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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

SUBMITTER: Berndt SI

PROVIDER: S-EPMC3973018 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

Berndt Sonja I SI Gustafsson Stefan S Mägi Reedik R Ganna Andrea A Wheeler Eleanor E Feitosa Mary F MF Justice Anne E AE Monda Keri L KL Croteau-Chonka Damien C DC Day Felix R FR Esko Tõnu T Fall Tove T Ferreira Teresa T Gentilini Davide D Jackson Anne U AU Luan Jian'an J Randall Joshua C JC Vedantam Sailaja S Willer Cristen J CJ Winkler Thomas W TW Wood Andrew R AR Workalemahu Tsegaselassie T Hu Yi-Juan YJ Lee Sang Hong SH Liang Liming L Lin Dan-Yu DY Min Josine L JL Neale Benjamin M BM Thorleifsson Gudmar G Yang Jian J Albrecht Eva E Amin Najaf N Bragg-Gresham Jennifer L JL Cadby Gemma G den Heijer Martin M Eklund Niina N Fischer Krista K Goel Anuj A Hottenga Jouke-Jan JJ Huffman Jennifer E JE Jarick Ivonne I Johansson Åsa Å Johnson Toby T Kanoni Stavroula S Kleber Marcus E ME König Inke R IR Kristiansson Kati K Kutalik Zoltán Z Lamina Claudia C Lecoeur Cecile C Li Guo G Mangino Massimo M McArdle Wendy L WL Medina-Gomez Carolina C Müller-Nurasyid Martina M Ngwa Julius S JS Nolte Ilja M IM Paternoster Lavinia L Pechlivanis Sonali S Perola Markus M Peters Marjolein J MJ Preuss Michael M Rose Lynda M LM Shi Jianxin J Shungin Dmitry D Smith Albert Vernon AV Strawbridge Rona J RJ Surakka Ida I Teumer Alexander A Trip Mieke D MD Tyrer Jonathan J Van Vliet-Ostaptchouk Jana V JV Vandenput Liesbeth L Waite Lindsay L LL Zhao Jing Hua JH Absher Devin D Asselbergs Folkert W FW Atalay Mustafa M Attwood Antony P AP Balmforth Anthony J AJ Basart Hanneke H Beilby John J Bonnycastle Lori L LL Brambilla Paolo P Bruinenberg Marcel M Campbell Harry H Chasman Daniel I DI Chines Peter S PS Collins Francis S FS Connell John M JM Cookson William O WO de Faire Ulf U de Vegt Femmie F Dei Mariano M Dimitriou Maria M Edkins Sarah S Estrada Karol K Evans David M DM Farrall Martin M Ferrario Marco M MM Ferrières Jean J Franke Lude L Frau Francesca F Gejman Pablo V PV Grallert Harald H Grönberg Henrik H Gudnason Vilmundur V Hall Alistair S AS Hall Per P Hartikainen Anna-Liisa AL Hayward Caroline C Heard-Costa Nancy L NL Heath Andrew C AC Hebebrand Johannes J Homuth Georg G Hu Frank B FB Hunt Sarah E SE Hyppönen Elina E Iribarren Carlos C Jacobs Kevin B KB Jansson John-Olov JO Jula Antti A Kähönen Mika M Kathiresan Sekar S Kee Frank F Khaw Kay-Tee KT Kivimäki Mika M Koenig Wolfgang W Kraja Aldi T AT Kumari Meena M Kuulasmaa Kari K Kuusisto Johanna J Laitinen Jaana H JH Lakka Timo A TA Langenberg Claudia C Launer Lenore J LJ Lind Lars L Lindström Jaana J Liu Jianjun J Liuzzi Antonio A Lokki Marja-Liisa ML Lorentzon Mattias M Madden Pamela A PA Magnusson Patrik K PK Manunta Paolo P Marek Diana D März Winfried W Mateo Leach Irene I McKnight Barbara B Medland Sarah E SE Mihailov Evelin E Milani Lili L Montgomery Grant W GW Mooser Vincent V Mühleisen Thomas W TW Munroe Patricia B PB Musk Arthur W AW Narisu Narisu N Navis Gerjan G Nicholson George G Nohr Ellen A EA Ong Ken K KK Oostra Ben A BA Palmer Colin N A CN Palotie Aarno A Peden John F JF Pedersen Nancy N Peters Annette A Polasek Ozren O Pouta Anneli A Pramstaller Peter