@article {12121, title = {Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.}, journal = {The American Journal of Human Genetics}, volume = {108}, year = {2021}, pages = {564-582}, abstract = {

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5\%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained <=20 variants in the credible sets that jointly account for 99\% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

}, keywords = {Africa, African Americans, Blacks, Body Height, Europe, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.011}, author = {Graff, Mariaelisa and Justice, Anne E and Young, Kristin L and Marouli, Eirini and Zhang, Xinruo and Fine, Rebecca S and Lim, Elise and Buchanan, Victoria and Rand, Kristin and Feitosa, Mary F and Wojczynski, Mary K and Yanek, Lisa R and Shao, Yaming and Rohde, Rebecca and Adeyemo, Adebowale A and Aldrich, Melinda C and Matthew A. Allison and Ambrosone, Christine B and Ambs, Stefan and Amos, Christopher and Donna K Arnett and Atwood, Larry and Bandera, Elisa V and Traci M Bartz and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Bielak, Lawrence F and Blot, William J and Erwin P Bottinger and Bowden, Donald W and Bradfield, Jonathan P and Brody, Jennifer A and Broeckel, Ulrich and Burke, Gregory and Brian E Cade and Cai, Qiuyin and Caporaso, Neil and Carlson, Chris and John Carpten and Casey, Graham and Chanock, Stephen J and Chen, Guanjie and Chen, Minhui and Chen, Yii-Der I and Chen, Wei-Min and Chesi, Alessandra and Chiang, Charleston W K and Chu, Lisa and Coetzee, Gerry A and Conti, David V and Cooper, Richard S and Cushman, Mary and Ellen W Demerath and Deming, Sandra L and Dimitrov, Latchezar and Ding, Jingzhong and Diver, W Ryan and Duan, Qing and Michele K Evans and Falusi, Adeyinka G and Jessica Faul and Myriam Fornage and Caroline S Fox and Freedman, Barry I and Garcia, Melissa and Gillanders, Elizabeth M and Phyllis J Goodman and Gottesman, Omri and Grant, Struan F A and Guo, Xiuqing and Hakonarson, Hakon and Haritunians, Talin and Tamara B Harris and Harris, Curtis C and Henderson, Brian E and Hennis, Anselm and Dena G Hernandez and Hirschhorn, Joel N and McNeill, Lorna Haughton and Howard, Timothy D and Howard, Barbara and Hsing, Ann W and Hsu, Yu-Han H and Hu, Jennifer J and Huff, Chad D and Huo, Dezheng and Ingles, Sue A and Irvin, Marguerite R and John, Esther M and Johnson, Karen C and Jordan, Joanne M and Kabagambe, Edmond K and Kang, Sun J and Sharon L R Kardia and Keating, Brendan J and Rick A Kittles and Eric A Klein and Kolb, Suzanne and Kolonel, Laurence N and Charles Kooperberg and Kuller, Lewis and Kutlar, Abdullah and Leslie A Lange and Langefeld, Carl D and Loic Le Marchand and Leonard, Hampton and Lettre, Guillaume and Levin, Albert M and Li, Yun and Li, Jin and Liu, Yongmei and Liu, Youfang and Liu, Simin and Kurt Lohman and Lotay, Vaneet and Lu, Yingchang and Maixner, William and JoAnn E Manson and McKnight, Barbara and Meng, Yan and Monda, Keri L and Monroe, Kris and Moore, Jason H and Thomas H Mosley and Mudgal, Poorva and Murphy, Adam B and Nadukuru, Rajiv and Michael A Nalls and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}Diaye, Amidou and