TY - JOUR T1 - Rare and low-frequency coding variants alter human adult height. JF - Nature Y1 - 2017 A1 - Marouli, Eirini A1 - Graff, Mariaelisa A1 - Medina-Gomez, Carolina A1 - Lo, Ken Sin A1 - Wood, Andrew R A1 - Kjaer, Troels R A1 - Fine, Rebecca S A1 - Lu, Yingchang A1 - Schurmann, Claudia A1 - Highland, Heather M A1 - Rüeger, Sina A1 - Thorleifsson, Gudmar A1 - Justice, Anne E A1 - Lamparter, David A1 - Stirrups, Kathleen E A1 - Turcot, Valérie A1 - Young, Kristin L A1 - Winkler, Thomas W A1 - Esko, Tõnu A1 - Karaderi, Tugce A1 - Locke, Adam E A1 - Masca, Nicholas G D A1 - Ng, Maggie C Y A1 - Mudgal, Poorva A1 - Rivas, Manuel A A1 - Vedantam, Sailaja A1 - Mahajan, Anubha A1 - Guo, Xiuqing A1 - Abecasis, Goncalo A1 - Aben, Katja K A1 - Adair, Linda S A1 - Alam, Dewan S A1 - Albrecht, Eva A1 - Allin, Kristine H A1 - Allison, Matthew A1 - Amouyel, Philippe A1 - Appel, Emil V A1 - Arveiler, Dominique A1 - Asselbergs, Folkert W A1 - Auer, Paul L A1 - Balkau, Beverley A1 - Banas, Bernhard A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bergmann, Sven A1 - Bielak, Lawrence F A1 - Blüher, Matthias A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Böger, Carsten A A1 - Bonnycastle, Lori L A1 - Bork-Jensen, Jette A1 - Bots, Michiel L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Brandslund, Ivan A1 - Breen, Gerome A1 - Brilliant, Murray H A1 - Broer, Linda A1 - Burt, Amber A A1 - Butterworth, Adam S A1 - Carey, David J A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Cook, James P A1 - Corley, Janie A1 - Galbany, Jordi Corominas A1 - Cox, Amanda J A1 - Cuellar-Partida, Gabriel A1 - Danesh, John A1 - Davies, Gail A1 - de Bakker, Paul I W A1 - de Borst, Gert J A1 - de Denus, Simon A1 - de Groot, Mark C H A1 - de Mutsert, Renée A1 - Deary, Ian J A1 - Dedoussis, George A1 - Demerath, Ellen W A1 - den Hollander, Anneke I A1 - Dennis, Joe G A1 - Di Angelantonio, Emanuele A1 - Drenos, Fotios A1 - Du, Mengmeng A1 - Dunning, Alison M A1 - Easton, Douglas F A1 - Ebeling, Tapani A1 - Edwards, Todd L A1 - Ellinor, Patrick T A1 - Elliott, Paul A1 - Evangelou, Evangelos A1 - Farmaki, Aliki-Eleni A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Feng, Shuang A1 - Ferrannini, Ele A1 - Ferrario, Marco M A1 - Ferrières, Jean A1 - Florez, Jose C A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frikke-Schmidt, Ruth A1 - Galesloot, Tessel E A1 - Gan, Wei A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Giri, Ayush A1 - Girotto, Giorgia A1 - Gordon, Scott D A1 - Gordon-Larsen, Penny A1 - Gorski, Mathias A1 - Grarup, Niels A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Hansen, Torben A1 - Harris, Kathleen Mullan A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - He, Liang A1 - Heid, Iris M A1 - Heikkilä, Kauko A1 - Helgeland, Øyvind A1 - Hernesniemi, Jussi A1 - Hewitt, Alex W A1 - Hocking, Lynne J A1 - Hollensted, Mette A1 - Holmen, Oddgeir L A1 - Hovingh, G Kees A1 - Howson, Joanna M M A1 - Hoyng, Carel B A1 - Huang, Paul L A1 - Hveem, Kristian A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Jackson, Anne U A1 - Jansson, Jan-Håkan A1 - Jarvik, Gail P A1 - Jensen, Gorm B A1 - Jhun, Min A A1 - Jia, Yucheng A1 - Jiang, Xuejuan A1 - Johansson, Stefan A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kahali, Bratati A1 - Kahn, René S A1 - Kähönen, Mika A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Kaprio, Jaakko A1 - Karaleftheri, Maria A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Keeman, Renske A1 - Kiemeney, Lambertus A A1 - Kitajima, Hidetoshi A1 - Kluivers, Kirsten B A1 - Kocher, Thomas A1 - Komulainen, Pirjo A1 - Kontto, Jukka A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kuivaniemi, Helena A1 - Küry, Sébastien A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Larson, Eric B A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Lewis, Cora E A1 - Li, Huaixing A1 - Li, Jin