A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
Authors: Ried Janina S. , Jeff M. Janina , Chu Audrey Y. , Bragg-Gresham Jennifer L. , van Dongen Jenny , Huffman Jennifer E. , Ahluwalia Tarunveer S. , Cadby Gemma , Eklund Niina , Eriksson Joel , Esko Tõnu , Feitosa Mary F. , Goel Anuj , Gorski Mathias , Hayward Caroline , Heard-Costa Nancy L. , Jackson Anne U. , Jokinen Eero , Kanoni Stavroula , Kristiansson Kati , Kutalik Zoltán , Lahti Jari , Luan Jian'an , Mägi Reedik , Mahajan Anubha , Mangino Massimo , Medina-Gomez Carolina , Monda Keri L. , Nolte Ilja M. , Pérusse Louis , Prokopenko Inga , Qi Lu , Rose Lynda M. , Salvi Erika , Smith Megan T. , Snieder Harold , Stančáková Alena , Ju Sung Yun , Tachmazidou Ioanna , Teumer Alexander , Thorleifsson Gudmar , van der Harst Pim , Walker Ryan W. , Wang Sophie R. , Wild Sarah H. , Willems Sara M. , Wong Andrew , Zhang Weihua , Albrecht Eva , Couto Alves Alexessander , Bakker Stephan J. L. , Barlassina Cristina , Bartz Traci M. , Beilby John , Bellis Claire , Bergman Richard N. , Bergmann Sven , Blangero John , Blüher Matthias , Boerwinkle Eric , Bonnycastle Lori L. , Bornstein Stefan R. , Bruinenberg Marcel , Campbell Harry , Chen Yii-Der Ida , Chiang Charleston W. K. , Chines Peter S. , Collins Francis S , Cucca Fracensco , Cupples L Adrienne , D’Avila Francesca , de Geus Eco J .C. , Dedoussis George , Dimitriou Maria , Döring Angela , Eriksson Johan G. , Farmaki Aliki-Eleni , Farrall Martin , Ferreira Teresa , Fischer Krista , Forouhi Nita G. , Friedrich Nele , Gjesing Anette Prior , Glorioso Nicola , Graff Mariaelisa , Grallert Harald , Grarup Niels , Gräßler Jürgen , Grewal Jagvir , Hamsten Anders , Harder Marie Neergaard , Hartman Catharina A. , Hassinen Maija , Hastie Nicholas , Hattersley Andrew Tym , Havulinna Aki S. , Heliövaara Markku , Hillege Hans , Hofman Albert , Holmen Oddgeir , Homuth Georg , Hottenga Jouke-Jan , Hui Jennie , Husemoen Lise Lotte , Hysi Pirro G. , Isaacs Aaron , Ittermann Till , Jalilzadeh Shapour , James Alan L. , Jørgensen Torben , Jousilahti Pekka , Jula Antti , Marie Justesen Johanne , Justice Anne E. , Kähönen Mika , Karaleftheri Maria , Tee Khaw Kay , Keinanen-Kiukaanniemi Sirkka M. , Kinnunen Leena , Knekt Paul B. , Koistinen Heikki A. , Kolcic Ivana , Kooner Ishminder K. , Koskinen Seppo , Kovacs Peter , Kyriakou Theodosios , Laitinen Tomi , Langenberg Claudia , Lewin Alexandra M. , Lichtner Peter , Lindgren Cecilia M. , Lindström Jaana , Linneberg Allan , Lorbeer Roberto , Lorentzon Mattias , Luben Robert , Lyssenko Valeriya , Männistö Satu , Manunta Paolo , Leach Irene Mateo , McArdle Wendy L. , Mcknight Barbara , Mohlke Karen L. , Mihailov Evelin , Milani Lili , Mills Rebecca , Montasser May E. , Morris Andrew P. , Müller Gabriele , Musk Arthur W. , Narisu Narisu , Ong Ken K. , Oostra Ben A. , Osmond Clive , Palotie Aarno , Pankow James S. , Paternoster Lavinia , Penninx Brenda W. , Pichler Irene , Pilia Maria G. , Polašek Ozren , Pramstaller Peter P. , Raitakari Olli T , Rankinen Tuomo , Rao D. C. , Rayner Nigel W. , Ribel-Madsen Rasmus , Rice Treva K. , Richards Marcus , Ridker Paul M. , Rivadeneira Fernando , Ryan Kathy A. , Sanna Serena , Sarzynski Mark A. , Scholtens Salome , Scott Robert A. , Sebert Sylvain , Southam Lorraine , Sparsø Thomas Hempel , Steinthorsdottir Valgerdur , Stirrups Kathleen , Stolk Ronald P. , Strauch Konstantin , Stringham Heather M. , Swertz Morris A. , Swift Amy J. , Tönjes Anke , Tsafantakis Emmanouil , van der Most Peter J. , Van Vliet-Ostaptchouk Jana V. , Vandenput Liesbeth , Vartiainen Erkki , Venturini Cristina , Verweij Niek , Viikari Jorma S. , Vitart Veronique , Vohl Marie-Claude , Vonk Judith M. , Waeber Gérard , Widén Elisabeth , Willemsen Gonneke , Wilsgaard Tom , Winkler Thomas W. , Wright Alan F. , Yerges-Armstrong Laura M. , Hua Zhao Jing , Carola Zillikens M. , Boomsma Dorret I. , Bouchard Claude , Chambers John C. , Chasman Daniel I. , Cusi Daniele , Gansevoort Ron T. , Gieger Christian , Hansen Torben , Hicks Andrew A. , Hu Frank , Hveem Kristian , Jarvelin Marjo-Riitta , Kajantie Eero , Kooner Jaspal S. , Kuh Diana , Kuusisto Johanna , Laakso Markku , Lakka Timo A. , Lehtimäki Terho , Metspalu Andres , Njølstad Inger , Ohlsson Claes , Oldehinkel Albertine J. , Palmer Lyle J. , Pedersen Oluf , Perola Markus , Peters Annette , Psaty Bruce M. , Puolijoki Hannu , Rauramaa Rainer , Rudan Igor , Salomaa Veikko , Schwarz Peter E. H. , Shudiner Alan R. , Smit Jan H. , Sørensen Thorkild I. A. , Spector Timothy D. , Stefansson Kari , Stumvoll Michael , Tremblay Angelo , Tuomilehto Jaakko , Uitterlinden André G. , Uusitupa Matti , Völker Uwe , Vollenweider Peter , Wareham Nicholas J. , Watkins Hugh , Wilson James F. , Zeggini Eleftheria , Abecasis Goncalo R. , Boehnke Michael , Borecki Ingrid B. , Deloukas Panos , van Duijn Cornelia M. , Fox Caroline , Groop Leif C. , Heid Iris M. , Hunter David J. , Kaplan Robert C. , McCarthy Mark I. , North Kari E. , O'Connell Jeffrey R. , Schlessinger David , Thorsteinsdottir Unnur , Strachan David P. , Frayling Timothy , Hirschhorn Joel N. , Müller-Nurasyid Martina , Loos Ruth J. F. 
Published: November 2016

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.