Nemesure, Barbara and Neslund-Dudas, Christine and Neuhouser, Marian L and Nyante, Sarah and Ochs-Balcom, Heather and Ogundiran, Temidayo O and Ogunniyi, Adesola and Ojengbede, Oladosu and Okut, Hayrettin and Olopade, Olufunmilayo I and Olshan, Andrew and Padhukasahasram, Badri and Palmer, Julie and Palmer, Cameron D and Palmer, Nicholette D and George J Papanicolaou and Patel, Sanjay R and Pettaway, Curtis A and Peyser, Patricia A and Press, Michael F and Rao, D C and Rasmussen-Torvik, Laura J and Redline, Susan and Reiner, Alex P and Rhie, Suhn K and Rodriguez-Gil, Jorge L and Charles N Rotimi and Rotter, Jerome I and Ruiz-Narvaez, Edward A and Rybicki, Benjamin A and Babatunde Salako and Sale, Michele M and Sanderson, Maureen and Eric E Schadt and Schreiner, Pamela J and Schurmann, Claudia and Schwartz, Ann G and Daniel Shriner and Signorello, Lisa B and Andrew B Singleton and David S Siscovick and Smith, Jennifer A and Smith, Shad and Elizabeth K Speliotes and Spitz, Margaret and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Sucheston, Lara and Yan V Sun and Tajuddin, Salman M and Taylor, Herman and Taylor, Kira and Bamidele O Tayo and Michael J Thun and Tucker, Margaret A and Vaidya, Dhananjay and Van Den Berg, David J and Vedantam, Sailaja and Vitolins, Mara and Wang, Zhaoming and Erin B Ware and Wassertheil-Smoller, Sylvia and David R Weir and Wiencke, John K and Williams, Scott M and L Keoki Williams and Wilson, James G and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yao, Jie and Zakai, Neil and Zanetti, Krista and Zemel, Babette S and Zhao, Wei and Jing Hua Zhao and Zheng, Wei and Zhi, Degui and Zhou, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zmuda, Joe and Alan B Zonderman and Psaty, Bruce M and Ingrid B Borecki and Cupples, L Adrienne and Liu, Ching-Ti and Christopher A Haiman and Ruth J F Loos and Ng, Maggie C Y and Kari E North} } @article {12124, title = {Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.}, journal = {Molecular Psychiatry}, volume = {25}, year = {2020}, pages = {2392-2409}, abstract = {

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 {\texttimes} 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 {\texttimes} 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 {\texttimes} 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.

}, keywords = {Biological Specimen Banks, Databases, Factual, Europe, Exome, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Smoking, United Kingdom}, issn = {1476-5578}, doi = {10.1038/s41380-018-0313-0}, author = {Erzurumluoglu, A Mesut and Liu, Mengzhen and Jackson, Victoria E and Barnes, Daniel R and Datta, Gargi and Melbourne, Carl A and Young, Robin and Batini, Chiara and Surendran, Praveen and Jiang, Tao and Adnan, Sheikh Daud and Afaq, Saima and Agrawal, Arpana and Altmaier, Elisabeth and Antoniou, Antonis C and Asselbergs, Folkert W and Baumbach, Clemens and Laura Bierut and Bertelsen, Sarah and Boehnke, Michael and Bots, Michiel L and Brazel, David M and Chambers, John C and Chang-Claude, Jenny and Chen, Chu and Corley, Janie and Chou, Yi-Ling and David, Sean P and de Boer, Rudolf A and Christiaan de Leeuw and Joe G Dennis and Dominiczak, Anna