A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Lin, Li-An A1 - Lin, Xu A1 - Lind, Lars A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Liu, Yeheng A1 - Liu, Yongmei A1 - Lophatananon, Artitaya A1 - Luan, Jian'an A1 - Lubitz, Steven A A1 - Lyytikäinen, Leo-Pekka A1 - Mackey, David A A1 - Madden, Pamela A F A1 - Manning, Alisa K A1 - Männistö, Satu A1 - Marenne, Gaëlle A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mazul, Angela L A1 - Meidtner, Karina A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Nikus, Kjell A1 - Njølstad, Pål R A1 - Nordestgaard, Børge G A1 - Ntalla, Ioanna A1 - O'Connel, Jeffrey R A1 - Oksa, Heikki A1 - Loohuis, Loes M Olde A1 - Ophoff, Roel A A1 - Owen, Katharine R A1 - Packard, Chris J A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasterkamp, Gerard A1 - Patel, Aniruddh P A1 - Pattie, Alison A1 - Pedersen, Oluf A1 - Peissig, Peggy L A1 - Peloso, Gina M A1 - Pennell, Craig E A1 - Perola, Markus A1 - Perry, James A A1 - Perry, John R B A1 - Person, Thomas N A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Raitakari, Olli T A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil A1 - Robino, Antonietta A1 - Rolandsson, Olov A1 - Rudan, Igor A1 - Ruth, Katherine S A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sandow, Kevin A1 - Sapkota, Yadav A1 - Sattar, Naveed A1 - Schmidt, Marjanka K A1 - Schreiner, Pamela J A1 - Schulze, Matthias B A1 - Scott, Robert A A1 - Segura-Lepe, Marcelo P A1 - Shah, Svati A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert Vernon A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Surendran, Praveen A1 - 't Hart, Leen M A1 - Tansey, Katherine E A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Thorsteinsdottir, Unnur A1 - Thuesen, Betina H A1 - Tönjes, Anke A1 - Tromp, Gerard A1 - Trompet, Stella A1 - Tsafantakis, Emmanouil A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - Tyrer, Jonathan P A1 - Uher, Rudolf A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - van der Laan, Sander W A1 - Van Der Leij, Andries R A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - van Setten, Jessica A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Varma, Rohit A1 - Edwards, Digna R Velez A1 - Vermeulen, Sita H A1 - Vestergaard, Henrik A1 - Vitart, Veronique A1 - Vogt, Thomas F A1 - Vozzi, Diego A1 - Walker, Mark A1 - Wang, Feijie A1 - Wang, Carol A A1 - Wang, Shuai A1 - Wang, Yiqin A1 - Wareham, Nicholas J A1 - Warren, Helen R A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Wilson, James G A1 - Witte, Daniel R A1 - Woods, Michael O A1 - Wu, Ying A1 - Yaghootkar, Hanieh A1 - Yao, Jie A1 - Yao, Pang A1 - Yerges-Armstrong, Laura M A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhan, Xiaowei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zhao, Wei A1 - Zheng, He A1 - Zhou, Wei A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - Kathiresan, Sekar A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Stefansson, Kari A1 - Borecki, Ingrid B A1 - Liu, Dajiang J A1 - North, Kari E A1 - Heard-Costa, Nancy L A1 - Pers, Tune H A1 - Lindgren, Cecilia M A1 - Oxvig, Claus A1 - Kutalik, Zoltán A1 - Rivadeneira, Fernando A1 - Loos, Ruth J F A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Deloukas, Panos A1 - Lettre, Guillaume KW - ADAMTS Proteins KW - Adult KW - Alleles KW - Body Height KW - Cell Adhesion Molecules KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome, Human KW - Glycoproteins KW - Glycosaminoglycans KW - Hedgehog Proteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Interferon Regulatory Factors KW - Interleukin-11 Receptor alpha Subunit KW - Male KW - Multifactorial Inheritance KW - NADPH Oxidase 4 KW - NADPH Oxidases KW - Phenotype KW - Pregnancy-Associated Plasma Protein-A KW - Procollagen N-Endopeptidase KW - Proteoglycans KW - Proteolysis KW - Receptors, Androgen KW - Somatomedins AB -

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.

