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Meta-Analysis
. 2016 Feb 1:7:10495.
doi: 10.1038/ncomms10495.

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Yingchang Lu  1   2 , Felix R Day  3 , Stefan Gustafsson  4   5 , Martin L Buchkovich  6 , Jianbo Na  7 , Veronique Bataille  8   9 , Diana L Cousminer  10 , Zari Dastani  11 , Alexander W Drong  12 , Tõnu Esko  13   14   15   16 , David M Evans  17   18 , Mario Falchi  9   19 , Mary F Feitosa  20 , Teresa Ferreira  12 , Åsa K Hedman  4   5   12 , Robin Haring  21   22 , Pirro G Hysi  9 , Mark M Iles  23 , Anne E Justice  24 , Stavroula Kanoni  25   26 , Vasiliki Lagou  12   27 , Rui Li  11 , Xin Li  28 , Adam Locke  29 , Chen Lu  30 , Reedik Mägi  12   13 , John R B Perry  3 , Tune H Pers  15   16   31   32   33 , Qibin Qi  34 , Marianna Sanna  9   19 , Ellen M Schmidt  35 , William R Scott  36   37 , Dmitry Shungin  38   39   40 , Alexander Teumer  41   42 , Anna A E Vinkhuyzen  43 , Ryan W Walker  1   2 , Harm-Jan Westra  44   45   46 , Mingfeng Zhang  47 , Weihua Zhang  36   37 , Jing Hua Zhao  3 , Zhihong Zhu  43 , Uzma Afzal  36   37 , Tarunveer Singh Ahluwalia  31   48   49   50 , Stephan J L Bakker  51 , Claire Bellis  52 , Amélie Bonnefond  53   54   55 , Katja Borodulin  56 , Aron S Buchman  57 , Tommy Cederholm  58 , Audrey C Choh  59 , Hyung Jin Choi  60 , Joanne E Curran  61 , Lisette C P G M de Groot  62 , Philip L De Jager  44   63   64 , Rosalie A M Dhonukshe-Rutten  62 , Anke W Enneman  65 , Elodie Eury  53   54   55 , Daniel S Evans  66 , Tom Forsen  67 , Nele Friedrich  21 , Frédéric Fumeron  68   69   70   71 , Melissa E Garcia  72 , Simone Gärtner  73 , Bok-Ghee Han  74 , Aki S Havulinna  56 , Caroline Hayward  75 , Dena Hernandez  76 , Hans Hillege  77 , Till Ittermann  41 , Jack W Kent  52 , Ivana Kolcic  78 , Tiina Laatikainen  56   79   80 , Jari Lahti  81   82 , Irene Mateo Leach  77 , Christine G Lee  83   84 , Jong-Young Lee  74 , Tian Liu  85   86 , Youfang Liu  87 , Stéphane Lobbens  53   54   55 , Marie Loh  36   88 , Leo-Pekka Lyytikäinen  89   90 , Carolina Medina-Gomez  65   91   92 , Karl Michaëlsson  93 , Mike A Nalls  76 , Carrie M Nielson  94   95 , Laticia Oozageer  37 , Laura Pascoe  96 , Lavinia Paternoster  18 , Ozren Polašek  78   97 , Samuli Ripatti  10   26   98 , Mark A Sarzynski  99 , Chan Soo Shin  100 , Nina Smolej Narančić  101 , Dominik Spira  102   103 , Priya Srikanth  94   95 , Elisabeth Steinhagen-Thiessen  102   103 , Yun Ju Sung  104 , Karin M A Swart  105   106 , Leena Taittonen  107   108 , Toshiko Tanaka  109 , Emmi Tikkanen  10   98 , Nathalie van der Velde  65 , Natasja M van Schoor  105   106 , Niek Verweij  77 , Alan F Wright  75 , Lei Yu  57 , Joseph M Zmuda  110 , Niina Eklund  56 , Terrence Forrester  111 , Niels Grarup  31 , Anne U Jackson  29 , Kati Kristiansson  10   56 , Teemu Kuulasmaa  112 , Johanna Kuusisto  112   113   114 , Peter Lichtner  115 , Jian'an Luan  3 , Anubha Mahajan  12 , Satu Männistö  56 , Cameron D Palmer  14   15 , Janina S Ried  116 , Robert A Scott  3 , Alena Stancáková  117 , Peter J Wagner  10   56 , Ayse Demirkan  118 , Angela Döring  119   120 , Vilmundur Gudnason  121   122 , Douglas P Kiel  123   124 , Brigitte Kühnel  116   120   125 , Massimo Mangino  9 , Barbara Mcknight  126   127   128 , Cristina Menni  9 , Jeffrey R