F and Dunning, Alison M and Easton, Douglas F and Charles B Eaton and Elliott, Paul and Evangelou, Evangelos and Jessica Faul and Tatiana Foroud and Goate, Alison and Gong, Jian and Hans-J{\"o}rgen Grabe and Jeffrey Haessler and Christopher A Haiman and Hallmans, G{\"o}ran and Anke R Hammerschlag and Sarah E Harris and Andrew T Hattersley and Andrew C Heath and Hsu, Chris and Iacono, William G and Kanoni, Stavroula and Kapoor, Manav and Kaprio, Jaakko and Sharon L R Kardia and Karpe, Fredrik and Kontto, Jukka and Kooner, Jaspal S and Charles Kooperberg and Kuulasmaa, Kari and Laakso, Markku and Lai, Dongbing and Langenberg, Claudia and Le, Nhung and Lettre, Guillaume and Loukola, Anu and Luan, Jian{\textquoteright}an and Pamela A F Madden and Mangino, Massimo and Riccardo E Marioni and Marouli, Eirini and Marten, Jonathan and Nicholas G Martin and McGue, Matt and Michailidou, Kyriaki and Mihailov, Evelin and Moayyeri, Alireza and Moitry, Marie and M{\"u}ller-Nurasyid, Martina and Naheed, Aliya and Nauck, Matthias and Neville, Matthew J and Sune Fallgaard Nielsen and Kari E North and Markus Perola and Pharoah, Paul D P and Pistis, Giorgio and Tinca J Polderman and Posthuma, Danielle and Neil Poulter and Qaiser, Beenish and Rasheed, Asif and Reiner, Alex and Renstrom, Frida and Rice, John and Rohde, Rebecca and Rolandsson, Olov and Nilesh J Samani and Samuel, Maria and Schlessinger, David and H Steven Scholte and Scott, Robert A and Peter Sever and Shao, Yaming and Shrine, Nick and Smith, Jennifer A and John M Starr and Kathleen E Stirrups and Stram, Danielle and Heather M Stringham and Tachmazidou, Ioanna and Tardif, Jean-Claude and Thompson, Deborah J and Hilary A Tindle and Tragante, Vinicius and Trompet, Stella and Turcot, Val{\'e}rie and Tyrrell, Jessica and Vaartjes, Ilonca and Van Der Leij, Andries R and van der Meer, Peter and Varga, Tibor V and Verweij, Niek and V{\"o}lzke, Henry and Wareham, Nicholas J and Warren, Helen R and David R Weir and Weiss, Stefan and Wetherill, Leah and Yaghootkar, Hanieh and Yavas, Ersin and Jiang, Yu and Chen, Fang and Zhan, Xiaowei and Zhang, Weihua and Zhao, Wei and Zhao, Wei and Zhou, Kaixin and Amouyel, Philippe and Blankenberg, Stefan and Caulfield, Mark J and Chowdhury, Rajiv and Francesco Cucca and Ian J Deary and Deloukas, Panos and Di Angelantonio, Emanuele and Marco M Ferrario and Ferri{\`e}res, Jean and Franks, Paul W and Timothy M Frayling and Frossard, Philippe and Hall, Ian P and Caroline Hayward and Jansson, Jan-H{\r a}kan and Jukema, J Wouter and Kee, Frank and M{\"a}nnist{\"o}, Satu and Andres Metspalu and Munroe, Patricia B and B{\o}rge G Nordestgaard and Palmer, Colin N A and Veikko Salomaa and Sattar, Naveed and Timothy Spector and David P Strachan and van der Harst, Pim and Zeggini, Eleftheria and Saleheen, Danish and Adam S Butterworth and Wain, Louise V and Gon{\c c}alo R Abecasis and Danesh, John and Tobin, Martin D and Scott Vrieze and Liu, Dajiang J and Howson, Joanna M M} } @article {9526, title = {Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jan}, pages = {26-41}, 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 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.

