Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

Mariaelisa Graff, Julius S. Ngwa, Tsegaselassie Workalemahu, Georg Homuth, Sabine Schipf, Alexander Teumer, Henry Völzke, Henri Wallaschofski, Goncalo R. Abecasis, Lakatta Edward, Cucca Francesco, Serena Sanna, Paul Scheet, David Schlessinger, Carlo Sidore, Xiangjun Xiao, Zhaoming Wang, Stephen J. Chanock, Kevin B. Jacobs, Richard B. HayesFrank Hu, Rob M. Van Dam, Richard J. Crout, Mary L. Marazita, John R. Shaffer, Larry D. Atwood, Caroline S. Fox, Nancy L. Heard-Costa, Charles White, Audrey C. Choh, Stefan A. Czerwinski, Ellen W. Demerath, Thomas D. Dyer, Bradford Towne, Najaf Amin, Ben A. Oostra, Cornelia M. Van Duijn, M. Carola Zillikens, Tönu Esko, Mari Nelis, Tit Nikopensius, Andres Metspalu, David P. Strachan, Keri Monda, Lu Qi, Kari E. North, L. Adrienne Cupples, Penny Gordon-Larsen, Sonja I. Berndt

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Genetic loci forbodymassindex (BMI) in adolescenceandyoungadulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10-8) near FTO (P = 3.72 × 10-23), TMEM18 (P = 3.24 × 10-17), MC4R (P = 4.41 × 10-11), TNNI3K (P = 4.32 × 10-9), SEC16B (P = 6.24 × 10-8), GNPDA2 (P = 1.11 × 10-8) and POMC (P = 4.94 × 1028) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10-5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.

Original languageEnglish (US)
Pages (from-to)3597-3607
Number of pages11
JournalHuman molecular genetics
Volume22
Issue number17
DOIs
StatePublished - Sep 2013

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health (R01HD057194).

Funding Information:
Framingham Heart Study (FramHS). This research was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (contract no: N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Analyses of the Framingham data were supported by subcontract to Boston University under NIH (R01HD057194).

Funding Information:
Fels Longitudinal Study (Fels). This work was supported by the National Institutes of Health (R01-HD012252, R01-HD053685, R01-DK064391, R01-AR052147).

Funding Information:
Dental Caries: Whole Genome Association and Gene x Environment Studies (GENEVA Dental Caries). Funding support for the GWAS project was provided by the National Institutes of Dental and Craniofacial Research (U01-DE018903). Data and samples were provided by the Center for Oral Health Research in Appalachia, a collaboration of the University of Pittsburgh and West Virginia University funded by NIDCR (R01-DE 014899); genotyping was done by the Johns Hopkins University Center for Inherited Disease Research (CIDR) which is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University (contract no: HHSN268200782096C). Funds for this project’s genotyping were provided by the NIDCR through CIDR’s NIH contract. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (www.genevastudy.org; U01-HG004446).

Funding Information:
Community Medicine Research net of the University of Greifs-wald, Germany, which is funded by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania.

Funding Information:
Estonian Genome Center, University of Tartu (EGCUT). EGCUT received financing by (ENGAGE, OPENGENE), targeted financing from Estonian Government (funding no: SF0180142s08), Estonian Research Roadmap through Estonian Ministry of Education and Research (3.2.0304.11-0312), Center of Excellence in Genomics (EXCEGEN) and Development Fund of University of Tartu (funding no: SP1GVARENG).

Funding Information:
Erasmus Rucphen Family (EUROSPAN) (ERF). The genotyp-ing for the ERF study was supported by EUROSPAN (European Special Populations Research Network) and the European Commission FP6 STRP (018947; LSHG-CT-2006-01947). The ERF study was further supported by grants from the Netherlands Organization for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology (CMSB) and the Netherlands Brain Foundation (HersenStichting Nederland).

Funding Information:
Study of Health in Sardinia, Italy (SardNIA). This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA) and National Institutes of Health (NIH) (NO1-AG-1-2109).

Funding Information:
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO/PLCO2). The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH.

Funding Information:
The Nurses’ Health Study/Health Professionals Follow up Study (NHS/HPFS). This study was supported by National Institutes of Health grants [HL71981 and DK46200 (Boston Obesity Nutrition Research Center)] and by an American Heart Association Scientist Development Award (0730094N).

Funding Information:
Atherosclerosis Risk in Communities (ARIC). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694); National Human Genome Research Institute (U01HG004402); and National Institutes of Health (HHSN268200625226C). Infrastructure was partly supported by a component of the National Institutes of Health and NIH Roadmap for Medical Research (UL1RR025005). The project described was supported by the National Center for Research Resources (NCRR) (UL1 RR 025005).

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