%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 Circulation: Cardiovascular Genetics %D 2017 %T New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. %A Kraja, Aldi T %A Cook, James P %A Warren, Helen R %A Surendran, Praveen %A Liu, Chunyu %A Evangelou, Evangelos %A Alisa Manning %A Grarup, Niels %A Drenos, Fotios %A Sim, Xueling %A Smith, Albert Vernon %A Amin, Najaf %A Alexandra I Blakemore %A Bork-Jensen, Jette %A Brandslund, Ivan %A Farmaki, Aliki-Eleni %A Fava, Cristiano %A Ferreira, Teresa %A Herzig, Karl-Heinz %A Giri, Ayush %A Giulianini, Franco %A Grove, Megan L %A Guo, Xiuqing %A Sarah E Harris %A Have, Christian T %A Havulinna, Aki S %A Zhang, He %A Jørgensen, Marit E %A Käräjämäki, AnneMari %A Charles Kooperberg %A Linneberg, Allan %A Little, Louis %A Liu, Yongmei %A Bonnycastle, Lori L %A Lu, Yingchang %A Mägi, Reedik %A Mahajan, Anubha %A Malerba, Giovanni %A Riccardo E Marioni %A Mei, Hao %A Menni, Cristina %A Alanna C Morrison %A Padmanabhan, Sandosh %A Walter R Palmas %A Poveda, Alaitz %A Rauramaa, Rainer %A Nigel W Rayner %A Riaz, Muhammad %A Rice, Ken %A Melissa Richard %A Smith, Jennifer A %A Southam, Lorraine %A Stančáková, Alena %A Kathleen E Stirrups %A Tragante, Vinicius %A Tuomi, Tiinamaija %A Tzoulaki, Ioanna %A Varga, Tibor V %A Weiss, Stefan %A Yiorkas, Andrianos M %A Young, Robin %A Zhang, Weihua %A Barnes, Michael R %A Cabrera, Claudia P %A Gao, He %A Boehnke, Michael %A Boerwinkle, Eric %A Chambers, John C %A Connell, John M %A Cramer Christensen %A de Boer, Rudolf A %A Ian J Deary %A George Dedoussis %A Deloukas, Panos %A Dominiczak, Anna F %A Dörr, Marcus %A Joehanes, Roby %A Edwards, Todd L %A Tõnu Esko %A Myriam Fornage %A Franceschini, Nora %A Franks, Paul W %A Gambaro, Giovanni %A Leif C Groop %A Hallmans, Göran %A Hansen, Torben %A Caroline Hayward %A Heikki, Oksa %A Ingelsson, Erik %A Tuomilehto, Jaakko %A Järvelin, Marjo-Riitta %A Sharon L R Kardia %A Karpe, Fredrik %A Kooner, Jaspal S %A Lakka, Timo A %A Langenberg, Claudia %A Lars Lind %A Ruth J F Loos %A Laakso, Markku %A McCarthy, Mark I %A Melander, Olle %A Mohlke, Karen L %A Morris, Andrew P %A Palmer, Colin N A %A Pedersen, Oluf %A Polasek, Ozren %A Neil Poulter %A Province, Michael A %A Psaty, Bruce M %A Ridker, Paul M %A Rotter, Jerome I %A Rudan, Igor %A Veikko Salomaa %A Nilesh J Samani %A Peter Sever %A Skaaby, Tea %A Stafford, Jeanette M %A John M Starr %A van der Harst, Pim %A van der Meer, Peter %A Cornelia M van Duijn %A Vergnaud, Anne-Claire %A Gudnason, Vilmundur %A Wareham, Nicholas J %A Wilson, James G %A Willer, Cristen J %A Daniel Witte %A Zeggini, Eleftheria %A Saleheen, Danish %A Adam S Butterworth %A Danesh, John %A Asselbergs, Folkert W %A Wain, Louise V %A Georg B Ehret %A Daniel I Chasman %A Caulfield, Mark J %A Elliott, Paul %A Lindgren, Cecilia M %A Levy, Daniel %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Howson, Joanna M M %K Antiporters %K Blood pressure %K Cell Adhesion Molecules, Neuronal %K Databases, Factual %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Microfilament Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Receptors, Lymphocyte Homing %X

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (<5×10) for BP, of which 4 are new BP loci: rs9678851 (missense, ), rs7437940 (), rs13303 (missense, ), and rs1055144 (). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, ) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at ) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

%B Circulation: Cardiovascular Genetics %V 10 %P e001778 %G eng %N 5 %R 10.1161/CIRCGENETICS.117.001778 %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 %0 Journal Article %J Nat Genet %D 2016 %T Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci. %A Liu, Chunyu %A Kraja, Aldi T %A Jennifer A Smith %A Brody, Jennifer A %A Franceschini, Nora %A Joshua C. Bis %A Kenneth Rice %A Alanna C Morrison %A Lu, Yingchang %A Weiss, Stefan %A Guo, Xiuqing %A Walter R Palmas %A Martin, Lisa W %A Yii-Der I Chen %A Surendran, Praveen %A Drenos, Fotios %A Cook, James P %A Auer, Paul L %A Chu, Audrey Y %A Giri, Ayush %A Wei Zhao %A Jakobsdottir, Johanna %A Lin, Li-An %A Stafford, Jeanette M %A Amin, Najaf %A Mei, Hao %A Yao, Jie %A Voorman, Arend %A Larson, Martin G %A Grove, Megan L %A Albert Vernon Smith %A Hwang, Shih-Jen %A Chen, Han %A Huan, Tianxiao %A Kosova, Gulum %A Stitziel, Nathan O %A Kathiresan, Sekar %A Nilesh J Samani %A Schunkert, Heribert %A Deloukas, Panos %A Li, Man %A Fuchsberger, Christian %A Pattaro, Cristian %A Gorski, Mathias %A Charles Kooperberg %A George J Papanicolaou %A Rossouw, Jacques E %A Jessica Faul %A Sharon L R Kardia %A Bouchard, Claude %A Raffel, Leslie J %A André G Uitterlinden %A Franco, Oscar H %A Ramachandran S Vasan %A O'Donnell, Christopher J %A Kent D Taylor %A Liu, Kiang %A Erwin P Bottinger %A Gottesman, Omri %A Daw, E Warwick %A Giulianini, Franco %A Ganesh, Santhi %A Salfati, Elias %A Tamara B Harris %A Lenore J Launer %A Dörr, Marcus %A Felix, Stephan B %A Rettig, Rainer %A Völzke, Henry %A Eric S Kim %A Lee, Wen-Jane %A Lee, I-Te %A Sheu, Wayne H-H %A Tsosie, Krystal S %A Digna R Velez Edwards %A Yongmei Liu %A Correa, Adolfo %A David R Weir %A Völker, Uwe %A Ridker, Paul M %A Boerwinkle, Eric %A Gudnason, Vilmundur %A Reiner, Alexander P %A Cornelia M van Duijn %A Ingrid B Borecki %A Edwards, Todd L %A Chakravarti, Aravinda %A Rotter, Jerome I %A Psaty, Bruce M %A Ruth J F Loos %A Myriam Fornage %A Georg B Ehret %A Newton-Cheh, Christopher %A Levy, Daniel %A Daniel I Chasman %X

Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

%B Nat Genet %V 48 %P 1162-70 %8 2016 Oct %G eng %N 10 %R 10.1038/ng.3660