}, issn = {1546-1718}, doi = {10.1038/s41588-017-0011-x}, author = {Turcot, Val{\'e}rie and Lu, Yingchang and Highland, Heather M and Schurmann, Claudia and Justice, Anne E and Fine, Rebecca S and Bradfield, Jonathan P and T{\~o}nu Esko and Giri, Ayush and Graff, Mariaelisa and Guo, Xiuqing and Hendricks, Audrey E and Karaderi, Tugce and Lempradl, Adelheid and Locke, Adam E and Mahajan, Anubha and Marouli, Eirini and Sivapalaratnam, Suthesh and Young, Kristin L and Alfred, Tamuno and Feitosa, Mary F and Masca, Nicholas G D and Alisa Manning and Medina-Gomez, Carolina and Mudgal, Poorva and Ng, Maggie C Y and Reiner, Alex P and Vedantam, Sailaja and Willems, Sara M and Thomas W Winkler and Gon{\c c}alo R Abecasis and Aben, Katja K and Alam, Dewan S and Alharthi, Sameer E and Matthew A. Allison and Amouyel, Philippe and Asselbergs, Folkert W and Auer, Paul L and Balkau, Beverley and Bang, Lia E and Barroso, In{\^e}s and Bastarache, Lisa and Benn, Marianne and Bergmann, Sven and Bielak, Lawrence F and Bl{\"u}her, Matthias and Boehnke, Michael and Boeing, Heiner and Boerwinkle, Eric and B{\"o}ger, Carsten A and Bork-Jensen, Jette and Bots, Michiel L and Erwin P Bottinger and Bowden, Donald W and Brandslund, Ivan and Breen, Gerome and Brilliant, Murray H and Broer, Linda and Brumat, Marco and Burt, Amber A and Adam S Butterworth and Campbell, Peter T and Cappellani, Stefania and Carey, David J and Catamo, Eulalia and Caulfield, Mark J and Chambers, John C and Daniel I Chasman and Yii-Der I Chen and Chowdhury, Rajiv and Cramer Christensen and Chu, Audrey Y and Cocca, Massimiliano and Collins, Francis S and Cook, James P and Corley, Janie and Jordi Corominas Galbany and Cox, Amanda J and Crosslin, David S and Cuellar-Partida, Gabriel and D{\textquoteright}Eustacchio, Angela and Danesh, John and Gail Davies and Bakker, Paul I W and Groot, Mark C H and Mutsert, Ren{\'e}e and Ian J Deary and George Dedoussis and Ellen W Demerath and Heijer, Martin and Anneke I den Hollander and Hester M den Ruijter and Joe G Dennis and Denny, Josh C and Angelantonio, Emanuele and Drenos, Fotios and Du, Mengmeng and Dub{\'e}, Marie-Pierre and Dunning, Alison M and Easton, Douglas F and Edwards, Todd L and Ellinghaus, David and Ellinor, Patrick T and Elliott, Paul and Evangelou, Evangelos and Farmaki, Aliki-Eleni and Farooqi, I Sadaf and Jessica Faul and Fauser, Sascha and Feng, Shuang and Ferrannini, Ele and Ferri{\`e}res, Jean and Florez, Jose C and Ford, Ian and Myriam Fornage and Franco, Oscar H and Franke, Andre and Franks, Paul W and Friedrich, Nele and Frikke-Schmidt, Ruth and Galesloot, Tessel E and Gan, Wei and Gandin, Ilaria and Paolo P. Gasparini and Gibson, Jane and Giedraitis, Vilmantas and Gjesing, Anette P and Gordon-Larsen, Penny and Gorski, Mathias and Hans-J{\"o}rgen Grabe and Grant, Struan F A and Grarup, Niels and Griffiths, Helen L and Grove, Megan L and Gudnason, Vilmundur and Gustafsson, Stefan and Jeffrey Haessler and Hakonarson, Hakon and Anke R Hammerschlag and Hansen, Torben and Tamara B Harris and Andrew T Hattersley and Have, Christian T and Caroline Hayward and He, Liang and Heard-Costa, Nancy L and Andrew C Heath and Iris M Heid and Helgeland, {\O}yvind and Hernesniemi, Jussi and Hewitt, Alex W and Oddgeir L Holmen and Hovingh, G Kees and