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Meta-Analysis
. 2016 Jan 15;25(2):389-403.
doi: 10.1093/hmg/ddv472. Epub 2015 Nov 24.

Genome-wide Association Analysis Identifies Three New Susceptibility Loci for Childhood Body Mass Index

Janine F Felix  1 Jonathan P Bradfield  2 Claire Monnereau  3 Ralf J P van der Valk  4 Evie Stergiakouli  5 Alessandra Chesi  6 Romy Gaillard  3 Bjarke Feenstra  7 Elisabeth Thiering  8 Eskil Kreiner-Møller  9 Anubha Mahajan  10 Niina Pitkänen  11 Raimo Joro  12 Alana Cavadino  13 Ville Huikari  14 Steve Franks  15 Maria M Groen-Blokhuis  16 Diana L Cousminer  17 Julie A Marsh  18 Terho Lehtimäki  19 John A Curtin  20 Jesus Vioque  21 Tarunveer S Ahluwalia  22 Ronny Myhre  23 Thomas S Price  24 Natalia Vilor-Tejedor  25 Loïc Yengo  26 Niels Grarup  27 Ioanna Ntalla  28 Wei Ang  18 Mustafa Atalay  12 Hans Bisgaard  9 Alexandra I Blakemore  29 Amelie Bonnefond  26 Lisbeth Carstensen  7 Bone Mineral Density in Childhood Study (BMDCS)Early Genetics and Lifecourse Epidemiology (EAGLE) consortiumJohan Eriksson  30 Claudia Flexeder  31 Lude Franke  32 Frank Geller  7 Mandy Geserick  33 Anna-Liisa Hartikainen  34 Claire M A Haworth  35 Joel N Hirschhorn  36 Albert Hofman  37 Jens-Christian Holm  38 Momoko Horikoshi  39 Jouke Jan Hottenga  16 Jinyan Huang  40 Haja N Kadarmideen  41 Mika Kähönen  42 Wieland Kiess  43 Hanna-Maaria Lakka  12 Timo A Lakka  44 Alexandra M Lewin  45 Liming Liang  46 Leo-Pekka Lyytikäinen  19 Baoshan Ma  47 Per Magnus  48 Shana E McCormack  49 George McMahon  5 Frank D Mentch  2 Christel M Middeldorp  16 Clare S Murray  20 Katja Pahkala  50 Tune H Pers  51 Roland Pfäffle  52 Dirkje S Postma  4 Christine Power  53 Angela Simpson  54 Verena Sengpiel  55 Carla M T Tiesler  8 Maties Torrent  56 André G Uitterlinden  57 Joyce B van Meurs  58 Rebecca Vinding  59 Johannes Waage  9 Jane Wardle  60 Eleftheria Zeggini  61 Babette S Zemel  62 George V Dedoussis  63 Oluf Pedersen  27 Philippe Froguel  64 Jordi Sunyer  65 Robert Plomin  66 Bo Jacobsson  67 Torben Hansen  27 Juan R Gonzalez  25 Adnan Custovic  20 Olli T Raitakari  68 Craig E Pennell  18 Elisabeth Widén  17 Dorret I Boomsma  16 Gerard H Koppelman  69 Sylvain Sebert  70 Marjo-Riitta Järvelin  71 Elina Hyppönen  72 Mark I McCarthy  73 Virpi Lindi  12 Niinikoski Harri  74 Antje Körner  43 Klaus Bønnelykke  9 Joachim Heinrich  31 Mads Melbye  75 Fernando Rivadeneira  57 Hakon Hakonarson  76 Susan M Ring  77 George Davey Smith  5 Thorkild I A Sørensen  78 Nicholas J Timpson  5 Struan F A Grant  79 Vincent W V Jaddoe  3 Early Growth Genetics (EGG) ConsortiumBone Mineral Density in Childhood Study BMDCS
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Free PMC article
Meta-Analysis

Genome-wide Association Analysis Identifies Three New Susceptibility Loci for Childhood Body Mass Index

Janine F Felix et al. Hum Mol Genet. .
Free PMC article

Abstract

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

Figures

Figure 1.
Figure 1.
Manhattan plot of results of the discovery meta-analysis of 20 studies. Chromosomes are shown on the x-axis, the –log10 of the P-value on the y-axis. The gray dotted line represents the genome-wide significance cutoff of 5 × 10−8. Genes shown in black are the known loci that were significantly associated with childhood BMI in the joint discovery and replication analysis. Genes shown in gray were significant in the discovery, but not in the joint discovery and replication analysis. *indicates novel loci that were significantly associated with childhood BMI in the joint discovery and replication analysis. See also Table 1.
Figure 2.
Figure 2.
Regional plots of the three novel loci for childhood BMI. On the x-axis, the position of SNPs on the chromosome is shown. On the left y-axis is the –log10 of the P-values from the discovery analysis, on the right y-axis is the estimated recombination rate (from HapMap), shown by the light blue line in the figure. The named SNP is the most significant SNP in the locus from the discovery meta-analysis. The linkage disequilibrium of all SNPs with the most significant SNP is shown by the symbols, with dark gray diamonds indicating an R2 of ≥0.8, inversed dark gray triangles indicating an R2 of 0.6–0.8, dark gray triangles indicating an R2 of 0.4–0.6, dark gray circles indicating an R2 of 0.2–0.4 and light gray circles indicating an R2 of 0–0.2. Genes (from HapMap release 22) are plotted below the x-axis.
Figure 3.
Figure 3.
Association of the weighted risk score with BMI. Along the x-axis, categories of the weighted risk score are presented, the mean standard deviation score (SDS)-BMI per group is shown on the right y-axis, with the line representing the regression of the mean SDS–BMI values on the categories of the weighted risk score. The left y-axis represents the number of children in each risk score category, shown in the histogram. The P-value is derived from the analysis of the continuous risk score. Analysis was performed in the PIAMA Study (n = 1955).

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