A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity

Jonathan P. Bradfield, Suzanne Vogelezang, Janine F. Felix, Alessandra Chesi, Øyvind Helgeland, Momoko Horikoshi, Ville Karhunen, Estelle Lowry, Diana L. Cousminer, Tarunveer S. Ahluwalia, Elisabeth Thiering, Eileen Tai Hui Boh, Mohammad H. Zafarmand, Natalia Vilor-Tejedor, Carol A. Wang, Raimo Joro, Zhanghua Chen, William J. Gauderman, Niina Pitkänen, Esteban J. ParraLindsay Fernandez-Rhodes, Akram Alyass, Claire Monnereau, John A. Curtin, Christian T. Have, Shana E. McCormack, Mette Hollensted, Christine Frithioff-Bøjsøe, Adan Valladares-Salgado, Jesus Peralta-Romero, Yik Ying Teo, Marie Standl, Jaakko T. Leinonen, Jens Christian Holm, Triinu Peters, Jesus Vioque, Martine Vrijheid, Angela Simpson, Adnan Custovic, Marc Vaudel, Mickaël Canouil, Virpi Lindi, Mustafa Atalay, Mika Kähönen, Olli T. Raitakari, Barbera D.C. Van Schaik, Robert I. Berkowitz, Shelley A. Cole, V. Saroja Voruganti, Yujie Wang, Heather M. Highland, Anthony G. Comuzzie, Nancy F. Butte, Anne E. Justice, Sheila Gahagan, Estela Blanco, Terho Lehtimäki, Timo A. Lakka, Johannes Hebebrand, Amélie Bonnefond, Niels Grarup, Philippe Froguel, Leo Pekka Lyytikäinen, Miguel Cruz, Sayuko Kobes, Robert L. Hanson, Babette S. Zemel, Anke Hinney, Koon K. Teo, David Meyre, Kari E. North, Frank D. Gilliland, Hans Bisgaard, Mariona Bustamante, Klaus Bonnelykke, Craig E. Pennell, Fernando Rivadeneira, André G. Uitterlinden, Leslie J. Baier, Tanja G.M. Vrijkotte, Joachim Heinrich, Thorkild I.A. Sørensen, Seang Mei Saw, Oluf Pedersen, Torben Hansen, Johan Eriksson, Elisabeth Widén, Mark I. McCarthy, Pål R. Njølstad, Christine Power, Elina Hyppönen, Sylvain Sebert, Christopher D. Brown, Marjo Riitta Järvelin, Nicholas J. Timpson, Stefan Johansson, Hakon Hakonarson, Vincent W.V. Jaddoe, F. A. Struan

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Abstract

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

Original languageEnglish (US)
Pages (from-to)3327-3338
Number of pages12
JournalHuman molecular genetics
Volume28
Issue number19
DOIs
StatePublished - Oct 1 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Bradfield, J. P., Vogelezang, S., Felix, J. F., Chesi, A., Helgeland, Ø., Horikoshi, M., Karhunen, V., Lowry, E., Cousminer, D. L., Ahluwalia, T. S., Thiering, E., Boh, E. T. H., Zafarmand, M. H., Vilor-Tejedor, N., Wang, C. A., Joro, R., Chen, Z., Gauderman, W. J., Pitkänen, N., ... Struan, F. A. (2019). A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity. Human molecular genetics, 28(19), 3327-3338. https://doi.org/10.1093/hmg/ddz161