mark %A Wallentin, Lars %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Erin B Ware %A Wareham, Nicholas J %A Warren, Helen R %A Dawn M Waterworth %A Wessel, Jennifer %A White, Harvey D %A Willer, Cristen J %A Wilson, James G %A Daniel Witte %A Andrew R Wood %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Laura M Yerges-Armstrong %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Wei Zhao %A Zhou, Wei %A Krina T Zondervan %A Rotter, Jerome I %A Pospisilik, John A %A Fernando Rivadeneira %A Ingrid B Borecki %A Deloukas, Panos %A Timothy M Frayling %A Lettre, Guillaume %A Kari E North %A Lindgren, Cecilia M %A Joel N Hirschhron %A Ruth J F Loos %X

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.

%B Nat Genet %V 50 %P 26-41 %8 2018 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29273807?dopt=Abstract %R 10.1038/s41588-017-0011-x %0 Journal Article %J Nature %D 2017 %T Rare and low-frequency coding variants alter human adult height. %A Marouli, Eirini %A Graff, Mariaelisa %A Medina-Gomez, Carolina %A Ken Sin Lo %A Andrew R Wood %A Kjaer, Troels R %A Fine, Rebecca S %A Lu, Yingchang %A Schurmann, Claudia %A Highland, Heather M %A Rüeger, Sina %A Thorleifsson, Gudmar %A Justice, Anne E %A Lamparter, David %A Kathleen E Stirrups %A Turcot, Valérie %A Young, Kristin L %A Thomas W Winkler %A Tõnu Esko %A Karaderi, Tugce %A Locke, Adam E %A Masca, Nicholas G D %A Ng, Maggie C Y %A Mudgal, Poorva %A Rivas, Manuel A %A Vedantam, Sailaja %A Mahajan, Anubha %A Guo, Xiuqing %A Gonçalo R Abecasis %A Aben, Katja K %A Adair, Linda S %A Alam, Dewan S %A Albrecht, Eva %A Allin, Kristine H %A Matthew A. Allison %A Amouyel, Philippe %A Appel, Emil V %A Arveiler, Dominique %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Banas, Bernhard %A Bang, Lia E %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Bots, Michiel L %A Erwin P Bottinger %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Burt, Amber A %A Adam S Butterworth %A Carey, David J %A Caulfield, Mark J %A Chambers, John C %A Daniel I Chasman %A Yii-Der I Chen %A Chowdhury, Rajiv %A Cramer Christensen %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Jordi Corominas Galbany %A Cox, Amanda J %A Cuellar-Partida, Gabriel %A Danesh, John %A Gail Davies %A de Bakker, Paul I W %A de Borst, Gert J %A de Denus, Simon %A de Groot, Mark C H %A de Mutsert, Renée %A Ian J Deary %A George Dedoussis %A Ellen W Demerath %A Anneke I den Hollander %A Joe G Dennis %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dunning, Alison M %A Easton, Douglas F %A Ebeling, Tapani %A Edwards, Todd L %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Jessica Faul %A Feitosa, Mary F %A Feng, Shuang %A Ferrannini, Ele %A Marco M Ferrario %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Myriam Fornage %A Franks, Paul W %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Paolo P. Gasparini %A Giedraitis, Vilmantas %A Giri, Ayush %A Giorgia G Girotto %A Gordon, Scott D %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grarup, Niels %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Hansen, Torben %A Kathleen Mullan Harris %A Tamara B Harris %A Andrew T Hattersley %A Caroline Hayward %A He, Liang %A Iris M Heid %A Heikkilä, Kauko %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Lynne J Hocking %A Hollensted, Mette %A Oddgeir L Holmen %A Hovingh, G Kees %A Howson, Joanna M M %A Hoyng, Carel B %A Huang, Paul L %A Hveem, Kristian %A Mohammed Arfan Ikram %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jhun, Min A %A Jia, Yucheng %A Jiang, Xuejuan %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jousilahti, Pekka %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Sharon L R Kardia %A Karpe, Fredrik %A Kee, Frank %A Keeman, Renske %A Lambertus A Kiemeney %A Kitajima, Hidetoshi %A Kluivers, Kirsten B %A Kocher, Thomas %A Komulainen, Pirjo %A Kontto, Jukka %A Kooner, Jaspal S %A Charles Kooperberg %A Kovacs, Peter %A Kriebel, Jennifer %A Kuivaniemi, Helena %A Küry, Sébastien %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lakka, Timo A %A Lange, Ethan M %A Leslie A Lange %A Langefeld, Carl D %A Langenberg, Claudia %A Eric B Larson %A Lee, I-Te %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Li-An %A Lin, Xu %A Lars Lind %A Lindström, Jaana %A Linneberg, Allan %A Liu, Yeheng %A Yongmei Liu %A Lophatananon, Artitaya %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Mackey, David A %A Pamela A F Madden %A Alisa Manning %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Nicholas G Martin %A Mazul, Angela L %A Meidtner, Karina %A Andres Metspalu %A Mitchell, Paul %A Mohlke, Karen L %A Dennis O Mook-Kanamori %A Morgan, Anna %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Michael A Nalls %A Nauck, Matthias %A Nelson, Christopher P %A Neville, Matt %A Sune Fallgaard Nielsen %A Nikus, Kjell %A Njølstad, Pål R %A Børge G Nordestgaard %A Ntalla, Ioanna %A Jeff O'Connell %A Oksa, Heikki %A Loes M Olde Loohuis %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Markus Perola %A Perry, James A %A Perry, John R B %A Person, Thomas N %A Pirie, Ailith %A Polasek, Ozren %A Posthuma, Danielle %A Olli T Raitakari %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Ridker, Paul M %A Rioux, John D %A Neil R Robertson %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Veikko Salomaa %A Nilesh J Samani %A Sandow, Kevin %A Sapkota, Yadav %A Sattar, Naveed %A Schmidt, Marjanka K %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Svati H Shah %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Albert Vernon Smith %A Jennifer A Smith %A Southam, Lorraine %A Timothy Spector %A Elizabeth K Speliotes %A John M Starr %A Steinthorsdottir, Valgerdur %A Heather M Stringham %A Stumvoll, Michael %A Surendran, Praveen %A 't Hart, Leen M %A Tansey, Katherine E %A Tardif, Jean-Claude %A Kent D Taylor %A Teumer, Alexander %A Thompson, Deborah J %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A André G Uitterlinden %A Ulivi, Sheila %A van der Laan, Sander W %A Van Der Leij, Andries R %A Cornelia M van Duijn %A van Schoor, Natasja M %A van Setten, Jessica %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Digna R Velez Edwards %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vozzi, Diego %A Walker, Mark %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Wareham, Nicholas J %A Warren, Helen R %A Wessel, Jennifer %A Willems, Sara M %A Wilson, James G %A Daniel Witte %A Woods, Michael O %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Laura M Yerges-Armstrong %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Jing Hua Zhao %A Wei Zhao %A Wei Zhao %A Zheng, He %A Zhou, Wei %A Rotter, Jerome I %A Boehnke, Michael %A Kathiresan, Sekar %A McCarthy, Mark I %A Willer, Cristen J %A Stefansson, Kari %A Ingrid B Borecki %A Liu, Dajiang J %A Kari E North %A Heard-Costa, Nancy L %A Pers, Tune H %A Lindgren, Cecilia M %A Oxvig, Claus %A Kutalik, Zoltán %A Fernando Rivadeneira %A Ruth J F Loos %A Timothy M Frayling %A Joel N Hirschhron %A Deloukas, Panos %A Lettre, Guillaume %X

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

%B Nature %V 542 %P 186-190 %8 2017 Feb 09 %G eng %N 7640 %1 http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039