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CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

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.

SUBMITTER: Mace A

PROVIDER: S-EPMC5622064 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

Macé Aurélien A Tuke Marcus A MA Deelen Patrick P Kristiansson Kati K Mattsson Hannele H Nõukas Margit M Sapkota Yadav Y Schick Ursula U Porcu Eleonora E Rüeger Sina S McDaid Aaron F AF Porteous David D Winkler Thomas W TW Salvi Erika E Shrine Nick N Liu Xueping X Ang Wei Q WQ Zhang Weihua W Feitosa Mary F MF Venturini Cristina C van der Most Peter J PJ Rosengren Anders A Wood Andrew R AR Beaumont Robin N RN Jones Samuel E SE Ruth Katherine S KS Yaghootkar Hanieh H Tyrrell Jessica J Havulinna Aki S AS Boers Harmen H Mägi Reedik R Kriebel Jennifer J Müller-Nurasyid Martina M Perola Markus M Nieminen Markku M Lokki Marja-Liisa ML Kähönen Mika M Viikari Jorma S JS Geller Frank F Lahti Jari J Palotie Aarno A Koponen Päivikki P Lundqvist Annamari A Rissanen Harri H Bottinger Erwin P EP Afaq Saima S Wojczynski Mary K MK Lenzini Petra P Nolte Ilja M IM Sparsø Thomas T Schupf Nicole N Christensen Kaare K Perls Thomas T TT Newman Anne B AB Werge Thomas T Snieder Harold H Spector Timothy D TD Chambers John C JC Koskinen Seppo S Melbye Mads M Raitakari Olli T OT Lehtimäki Terho T Tobin Martin D MD Wain Louise V LV Sinisalo Juha J Peters Annette A Meitinger Thomas T Martin Nicholas G NG Wray Naomi R NR Montgomery Grant W GW Medland Sarah E SE Swertz Morris A MA Vartiainen Erkki E Borodulin Katja K Männistö Satu S Murray Anna A Bochud Murielle M Jacquemont Sébastien S Rivadeneira Fernando F Hansen Thomas F TF Oldehinkel Albertine J AJ Mangino Massimo M Province Michael A MA Deloukas Panos P Kooner Jaspal S JS Freathy Rachel M RM Pennell Craig C Feenstra Bjarke B Strachan David P DP Lettre Guillaume G Hirschhorn Joel J Cusi Daniele D Heid Iris M IM Hayward Caroline C Männik Katrin K Beckmann Jacques S JS Loos Ruth J F RJF Nyholt Dale R DR Metspalu Andres A Eriksson Johan G JG Weedon Michael N MN Salomaa Veikko V Franke Lude L Reymond Alexandre A Frayling Timothy M TM Kutalik Zoltán Z

Nature communications 20170929 1

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%), ...[more]

PMID: 28963451

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Project description:Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10-6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10-8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.

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CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

Publications

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

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