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Meta-Analysis
. 2017 Sep 29;8(1):744.
doi: 10.1038/s41467-017-00556-x.

CNV-association Meta-Analysis in 191,161 European Adults Reveals New Loci Associated With Anthropometric Traits

Aurélien Macé  1   2   3 Marcus A Tuke  4 Patrick Deelen  5   6 Kati Kristiansson  7   8 Hannele Mattsson  7   8 Margit Nõukas  9   10 Yadav Sapkota  11   12 Ursula Schick  13 Eleonora Porcu  2   14 Sina Rüeger  1   2 Aaron F McDaid  1   2 David Porteous  15 Thomas W Winkler  16 Erika Salvi  17 Nick Shrine  18 Xueping Liu  19 Wei Q Ang  20 Weihua Zhang  21   22 Mary F Feitosa  23 Cristina Venturini  24 Peter J van der Most  25 Anders Rosengren  26   27 Andrew R Wood  4 Robin N Beaumont  4 Samuel E Jones  4 Katherine S Ruth  4 Hanieh Yaghootkar  4 Jessica Tyrrell  4 Aki S Havulinna  7 Harmen Boers  5   6 Reedik Mägi  9 Jennifer Kriebel  28   29   30 Martina Müller-Nurasyid  31   32   33 Markus Perola  7   34 Markku Nieminen  35 Marja-Liisa Lokki  36 Mika Kähönen  37   38 Jorma S Viikari  39   40 Frank Geller  19 Jari Lahti  41   42 Aarno Palotie  8   43   44 Päivikki Koponen  7 Annamari Lundqvist  7 Harri Rissanen  7 Erwin P Bottinger  13 Saima Afaq  21 Mary K Wojczynski  23 Petra Lenzini  23 Ilja M Nolte  25 Thomas Sparsø  26   27 Nicole Schupf  45 Kaare Christensen  46 Thomas T Perls  47 Anne B Newman  48 Thomas Werge  26   27   49 Harold Snieder  25 Timothy D Spector  24 John C Chambers  21   22   50 Seppo Koskinen  7 Mads Melbye  19   51   52 Olli T Raitakari  53   54 Terho Lehtimäki  55   56 Martin D Tobin  18   57 Louise V Wain  18   57 Juha Sinisalo  35 Annette Peters  29   30   33 Thomas Meitinger  58   59 Nicholas G Martin  60 Naomi R Wray  61 Grant W Montgomery  11   62 Sarah E Medland  11 Morris A Swertz  5   6 Erkki Vartiainen  7 Katja Borodulin  7 Satu Männistö  7 Anna Murray  4 Murielle Bochud  1 Sébastien Jacquemont  63   64 Fernando Rivadeneira  65   66 Thomas F Hansen  26   27 Albertine J Oldehinkel  67 Massimo Mangino  24   68 Michael A Province  23 Panos Deloukas  69   70 Jaspal S Kooner  22   50   71 Rachel M Freathy  4 Craig Pennell  20 Bjarke Feenstra  19 David P Strachan  72 Guillaume Lettre  73   74 Joel Hirschhorn  75   76   77 Daniele Cusi  17   78 Iris M Heid  16 Caroline Hayward  79 Katrin Männik  9   14 Jacques S Beckmann  2 Ruth J F Loos  13   80 Dale R Nyholt  11   81 Andres Metspalu  9 Johan G Eriksson  82   83 Michael N Weedon  4 Veikko Salomaa  7 Lude Franke  5 Alexandre Reymond  14 Timothy M Frayling  4 Zoltán Kutalik  84   85
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Free PMC article
Meta-Analysis

CNV-association Meta-Analysis in 191,161 European Adults Reveals New Loci Associated With Anthropometric Traits

Aurélien Macé et al. Nat Commun. .
Free PMC article

Abstract

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Genome-wide Manhattan plots for four anthropometric traits. Genome-wide association study for CNVs associated with BMI, height, weight, and waist-to-hip ratio in 191,161 Europeans
Fig. 2
Fig. 2
Regional association plot for the 16p11.2 220 kb rearrangement. The blue dots represent −log10 BMI-association P values, the red dots show the corresponding effect sizes. At the bottom the black and gray lines are the deletion and duplication frequencies. Finally, the dots at the bottom indicate the probe positions for the GIANT cohorts (above) and the UK Biobank (below). Positions of the protein-coding genes are shown at the top of the plot. The probes positions correspond to the human genome build 36
Fig. 3
Fig. 3
Regional association plot for the rearrangement near MC4R. The blue dots represent –log10 BMI-association P values, the red dots show the corresponding effect sizes. At the bottom the black and gray lines are the deletions and duplications frequencies. Finally, the dots at the bottom are the probes positions for the GIANT cohorts above and the UK BioBank below. Positions of the protein-coding genes are shown at the top of the plot along with the position of the BMI-associated GWAS SNP. The probes positions correspond to the human genome build 36

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References

    1. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav. Genet. 1997;27:325–351. doi: 10.1023/A:1025635913927. - DOI - PubMed
    1. Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery. Am. J. Hum. Genet. 2012;90:7–24. doi: 10.1016/j.ajhg.2011.11.029. - DOI - PMC - PubMed
    1. Zaitlen N, et al. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. PLoS Genet. 2013;9:e1003520. doi: 10.1371/journal.pgen.1003520. - DOI - PMC - PubMed
    1. Hjelmborg J, et al. Genetic influences on growth traits of BMI: a longitudinal study of adult twins. Obesity. 2008;16:847–852. doi: 10.1038/oby.2007.135. - DOI - PubMed
    1. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N. Engl. J. Med. 1990;322:1483–1487. doi: 10.1056/NEJM199005243222102. - DOI - PubMed

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