VL - 542 IS - 7640 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic meta-analysis of white blood cell phenotypes. JF - Hum Mol Genet Y1 - 2014 A1 - Keller, Margaux F A1 - Reiner, Alexander P A1 - Okada, Yukinori A1 - van Rooij, Frank J A A1 - Johnson, Andrew D A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Morris, Andrew P A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Zonderman, Alan B A1 - Lettre, Guillaume A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Bandinelli, Stefania A1 - Qayyum, Rehan A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Kooperberg, Charles A1 - Keating, Brendan A1 - Reis, Jared A1 - Tang, Hua A1 - Boerwinkle, Eric A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Nakamura, Yusuke A1 - Kubo, Michiaki A1 - Liu, Simin A1 - Dehghan, Abbas A1 - Felix, Janine F A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Longo, Dan L A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Evans, Michelle K A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Takahashi, Atsushi A1 - Wilson, James G A1 - Ganesh, Santhi K A1 - Nalls, Mike A KW - African Americans KW - Asian Continental Ancestry Group KW - Bayes Theorem KW - European Continental Ancestry Group KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Linkage Disequilibrium KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract ER - TY - JOUR T1 - Multiple loci are associated with white blood cell phenotypes. JF - PLoS Genet Y1 - 2011 A1 - Nalls, Michael A A1 - Couper, David J A1 - Tanaka, Toshiko A1 - van Rooij, Frank J A A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Toniolo, Daniela A1 - Zakai, Neil A A1 - Yang, Qiong A1 - Greinacher, Andreas A1 - Wood, Andrew R A1 - Garcia, Melissa A1 - Gasparini, Paolo A1 - Liu, Yongmei A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - Reiner, Alex P A1 - Gieger, Christian A1 - Lagou, Vasiliki A1 - Felix, Janine F A1 - Völzke, Henry A1 - Gouskova, Natalia A A1 - Biffi, Alessandro A1 - Döring, Angela A1 - Völker, Uwe A1 - Chong, Sean A1 - Wiggins, Kerri L A1 - Rendon, Augusto A1 - Dehghan, Abbas A1 - Moore, Matt A1 - Taylor, Kent A1 - Wilson, James G A1 - Lettre, Guillaume A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Pirastu, Nicola A1 - Fox, Caroline S A1 - Meisinger, Christa A1 - Sambrook, Jennifer A1 - Arepalli, Sampath A1 - Nauck, Matthias A1 - Prokisch, Holger A1 - Stephens, Jonathan A1 - Glazer, Nicole L A1 - Cupples, L Adrienne A1 - Okada, Yukinori A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Tsunoda, Tatsuhiko A1 - Tanaka, Toshihiro A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Yamamoto, Kazuhiko A1 - Kamatani, Naoyuki A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Prokopenko, Inga A1 - Illig, Thomas A1 - Patel, Kushang V A1 - Garner, Stephen F A1 - Kuhnel, Brigitte A1 - Mangino, Massimo A1 - Oostra, Ben A A1 - Thein, Swee Lay A1 - Coresh, Josef A1 - Wichmann, H-Erich A1 - Menzel, Stephan A1 - Lin, JingPing A1 - Pistis, Giorgio A1 - Uitterlinden, André G A1 - Spector, Tim D A1 - Teumer, Alexander A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Bandinelli, Stefania A1 - Frayling, Timothy M A1 - Chakravarti, Aravinda A1 - van Duijn, Cornelia M A1 - Melzer, David A1 - Ouwehand, Willem H A1 - Levy, Daniel A1 - Boerwinkle, Eric A1 - Singleton, Andrew B A1 - Hernandez, Dena G A1 - Longo, Dan L A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - O'Donnell, Christopher J A1 - Ganesh, Santhi K KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Molecular Epidemiology KW - Multigene Family KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738480?dopt=Abstract ER -