Macé Aurélien, Tuke Marcus A, Deelen Patrick, Kristiansson Kati, Mattsson Hannele, Nõukas Margit, Sapkota Yadav, Schick Ursula, Porcu Eleonora, Rüeger Sina, McDaid Aaron F, Porteous David, Winkler Thomas W, Salvi Erika, Shrine Nick, Liu Xueping, Ang Wei Q, Zhang Weihua, Feitosa Mary F, Venturini Cristina, van der Most Peter J, Rosengren Anders, Wood Andrew R, Beaumont Robin N, Jones Samuel E, Ruth Katherine S, Yaghootkar Hanieh, Tyrrell Jessica, Havulinna Aki S, Boers Harmen, Mägi Reedik, Kriebel Jennifer, Müller-Nurasyid Martina, Perola Markus, Nieminen Markku, Lokki Marja-Liisa, Kähönen Mika, Viikari Jorma S, Geller Frank, Lahti Jari, Palotie Aarno, Koponen Päivikki, Lundqvist Annamari, Rissanen Harri, Bottinger Erwin P, Afaq Saima, Wojczynski Mary K, Lenzini Petra, Nolte Ilja M, Sparsø Thomas, Schupf Nicole, Christensen Kaare, Perls Thomas T, Newman Anne B, Werge Thomas, Snieder Harold, Spector Timothy D, Chambers John C, Koskinen Seppo, Melbye Mads, Raitakari Olli T, Lehtimäki Terho, Tobin Martin D, Wain Louise V, Sinisalo Juha, Peters Annette, Meitinger Thomas, Martin Nicholas G, Wray Naomi R, Montgomery Grant W, Medland Sarah E, Swertz Morris A, Vartiainen Erkki, Borodulin Katja, Männistö Satu, Murray Anna, Bochud Murielle, Jacquemont Sébastien, Rivadeneira Fernando, Hansen Thomas F, Oldehinkel Albertine J, Mangino Massimo, Province Michael A, Deloukas Panos, Kooner Jaspal S, Freathy Rachel M, Pennell Craig, Feenstra Bjarke, Strachan David P, Lettre Guillaume, Hirschhorn Joel, Cusi Daniele, Heid Iris M, Hayward Caroline, Männik Katrin, Beckmann Jacques S, Loos Ruth J F, Nyholt Dale R, Metspalu Andres, Eriksson Johan G, Weedon Michael N, Salomaa Veikko, Franke Lude, Reymond Alexandre, Frayling Timothy M, Kutalik Zoltán
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland.
Nat Commun. 2017 Sep 29;8(1):744. doi: 10.1038/s41467-017-00556-x.
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/m). 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/m for each Mb of total deletion burden (P = 2.5 × 10, 6.0 × 10, and 2.9 × 10). 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.
罕见拷贝数变异（CNV）与复杂的人类连续性状之间存在强关联的例子很少。在此，我们对来自26个队列的多达191,161名成年样本的人体测量性状进行了大规模CNV关联荟萃分析。该研究揭示了在1q21.1、3q29、7q11.23、11p14.2和18q21.32处的5个CNV关联，并证实了在16p11.2和22q11.21处的2个已知基因座，涉及至少一种人体测量性状。发现的CNV是反复出现且罕见的（0.01 - 0.2%），对身高（>2.4厘米）、体重（>5千克）和体重指数（BMI）（>3.5千克/米²）有较大影响。负担分析表明，每兆碱基的总缺失负担会使身高降低0.41厘米，腰臀比增加0.003，BMI增加0.14千克/米²（P = 2.5×10⁻⁶、6.0×10⁻⁶和2.9×10⁻⁵）。我们的研究提供了证据，表明相同的基因（如MC4R、FIBIN和FMO5）既包含影响体型的常见变异，也包含罕见变异，并且人体测量性状与发育和精神疾病共享基因座。单个单核苷酸多态性（SNP）对人体测量性状的影响较小，而CNV的影响在很大程度上仍不为人所知。在此，库塔利克及其同事对结构变异进行了大规模全基因组荟萃分析，发现了与身高、体重和BMI相关的罕见CNV，其效应大小较大。
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