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. 2016 Nov 23;7:13357.
doi: 10.1038/ncomms13357.

A Principal Component Meta-Analysis on Multiple Anthropometric Traits Identifies Novel Loci for Body Shape

Janina S Ried  1 Janina Jeff M  2 Audrey Y Chu  3 Jennifer L Bragg-Gresham  4 Jenny van Dongen  5 Jennifer E Huffman  6 Tarunveer S Ahluwalia  7   8   9 Gemma Cadby  10 Niina Eklund  11 Joel Eriksson  12 Tõnu Esko  13   14   15   16 Mary F Feitosa  17 Anuj Goel  18   19 Mathias Gorski  20   21 Caroline Hayward  6 Nancy L Heard-Costa  22   23 Anne U Jackson  24 Eero Jokinen  25 Stavroula Kanoni  26   27 Kati Kristiansson  11   28 Zoltán Kutalik  29   30   31 Jari Lahti  32   33 Jian'an Luan  34 Reedik Mägi  15   19 Anubha Mahajan  19 Massimo Mangino  35 Carolina Medina-Gomez  36   37 Keri L Monda  38   39 Ilja M Nolte  40 Louis Pérusse  41   42 Inga Prokopenko  19   43   44 Lu Qi  45   46 Lynda M Rose  3 Erika Salvi  47   48 Megan T Smith  49 Harold Snieder  40 Alena Stančáková  50 Yun Ju Sung  51 Ioanna Tachmazidou  26 Alexander Teumer  52   53 Gudmar Thorleifsson  54 Pim van der Harst  55   56   57 Ryan W Walker  2   58 Sophie R Wang  16   59   60   61 Sarah H Wild  62 Sara M Willems  63 Andrew Wong  64 Weihua Zhang  65   66 Eva Albrecht  1 Alexessander Couto Alves  67 Stephan J L Bakker  68 Cristina Barlassina  47   48 Traci M Bartz  49   69   70 John Beilby  71   72 Claire Bellis  73   74 Richard N Bergman  75 Sven Bergmann  29   30 John Blangero  76 Matthias Blüher  77   78 Eric Boerwinkle  79 Lori L Bonnycastle  80 Stefan R Bornstein  81 Marcel Bruinenberg  82 Harry Campbell  62 Yii-Der Ida Chen  83 Charleston W K Chiang  84 Peter S Chines  80 Francis S Collins  80 Fracensco Cucca  85 L Adrienne Cupples  22 Francesca D'Avila  47   48 Eco J C de Geus  5   86 George Dedoussis  87 Maria Dimitriou  26   87 Angela Döring  88   89 Johan G Eriksson  32   90   91 Aliki-Eleni Farmaki  87 Martin Farrall  18   19 Teresa Ferreira  19 Krista Fischer  15 Nita G Forouhi  34 Nele Friedrich  92 Anette Prior Gjesing  7 Nicola Glorioso  93 Mariaelisa Graff  38 Harald Grallert  89   94   95 Niels Grarup  7 Jürgen Gräßler  96 Jagvir Grewal  65   66 Anders Hamsten  97   98   99 Marie Neergaard Harder  7 Catharina A Hartman  100 Maija Hassinen  101 Nicholas Hastie  6 Andrew Tym Hattersley  102 Aki S Havulinna  11 Markku Heliövaara  11 Hans Hillege  57 Albert Hofman  36 Oddgeir Holmen  103 Georg Homuth  53 Jouke-Jan Hottenga  5 Jennie Hui  71   72   104 Lise Lotte Husemoen  105 Pirro G Hysi  35 Aaron Isaacs  63 Till Ittermann  52 Shapour Jalilzadeh  18   19 Alan L James  106 Torben Jørgensen  107   108   109 Pekka Jousilahti  11 Antti Jula  11 Johanne Marie Justesen  7 Anne E Justice  38 Mika Kähönen  110   111 Maria Karaleftheri  112 Kay Tee Khaw  113 Sirkka M Keinanen-Kiukaanniemi  114   115 Leena Kinnunen  116 Paul B Knekt  11 Heikki A Koistinen  116   117   118 Ivana Kolcic  119 Ishminder K Kooner  66 Seppo Koskinen  11 Peter Kovacs  77 Theodosios Kyriakou  18   19 Tomi Laitinen  120   121 Claudia Langenberg  34   122 Alexandra M Lewin  67 Peter Lichtner  123 Cecilia M Lindgren  13   19   124 Jaana Lindström  11 Allan Linneberg  105   107   125 Roberto Lorbeer  52 Mattias Lorentzon  12 Robert Luben  126 Valeriya Lyssenko  8   127 Satu Männistö  11 Paolo Manunta  128 Irene Mateo Leach  57 Wendy L McArdle  129 Barbara Mcknight  49   70   130 Karen L Mohlke  131 Evelin Mihailov  15 Lili Milani  15 Rebecca Mills  66 May E Montasser  132 Andrew P Morris  19   133 Gabriele Müller  134 Arthur W Musk  135 Narisu Narisu  80 Ken K Ong  34   64   136 Ben A Oostra  63 Clive Osmond  137 Aarno Palotie  28   138 James S Pankow  139 Lavinia Paternoster  140 Brenda W Penninx  141 Irene Pichler  142   143 Maria G Pilia  144 Ozren Polašek  62   119 Peter P Pramstaller  142   143   145   146 Olli T Raitakari  147   148 Tuomo Rankinen  149 D C Rao  51   150 Nigel W Rayner  19   44   151 Rasmus Ribel-Madsen  7 Treva K Rice  51   150 Marcus Richards  44   64 Paul M Ridker  3   152 Fernando Rivadeneira  36   37 Kathy A Ryan  132 Serena Sanna  144 Mark A Sarzynski  149 Salome Scholtens  40 Robert A Scott  34 Sylvain Sebert  43   153   154 Lorraine Southam  19   26 Thomas Hempel Sparsø  7 Valgerdur Steinthorsdottir  54 Kathleen Stirrups  26   27 Ronald P Stolk  40 Konstantin Strauch  1   155 Heather M Stringham  24 Morris A Swertz  56 Amy J Swift  80 Anke Tönjes  78 Emmanouil Tsafantakis  156 Peter J van der Most  40 Jana V Van Vliet-Ostaptchouk  157 Liesbeth Vandenput  12 Erkki Vartiainen  11 Cristina Venturini  35   158 Niek Verweij  57 Jorma S Viikari  159   160 Veronique Vitart  6 Marie-Claude Vohl  42   161 Judith M Vonk  40 Gérard Waeber  162 Elisabeth Widén  28 Gonneke Willemsen  5 Tom Wilsgaard  163 Thomas W Winkler  21 Alan F Wright  6 Laura M Yerges-Armstrong  132 Jing Hua Zhao  34 M Carola Zillikens  37 Dorret I Boomsma  5 Claude Bouchard  149 John C Chambers  65   66   164 Daniel I Chasman  3   152 Daniele Cusi  47   48 Ron T Gansevoort  68 Christian Gieger  1   89   95 Torben Hansen  7   165 Andrew A Hicks  142   143 Frank Hu  45   46 Kristian Hveem  103 Marjo-Riitta Jarvelin  153   166   167   168 Eero Kajantie  11   90   169   170 Jaspal S Kooner  66   164   171 Diana Kuh  64 Johanna Kuusisto  50 Markku Laakso  50 Timo A Lakka  101   172 Terho Lehtimäki  173   174 Andres Metspalu  15 Inger Njølstad  163   175 Claes Ohlsson  12 Albertine J Oldehinkel  100 Lyle J Palmer  176   177 Oluf Pedersen  7 Markus Perola  11   15   28 Annette Peters  89   95   178 Bruce M Psaty  70   69   179   180 Hannu Puolijoki  181 Rainer Rauramaa  101   182 Igor Rudan  62 Veikko Salomaa  11 Peter E H Schwarz  81   183 Alan R Shudiner  132   184 Jan H Smit  141 Thorkild I A Sørensen  7   185   186 Timothy D Spector  35 Kari Stefansson  54   187 Michael Stumvoll  77   78 Angelo Tremblay  41 Jaakko Tuomilehto  188   189   190 André G Uitterlinden  36   37 Matti Uusitupa  191   192 Uwe Völker  53   193 Peter Vollenweider  162 Nicholas J Wareham  34 Hugh Watkins  18   19 James F Wilson  6   62 Eleftheria Zeggini  26 Goncalo R Abecasis  24 Michael Boehnke  24 Ingrid B Borecki  17 Panos Deloukas  27   151   194 Cornelia M van Duijn  63   195 Caroline Fox  22   152 Leif C Groop  127   196 Iris M Heid  21   197 David J Hunter  13   45   46   198 Robert C Kaplan  199 Mark I McCarthy  19   44   200 Kari E North  201 Jeffrey R O'Connell  132 David Schlessinger  202 Unnur Thorsteinsdottir  54   187 David P Strachan  203 Timothy Frayling  204 Joel N Hirschhorn  13   14   16   59   60   61   205 Martina Müller-Nurasyid  1   155   178   206 Ruth J F Loos  2   34   58   207   208
Affiliations
Free PMC article

