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, Struan F A Grant

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Although hundreds of GWAS-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 thirty studies consisting of up to 13,005 cases (≥95th percentile of 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 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen 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 in 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 ten 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
JournalHuman Molecular Genetics
Early online date5 Jul 2019
Publication statusPublished - 2019


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