O'Connell  129 , Ben A Oostra  118 , Alan R Shuldiner  129   130 , Kijoung Song  131 , Liesbeth Vandenput  132 , Cornelia M van Duijn  91   118   133 , Peter Vollenweider  134 , Charles C White  30 , Michael Boehnke  29 , Yvonne Boettcher  135   136 , Richard S Cooper  137 , Nita G Forouhi  3 , Christian Gieger  116   120   125 , Harald Grallert  120   125   138 , Aroon Hingorani  139 , Torben Jørgensen  140   141   142 , Pekka Jousilahti  56 , Mika Kivimaki  143 , Meena Kumari  143 , Markku Laakso  112   113   114 , Claudia Langenberg  3   143 , Allan Linneberg  144 , Amy Luke  137 , Colin A Mckenzie  111 , Aarno Palotie  10   26   145 , Oluf Pedersen  31 , Annette Peters  120   125 , Konstantin Strauch  116   146 , Bamidele O Tayo  137 , Nicholas J Wareham  3 , David A Bennett  57 , Lars Bertram  147   148 , John Blangero  61 , Matthias Blüher  135   136 , Claude Bouchard  99 , Harry Campbell  97 , Nam H Cho  149 , Steven R Cummings  66 , Stefan A Czerwinski  59 , Ilja Demuth  102   150 , Rahel Eckardt  102 , Johan G Eriksson  56   67   81 , Luigi Ferrucci  109 , Oscar H Franco  91   92 , Philippe Froguel  53   54   55 , Ron T Gansevoort  51 , Torben Hansen  31   151 , Tamara B Harris  72 , Nicholas Hastie  75 , Markku Heliövaara  56 , Albert Hofman  91   92 , Joanne M Jordan  87 , Antti Jula  56 , Mika Kähönen  152   153 , Eero Kajantie  56   154   155 , Paul B Knekt  56 , Seppo Koskinen  56 , Peter Kovacs  135 , Terho Lehtimäki  89   90 , Lars Lind  156 , Yongmei Liu  157 , Eric S Orwoll  95 , Clive Osmond  158 , Markus Perola  10   13   56 , Louis Pérusse  159   160 , Olli T Raitakari  161   162 , Tuomo Rankinen  99 , D C Rao  20   104   163 , Treva K Rice  104   163 , Fernando Rivadeneira  65   91   92 , Igor Rudan  97 , Veikko Salomaa  56 , Thorkild I A Sørensen  18   31   164 , Michael Stumvoll  135   136 , Anke Tönjes  136 , Bradford Towne  59 , Gregory J Tranah  66 , Angelo Tremblay  159 , André G Uitterlinden  65   91   92 , Pim van der Harst  77   165   166 , Erkki Vartiainen  56 , Jorma S Viikari  167 , Veronique Vitart  75 , Marie-Claude Vohl  160   168 , Henry Völzke  41   169   170 , Mark Walker  44   171 , Henri Wallaschofski  21   169 , Sarah Wild  172 , James F Wilson  75   97 , Loïc Yengo  53   54   55 , D Timothy Bishop  23 , Ingrid B Borecki  20   173 , John C Chambers  36   37   174 , L Adrienne Cupples  30   175 , Abbas Dehghan  176 , Panos Deloukas  25   26   177 , Ghazaleh Fatemifar  18 , Caroline Fox  63   175 , Terrence S Furey  6   178 , Lude Franke  77   166 , Jiali Han  179 , David J Hunter  14   28   180   181 , Juha Karjalainen  166 , Fredrik Karpe  27   182 , Robert C Kaplan  34 , Jaspal S Kooner  37   174   183 , Mark I McCarthy  12   27   182 , Joanne M Murabito  184   185 , Andrew P Morris  12   186 , Julia A N Bishop  23 , Kari E North  187 , Claes Ohlsson  132 , Ken K Ong  3   188   189 , Inga Prokopenko  12   19   27 , J Brent Richards  11   190   191   192 , Eric E Schadt  193   194 , Tim D Spector  9 , Elisabeth Widén  10 , Cristen J Willer  35   195   196 , Jian Yang  43 , Erik Ingelsson  4   5   197 , Karen L Mohlke  6 , Joel N Hirschhorn  14   15   16 , John Andrew Pospisilik  198 , M Carola Zillikens  65   91 , Cecilia Lindgren  12   14   199 , Tuomas Oskari Kilpeläinen  3   31 , Ruth J F Loos  1   2   3   200   201
Affiliations
Meta-Analysis

