%0 Journal Article %J Molecular Psychiatry %D 2020 %T Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. %A Erzurumluoglu, A Mesut %A Liu, Mengzhen %A Jackson, Victoria E %A Barnes, Daniel R %A Datta, Gargi %A Melbourne, Carl A %A Young, Robin %A Batini, Chiara %A Surendran, Praveen %A Jiang, Tao %A Adnan, Sheikh Daud %A Afaq, Saima %A Agrawal, Arpana %A Altmaier, Elisabeth %A Antoniou, Antonis C %A Asselbergs, Folkert W %A Baumbach, Clemens %A Laura Bierut %A Bertelsen, Sarah %A Boehnke, Michael %A Bots, Michiel L %A Brazel, David M %A Chambers, John C %A Chang-Claude, Jenny %A Chen, Chu %A Corley, Janie %A Chou, Yi-Ling %A David, Sean P %A de Boer, Rudolf A %A Christiaan de Leeuw %A Joe G Dennis %A Dominiczak, Anna F %A Dunning, Alison M %A Easton, Douglas F %A Charles B Eaton %A Elliott, Paul %A Evangelou, Evangelos %A Jessica Faul %A Tatiana Foroud %A Goate, Alison %A Gong, Jian %A Hans-Jörgen Grabe %A Jeffrey Haessler %A Christopher A Haiman %A Hallmans, Göran %A Anke R Hammerschlag %A Sarah E Harris %A Andrew T Hattersley %A Andrew C Heath %A Hsu, Chris %A Iacono, William G %A Kanoni, Stavroula %A Kapoor, Manav %A Kaprio, Jaakko %A Sharon L R Kardia %A Karpe, Fredrik %A Kontto, Jukka %A Kooner, Jaspal S %A Charles Kooperberg %A Kuulasmaa, Kari %A Laakso, Markku %A Lai, Dongbing %A Langenberg, Claudia %A Le, Nhung %A Lettre, Guillaume %A Loukola, Anu %A Luan, Jian'an %A Pamela A F Madden %A Mangino, Massimo %A Riccardo E Marioni %A Marouli, Eirini %A Marten, Jonathan %A Nicholas G Martin %A McGue, Matt %A Michailidou, Kyriaki %A Mihailov, Evelin %A Moayyeri, Alireza %A Moitry, Marie %A Müller-Nurasyid, Martina %A Naheed, Aliya %A Nauck, Matthias %A Neville, Matthew J %A Sune Fallgaard Nielsen %A Kari E North %A Markus Perola %A Pharoah, Paul D P %A Pistis, Giorgio %A Tinca J Polderman %A Posthuma, Danielle %A Neil Poulter %A Qaiser, Beenish %A Rasheed, Asif %A Reiner, Alex %A Renstrom, Frida %A Rice, John %A Rohde, Rebecca %A Rolandsson, Olov %A Nilesh J Samani %A Samuel, Maria %A Schlessinger, David %A H Steven Scholte %A Scott, Robert A %A Peter Sever %A Shao, Yaming %A Shrine, Nick %A Smith, Jennifer A %A John M Starr %A Kathleen E Stirrups %A Stram, Danielle %A Heather M Stringham %A Tachmazidou, Ioanna %A Tardif, Jean-Claude %A Thompson, Deborah J %A Hilary A Tindle %A Tragante, Vinicius %A Trompet, Stella %A Turcot, Valérie %A Tyrrell, Jessica %A Vaartjes, Ilonca %A Van Der Leij, Andries R %A van der Meer, Peter %A Varga, Tibor V %A Verweij, Niek %A Völzke, Henry %A Wareham, Nicholas J %A Warren, Helen R %A David R Weir %A Weiss, Stefan %A Wetherill, Leah %A Yaghootkar, Hanieh %A Yavas, Ersin %A Jiang, Yu %A Chen, Fang %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Wei %A Zhao, Wei %A Zhou, Kaixin %A Amouyel, Philippe %A Blankenberg, Stefan %A Caulfield, Mark J %A Chowdhury, Rajiv %A Francesco Cucca %A Ian J Deary %A Deloukas, Panos %A Di Angelantonio, Emanuele %A Marco M Ferrario %A Ferrières, Jean %A Franks, Paul W %A Timothy M Frayling %A Frossard, Philippe %A Hall, Ian P %A Caroline Hayward %A Jansson, Jan-Håkan %A Jukema, J Wouter %A Kee, Frank %A Männistö, Satu %A Andres Metspalu %A Munroe, Patricia B %A Børge G Nordestgaard %A Palmer, Colin N A %A Veikko Salomaa %A Sattar, Naveed %A Timothy Spector %A David P Strachan %A van der Harst, Pim %A Zeggini, Eleftheria %A Saleheen, Danish %A Adam S Butterworth %A Wain, Louise V %A Gonçalo R Abecasis %A Danesh, John %A Tobin, Martin D %A Scott Vrieze %A Liu, Dajiang J %A Howson, Joanna M M %K Biological Specimen Banks %K Databases, Factual %K Europe %K Exome %K Female %K Genetic Loci %K Humans %K Male %K Polymorphism, Single Nucleotide %K Smoking %K United Kingdom %X

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

%B Molecular Psychiatry %V 25 %P 2392-2409 %G eng %N 10 %R 10.1038/s41380-018-0313-0 %0 Journal Article %J Biological Psychiatry %D 2019 %T Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use. %A Brazel, David M %A Jiang, Yu %A Hughey, Jordan M %A Turcot, Valérie %A Zhan, Xiaowei %A Gong, Jian %A Batini, Chiara %A Weissenkampen, J Dylan %A Liu, Mengzhen %A Barnes, Daniel R %A Bertelsen, Sarah %A Chou, Yi-Ling %A Erzurumluoglu, A Mesut %A Jessica Faul %A Jeffrey Haessler %A Anke R Hammerschlag %A Hsu, Chris %A Kapoor, Manav %A Lai, Dongbing %A Le, Nhung %A Christiaan de Leeuw %A Loukola, Anu %A Mangino, Massimo %A Melbourne, Carl A %A Pistis, Giorgio %A Qaiser, Beenish %A Rohde, Rebecca %A Shao, Yaming %A Heather M Stringham %A Wetherill, Leah %A Zhao, Wei %A Agrawal, Arpana %A Laura Bierut %A Chen, Chu %A Charles B Eaton %A Goate, Alison %A Christopher A Haiman %A Andrew C Heath %A Iacono, William G %A Nicholas G Martin %A Tinca J Polderman %A Reiner, Alex %A Rice, John %A Schlessinger, David %A H Steven Scholte %A Smith, Jennifer A %A Tardif, Jean-Claude %A Hilary A Tindle %A Van Der Leij, Andries R %A Boehnke, Michael %A Chang-Claude, Jenny %A Francesco Cucca %A David, Sean P %A Tatiana Foroud %A Howson, Joanna M M %A Sharon L R Kardia %A Charles Kooperberg %A Laakso, Markku %A Lettre, Guillaume %A Pamela A F Madden %A McGue, Matt %A Kari E North %A Posthuma, Danielle %A Timothy Spector %A Stram, Daniel %A Tobin, Martin D %A David R Weir %A Kaprio, Jaakko %A Gonçalo R Abecasis %A Liu, Dajiang J %A Scott Vrieze %K Alcohol Drinking %K Databases, Genetic %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Genotype %K Humans %K Oligonucleotide Array Sequence Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Smoking %X

BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.

METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.

RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.

CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

%B Biological Psychiatry %V 85 %P 946-955 %G eng %N 11 %R 10.1016/j.biopsych.2018.11.024 %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, 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%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