P PP Prokopenko Inga I Pütter Carolin C Radhakrishnan Aparna A Raitakari Olli O Rendon Augusto A Rivadeneira Fernando F Rudan Igor I Saaristo Timo E TE Sambrook Jennifer G JG Sanders Alan R AR Sanna Serena S Saramies Jouko J Schipf Sabine S Schreiber Stefan S Schunkert Heribert H Shin So-Youn SY Signorini Stefano S Sinisalo Juha J Skrobek Boris B Soranzo Nicole N Stančáková Alena A Stark Klaus K Stephens Jonathan C JC Stirrups Kathleen K Stolk Ronald P RP Stumvoll Michael M Swift Amy J AJ Theodoraki Eirini V EV Thorand Barbara B Tregouet David-Alexandre DA Tremoli Elena E Van der Klauw Melanie M MM van Meurs Joyce B J JB Vermeulen Sita H SH Viikari Jorma J Virtamo Jarmo J Vitart Veronique V Waeber Gérard G Wang Zhaoming Z Widén Elisabeth E Wild Sarah H SH Willemsen Gonneke G Winkelmann Bernhard R BR Witteman Jacqueline C M JC Wolffenbuttel Bruce H R BH Wong Andrew A Wright Alan F AF Zillikens M Carola MC Amouyel Philippe P Boehm Bernhard O BO Boerwinkle Eric E Boomsma Dorret I DI Caulfield Mark J MJ Chanock Stephen J SJ Cupples L Adrienne LA Cusi Daniele D Dedoussis George V GV Erdmann Jeanette J Eriksson Johan G JG Franks Paul W PW Froguel Philippe P Gieger Christian C Gyllensten Ulf U Hamsten Anders A Harris Tamara B TB Hengstenberg Christian C Hicks Andrew A AA Hingorani Aroon A Hinney Anke A Hofman Albert A Hovingh Kees G KG Hveem Kristian K Illig Thomas T Jarvelin Marjo-Riitta MR Jöckel Karl-Heinz KH Keinanen-Kiukaanniemi Sirkka M SM Kiemeney Lambertus A LA Kuh Diana D Laakso Markku M Lehtimäki Terho T Levinson Douglas F DF Martin Nicholas G NG Metspalu Andres A Morris Andrew D AD Nieminen Markku S MS Njølstad Inger I Ohlsson Claes C Oldehinkel Albertine J AJ Ouwehand Willem H WH Palmer Lyle J LJ Penninx Brenda B Power Chris C Province Michael A MA Psaty Bruce M BM Qi Lu L Rauramaa Rainer R Ridker Paul M PM Ripatti Samuli S Salomaa Veikko V Samani Nilesh J NJ Snieder Harold H Sørensen Thorkild I A TI Spector Timothy D TD Stefansson Kari K Tönjes Anke A Tuomilehto Jaakko J Uitterlinden André G AG Uusitupa Matti M van der Harst Pim P Vollenweider Peter P Wallaschofski Henri H Wareham Nicholas J NJ Watkins Hugh H Wichmann H-Erich HE Wilson James F JF Abecasis Goncalo R GR Assimes Themistocles L TL Barroso Inês I Boehnke Michael M Borecki Ingrid B IB Deloukas Panos P Fox Caroline S CS Frayling Timothy T Groop Leif C LC Haritunian Talin T Heid Iris M IM Hunter David D Kaplan Robert C RC Karpe Fredrik F Moffatt Miriam F MF Mohlke Karen L KL O'Connell Jeffrey R JR Pawitan Yudi Y Schadt Eric E EE Schlessinger David D Steinthorsdottir Valgerdur V Strachan David P DP Thorsteinsdottir Unnur U van Duijn Cornelia M CM Visscher Peter M PM Di Blasio Anna Maria AM Hirschhorn Joel N JN Lindgren Cecilia M CM Morris Andrew P AP Meyre David D Scherag André A McCarthy Mark I MI Speliotes Elizabeth K EK North Kari E KE Loos Ruth J F RJ Ingelsson Erik E

Nature genetics 20130407 5

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influenc ...[more]

PMID: 23563607

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Project description:Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

Publications

Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.

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