Howson, Joanna M M and Hu, Yao and Huang, Paul L and Huffman, Jennifer E and Mohammed Arfan Ikram and Ingelsson, Erik and Jackson, Anne U and Jansson, Jan-H{\r a}kan and Jarvik, Gail P and Jensen, Gorm B and Jia, Yucheng and Johansson, Stefan and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Jukema, J Wouter and Kahali, Bratati and Kahn, Ren{\'e} S and K{\"a}h{\"o}nen, Mika and Kamstrup, Pia R and Kanoni, Stavroula and Kaprio, Jaakko and Karaleftheri, Maria and Sharon L R Kardia and Karpe, Fredrik and Kathiresan, Sekar and Kee, Frank and Lambertus A Kiemeney and Eric S Kim and Kitajima, Hidetoshi and Komulainen, Pirjo and Kooner, Jaspal S and Charles Kooperberg and Korhonen, Tellervo and Kovacs, Peter and Kuivaniemi, Helena and Kutalik, Zolt{\'a}n and Kuulasmaa, Kari and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lamparter, David and Lange, Ethan M and Leslie A Lange and Langenberg, Claudia and Eric B Larson and Lee, Nanette R and Lehtim{\"a}ki, Terho and Lewis, Cora E and Li, Huaixing and Li, Jin and Li-Gao, Ruifang and Lin, Honghuang and Lin, Keng-Hung and Lin, Li-An and Lin, Xu and Lars Lind and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Ching-Ti and Liu, Dajiang J and Yongmei Liu and Ken Sin Lo and Lophatananon, Artitaya and Lotery, Andrew J and Loukola, Anu and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Lyytik{\"a}inen, Leo-Pekka and M{\"a}nnist{\"o}, Satu and Marenne, Ga{\"e}lle and Mazul, Angela L and McCarthy, Mark I and McKean-Cowdin, Roberta and Sarah E Medland and Meidtner, Karina and Lili Milani and Mistry, Vanisha and Mitchell, Paul and Mohlke, Karen L and Moilanen, Leena and Moitry, Marie and Grant W Montgomery and Dennis O Mook-Kanamori and Moore, Carmel and Mori, Trevor A and Morris, Andrew D and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Michael A Nalls and Narisu, Narisu and Nelson, Christopher P and Neville, Matt and Sune Fallgaard Nielsen and Nikus, Kjell and Nj{\o}lstad, P{\r a}l R and B{\o}rge G Nordestgaard and Nyholt, Dale R and Jeff O{\textquoteright}Connell and O{\textquoteright}Donoghue, Michelle L and Ophoff, Roel A and Owen, Katharine R and Packard, Chris J and Padmanabhan, Sandosh and Palmer, Colin N A and Palmer, Nicholette D and Pasterkamp, Gerard and Patel, Aniruddh P and Pattie, Alison and Pedersen, Oluf and Peissig, Peggy L and Peloso, Gina M and Pennell, Craig E and Markus Perola and Perry, James A and Perry, John R B and Pers, Tune H and Person, Thomas N and Peters, Annette and Petersen, Eva R B and Peyser, Patricia A and Pirie, Ailith and Polasek, Ozren and Tinca J Polderman and Puolijoki, Hannu and Olli T Raitakari and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Renstrom, Frida and Rheinberger, Myriam and Ridker, Paul M and Rioux, John D and Rivas, Manuel A and Roberts, David J and Neil R Robertson and Robino, Antonietta and Rolandsson, Olov and Rudan, Igor and Ruth, Katherine S and Saleheen, Danish and Veikko Salomaa and Nilesh J Samani and Sapkota, Yadav and Sattar, Naveed and Schoen, Robert E and Schreiner, Pamela J and Schulze, Matthias B and Scott, Robert A and Segura-Lepe, Marcelo P and Svati H Shah and Sheu, Wayne H-H and Sim, Xueling and Slater, Andrew J and Small, Kerrin S and Albert Vernon Smith and Southam, Lorraine and Timothy Spector and Elizabeth