CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.
Macé A., Tuke MA., Deelen P., Kristiansson K., Mattsson H., Nõukas M., Sapkota Y., Schick U., Porcu E., Rüeger S., McDaid AF., Porteous D., Winkler TW., Salvi E., Shrine N., Liu X., Ang WQ., Zhang W., Feitosa MF., Venturini C., van der Most PJ., Rosengren A., Wood AR., Beaumont RN., Jones SE., Ruth KS., Yaghootkar H., Tyrrell J., Havulinna AS., Boers H., Mägi R., Kriebel J., Müller-Nurasyid M., Perola M., Nieminen M., Lokki M-L., Kähönen M., Viikari JS., Geller F., Lahti J., Palotie A., Koponen P., Lundqvist A., Rissanen H., Bottinger EP., Afaq S., Wojczynski MK., Lenzini P., Nolte IM., Sparsø T., Schupf N., Christensen K., Perls TT., Newman AB., Werge T., Snieder H., Spector TD., Chambers JC., Koskinen S., Melbye M., Raitakari OT., Lehtimäki T., Tobin MD., Wain LV., Sinisalo J., Peters A., Meitinger T., Martin NG., Wray NR., Montgomery GW., Medland SE., Swertz MA., Vartiainen E., Borodulin K., Männistö S., Murray A., Bochud M., Jacquemont S., Rivadeneira F., Hansen TF., Oldehinkel AJ., Mangino M., Province MA., Deloukas P., Kooner JS., Freathy RM., Pennell C., Feenstra B., Strachan DP., Lettre G., Hirschhorn J., Cusi D., Heid IM., Hayward C., Männik K., Beckmann JS., Loos RJF., Nyholt DR., Metspalu A., Eriksson JG., Weedon MN., Salomaa V., Franke L., Reymond A., Frayling TM., Kutalik Z.
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.