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Yingchang Lu et al. Nat Commun. .

Abstract

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

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Conflict of interest statement

R.E. received honoraria for lectures from the following companies (within the past 2 years): MSD Sharp&Dohme and Pfizer. J.M.J. disclosed Trinity Partners, Inc., Osteoarthritis Research Society International, Chronic Osteoarthritis Management Initiative of US Bone and Joint Initiative, Samumed, Interleukin Genetics, Inc. and Algynomics, Inc. K.S. is a full-time employee of GlaxoSmithKline. D.S. received honoraria for lectures from the following companies (within the past 2 years): MSD Sharp&Dohme. E.S.-T. received honoraria for lectures, research grants and consultancy fees from the following companies (within the past 2 years): Aegerion, Fresenius, MSD Sharp&Dohme, Pfizer and Sanofi. Peter Vollenweider received an unrestricted grant from GSK to build the CoLaus study.

Figures

Figure 1
Figure 1. Regional plots of the four newly identified loci that reached genome-wide significant association with body fat percentage.
Regional plots of the four newly identified loci that reached genome-wide significant association with body fat percentage in all-ancestry analyses, in men and women combined for the COBLL1/GRB14 and IGF2BP1 loci (a,b), and separately for the CRTC1 and PLA2G6 (c,d). Each symbol represents the significance (P value on a −log10 scale) of a SNP with BF% as a function of the SNP's genomic position (NCBI Build 36). For each locus, the index SNP is represented in the purple colour. The colour of all other SNPs indicates LD with the index SNP (estimated by CEU r2 from the HapMap Project data Phase II CEU). Recombination rates are also estimated from International HapMap Project data, and gene annotations are obtained from the UCSC Genome Browser. GWAS catalogues SNPs with P value <5 × 10−8 are shown in the middle panel. Different shapes denote the different categories of the SNPs: up-triangle for framestop or splice SNPs, down-triangle for nonsynonymous SNPs, square for coding or untranslated region (UTR) SNPs; star for SNPs in tfbscons region, square filled with ‘X' symbol for SNPs located in mcs44placental region and circle for SNPs with no annotation information.
Figure 2
Figure 2. Comparison of effects of the 12 loci on body fat percentage (x axis) and on BMI (y axis).
Both outcomes (BMI and BF%) were inverse normally transformed (mean 0, s.d. 1) such that effects sizes are at the same scales and directly comparable. Effect sizes for BMI were obtained from Locke et al.. The allele effects for the PLA2G6 (square) and CRTC1 (round) loci were derived, respectively, from the men- and women-based meta-analyses. Six loci had first been identified for BMI (blue), whereas six others were first identified for BF% (green).
Figure 3
Figure 3. Genotype influences Pol2 binding at rs4808844.
(a) UCSC Genome browser track (hg19) of chromosome 16 displaying Pol2 binding signal in 10 lymphoblastoid cell lines (LCLs), grouped by genotype and correlations between DNaseI hypersensitivity and nearby gene transcription. (b) Binding signals from Pol2 ChIP-seq from 10 LCLs, grouped by genotype.
See this image and copyright information in PMC

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