K Speliotes and John M Starr and Stefansson, Kari and Steinthorsdottir, Valgerdur and Kathleen E Stirrups and Strauch, Konstantin and Heather M Stringham and Stumvoll, Michael and Sun, Liang and Surendran, Praveen and Swift, Amy J and Tada, Hayato and Tansey, Katherine E and Tardif, Jean-Claude and Kent D Taylor and Teumer, Alexander and Thompson, Deborah J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Thuesen, Betina H and T{\"o}njes, Anke and Tromp, Gerard and Trompet, Stella and Tsafantakis, Emmanouil and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and Tyrer, Jonathan P and Uher, Rudolf and Andr{\'e} G Uitterlinden and Uusitupa, Matti and Laan, Sander W and Duijn, Cornelia M and Leeuwen, Nienke and van Setten, Jessica and Vanhala, Mauno and Varbo, Anette and Varga, Tibor V and Varma, Rohit and Digna R Velez Edwards and Vermeulen, Sita H and Veronesi, Giovanni and Vestergaard, Henrik and Vitart, Veronique and Vogt, Thomas F and V{\"o}lker, Uwe and Vuckovic, Dragana and Wagenknecht, Lynne E and Walker, Mark and Wallentin, Lars and Wang, Feijie and Wang, Carol A and Wang, Shuai and Wang, Yiqin and Erin B Ware and Wareham, Nicholas J and Warren, Helen R and Dawn M Waterworth and Wessel, Jennifer and White, Harvey D and Willer, Cristen J and Wilson, James G and Daniel Witte and Andrew R Wood and Wu, Ying and Yaghootkar, Hanieh and Yao, Jie and Yao, Pang and Laura M Yerges-Armstrong and Young, Robin and Zeggini, Eleftheria and Zhan, Xiaowei and Zhang, Weihua and Wei Zhao and Zhou, Wei and Krina T Zondervan and Rotter, Jerome I and Pospisilik, John A and Fernando Rivadeneira and Ingrid B Borecki and Deloukas, Panos and Timothy M Frayling and Lettre, Guillaume and Kari E North and Lindgren, Cecilia M and Joel N Hirschhron and Ruth J F Loos} } @article {8886, title = {Rare and low-frequency coding variants alter human adult height.}, journal = {Nature}, volume = {542}, year = {2017}, month = {2017 Feb 09}, pages = {186-190}, abstract = {

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.

}, issn = {1476-4687}, doi = {10.1038/nature21039}, author = {Marouli, Eirini and Graff, Mariaelisa and Medina-Gomez, Carolina and Ken Sin Lo and Andrew R Wood and Kjaer, Troels R and Fine, Rebecca S and Lu, Yingchang and Schurmann, Claudia and Highland, Heather M and R{\"u}eger, Sina and Thorleifsson, Gudmar and Justice, Anne E and Lamparter, David and Kathleen E Stirrups and Turcot, Val{\'e}rie and Young, Kristin L and Thomas W Winkler and T{\~o}nu Esko and Karaderi, Tugce and Locke, Adam E and Masca, Nicholas G D and Ng, Maggie C Y and Mudgal, Poorva and Rivas, Manuel A and Vedantam, Sailaja and Mahajan, Anubha and Guo, Xiuqing and Gon{\c c}alo R Abecasis and Aben, Katja K and Adair, Linda S and Alam, Dewan S and Albrecht, Eva and Allin, Kristine H and Matthew A. Allison and Amouyel, Philippe and Appel, Emil V and Arveiler, Dominique and Asselbergs, Folkert W and Auer, Paul L and Balkau, Beverley and Banas, Bernhard and Bang, Lia E and Benn, Marianne and Bergmann, Sven and Bielak, Lawrence F and Bl{\"u}her, Matthias and Boeing, Heiner and Boerwinkle, Eric and B{\"o}ger, Carsten A and Bonnycastle, Lori L and Bork-Jensen, Jette and Bots, Michiel L and Erwin P Bottinger and Bowden, Donald W and Brandslund, Ivan and Breen, Gerome and Brilliant, Murray