A Principal Component Meta-Analysis on Multiple Anthropometric Traits Identifies Novel Loci for Body Shape

Janina S Ried et al. Nat Commun. .
Free PMC article

Abstract

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.

Conflict of interest statement

Kari Stefansson, Valgerdur Steinthorsdottir, Gudmar Thorleifsson and Unnur Thorsteinsdottir are used by deCODE Genetics/Amgen inc. Gérard Waeber and Peter Vollenweider received an unrestricted grant from GSK to build the CoLaus study. Bruce M. Psaty serves on a DSMB for a clinical trial of a device funded by the manufacturer (Zoll LifeCor).

Figures

Figure 1
Figure 1. Loadings and explained variance of AvPCs for body shape.
(a) Loadings of AvPCs, and (b) explained variance of AvPCs for body shape.
Figure 2
Figure 2. Manhattan and QQ-plots of association results on AvPCs of body shape.
P values of the first stage meta-analysis are given in the Manhattan and QQ-plots. All genome-wide significant loci are highlighted.
Figure 3
Figure 3. Number of loci associated with AvPCs and known from previous GIANT analyses on BMI, WHR or height.
(a–d) corresponds to each AvgPC respectively. The Venn diagrams specify for each AvPC how many significantly associated loci (promising P value in the first stage meta analysis (<5 × 10−6) and genome wide significant in first and second stage combined analysis (<5 × 10−8)) are known from previous GIANT analysis on BMI, height or WHR. In the upper right corner of each plot the number of loci is given that are not known from previous GIANT analyses.

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