H and Broer, Linda and Burt, Amber A and Adam S Butterworth and Carey, David J and Caulfield, Mark J and Chambers, John C and Daniel I Chasman and Yii-Der I Chen and Chowdhury, Rajiv and Cramer Christensen and Chu, Audrey Y and Cocca, Massimiliano and Collins, Francis S and Cook, James P and Corley, Janie and Jordi Corominas Galbany and Cox, Amanda J and Cuellar-Partida, Gabriel and Danesh, John and Gail Davies and de Bakker, Paul I W and de Borst, Gert J and de Denus, Simon and de Groot, Mark C H and de Mutsert, Ren{\'e}e and Ian J Deary and George Dedoussis and Ellen W Demerath and Anneke I den Hollander and Joe G Dennis and Di Angelantonio, Emanuele and Drenos, Fotios and Du, Mengmeng and Dunning, Alison M and Easton, Douglas F and Ebeling, Tapani and Edwards, Todd L and Ellinor, Patrick T and Elliott, Paul and Evangelou, Evangelos and Farmaki, Aliki-Eleni and Jessica Faul and Feitosa, Mary F and Feng, Shuang and Ferrannini, Ele and Marco M Ferrario and Ferri{\`e}res, Jean and Florez, Jose C and Ford, Ian and Myriam Fornage and Franks, Paul W and Frikke-Schmidt, Ruth and Galesloot, Tessel E and Gan, Wei and Gandin, Ilaria and Paolo P. Gasparini and Giedraitis, Vilmantas and Giri, Ayush and Giorgia G Girotto and Gordon, Scott D and Gordon-Larsen, Penny and Gorski, Mathias and Grarup, Niels and Grove, Megan L and Gudnason, Vilmundur and Gustafsson, Stefan and Hansen, Torben and Kathleen Mullan Harris and Tamara B Harris and Andrew T Hattersley and Caroline Hayward and He, Liang and Iris M Heid and Heikkil{\"a}, Kauko and Helgeland, {\O}yvind and Hernesniemi, Jussi and Hewitt, Alex W and Lynne J Hocking and Hollensted, Mette and Oddgeir L Holmen and Hovingh, G Kees and Howson, Joanna M M and Hoyng, Carel B and Huang, Paul L and Hveem, Kristian and Mohammed Arfan Ikram and Ingelsson, Erik and Jackson, Anne U and Jansson, Jan-H{\r a}kan and Jarvik, Gail P and Jensen, Gorm B and Jhun, Min A and Jia, Yucheng and Jiang, Xuejuan and Johansson, Stefan and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Jousilahti, Pekka and Jukema, J Wouter and Kahali, Bratati and Kahn, Ren{\'e} S and K{\"a}h{\"o}nen, Mika and Kamstrup, Pia R and Kanoni, Stavroula and Kaprio, Jaakko and Karaleftheri, Maria and Sharon L R Kardia and Karpe, Fredrik and Kee, Frank and Keeman, Renske and Lambertus A Kiemeney and Kitajima, Hidetoshi and Kluivers, Kirsten B and Kocher, Thomas and Komulainen, Pirjo and Kontto, Jukka and Kooner, Jaspal S and Charles Kooperberg and Kovacs, Peter and Kriebel, Jennifer and Kuivaniemi, Helena and K{\"u}ry, S{\'e}bastien and Kuusisto, Johanna and La Bianca, Martina and Laakso, Markku and Lakka, Timo A and Lange, Ethan M and Leslie A Lange and Langefeld, Carl D and Langenberg, Claudia and Eric B Larson and Lee, I-Te and Lehtim{\"a}ki, Terho and Lewis, Cora E and Li, Huaixing and Li, Jin and Li-Gao, Ruifang and Lin, Honghuang and Lin, Li-An and Lin, Xu and Lars Lind and Lindstr{\"o}m, Jaana and Linneberg, Allan and Liu, Yeheng and Yongmei Liu and Lophatananon, Artitaya and Luan, Jian{\textquoteright}an and Lubitz, Steven A and Lyytik{\"a}inen, Leo-Pekka and Mackey, David A and Pamela A F Madden and Alisa Manning and M{\"a}nnist{\"o}, Satu and Marenne, Ga{\"e}lle and Marten, Jonathan and Nicholas G Martin and Mazul, Angela L and Meidtner, Karina and Andres Metspalu and Mitchell, Paul and Mohlke, Karen L and Dennis O Mook-Kanamori and Morgan, Anna and Morris, Andrew D and Morris, Andrew P and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Michael A Nalls and Nauck, Matthias and Nelson, Christopher P and Neville, Matt and Sune Fallgaard Nielsen and Nikus, Kjell and Nj{\o}lstad, P{\r a}l R and B{\o}rge G Nordestgaard and Ntalla, Ioanna and Jeff O{\textquoteright}Connell and Oksa, Heikki and Loes M Olde Loohuis and Ophoff, Roel A and Owen, Katharine R and Packard, Chris J and Padmanabhan, Sandosh and Palmer, Colin N A and Pasterkamp, Gerard and Patel, Aniruddh P and Pattie, Alison and Pedersen, Oluf and Peissig, Peggy L and Peloso, Gina M and Pennell, Craig E and Markus Perola and Perry, James A and Perry, John R B and Person, Thomas N and Pirie, Ailith and Polasek, Ozren and Posthuma, Danielle and Olli T Raitakari and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Reiner, Alex P and Renstrom, Frida and Ridker, Paul M and Rioux, John D and Neil R Robertson and Robino, Antonietta and Rolandsson, Olov and Rudan, Igor and Ruth, Katherine S and Saleheen, Danish and Veikko Salomaa and Nilesh J Samani and Sandow, Kevin and Sapkota, Yadav and Sattar, Naveed and Schmidt, Marjanka K and Schreiner, Pamela J and Schulze, Matthias B and Scott, Robert A and Segura-Lepe, Marcelo P and Svati H Shah and Sim, Xueling and Sivapalaratnam, Suthesh and Small, Kerrin S and Albert Vernon Smith and Jennifer A Smith and Southam, Lorraine and Timothy Spector and Elizabeth K Speliotes and John M Starr and Steinthorsdottir, Valgerdur and Heather M Stringham and Stumvoll, Michael and Surendran, Praveen and {\textquoteright}t Hart, Leen M and Tansey, Katherine E and Tardif, Jean-Claude and Kent D Taylor and Teumer, Alexander and Thompson, Deborah J and Thorsteinsdottir, Unnur and Thuesen, Betina H and T{\"o}njes, Anke and Tromp, Gerard and Trompet, Stella and Tsafantakis, Emmanouil and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and Tyrer, Jonathan P and Uher, Rudolf and Andr{\'e} G Uitterlinden and Ulivi, Sheila and van der Laan, Sander W and Van Der Leij, Andries R and Cornelia M van Duijn and van Schoor, Natasja M and van Setten, Jessica and Varbo, Anette and Varga, Tibor V and Varma, Rohit and Digna R Velez Edwards and Vermeulen, Sita H and Vestergaard, Henrik and Vitart, Veronique and Vogt, Thomas F and Vozzi, Diego and Walker, Mark and Wang, Feijie and Wang, Carol A and Wang, Shuai and Wang, Yiqin and Wareham, Nicholas J and Warren, Helen R and Wessel, Jennifer and Willems, Sara M and Wilson, James G and Daniel Witte and Woods, Michael O and Wu, Ying and Yaghootkar, Hanieh and Yao, Jie and Yao, Pang and Laura M Yerges-Armstrong and Young, Robin and Zeggini, Eleftheria and Zhan, Xiaowei and Zhang, Weihua and Jing Hua Zhao and Wei Zhao and Wei Zhao and Zheng, He and Zhou, Wei and Rotter, Jerome I and Boehnke, Michael and Kathiresan, Sekar and McCarthy, Mark I and Willer, Cristen J and Stefansson, Kari and Ingrid B Borecki and Liu, Dajiang J and Kari E North and Heard-Costa, Nancy L and Pers, Tune H and Lindgren, Cecilia M and Oxvig, Claus and Kutalik, Zolt{\'a}n and Fernando Rivadeneira and Ruth J F Loos and Timothy M Frayling and Joel N Hirschhron and Deloukas, Panos and Lettre, Guillaume} }