A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity. (7th June 2019)

• Record Type: Journal Article
• Authors: Bradfield, Jonathan P; Vogelezang, Suzanne; Felix, Janine F; Chesi, Alessandra; Helgeland, Øyvind; Horikoshi, Momoko; Karhunen, Ville; Lowry, Estelle; Cousminer, Diana L; Ahluwalia, Tarunveer S; Thiering, Elisabeth; Boh, Eileen Tai-Hui; Zafarmand, Mohammad H; Vilor-Tejedor, Natalia; Wang, Carol A; Joro, Raimo; Chen, Zhanghua; Gauderman, William J; Pitkänen, Niina; Parra, Esteban J; Fernandez-Rhodes, Lindsay; Alyass, Akram; Monnereau, Claire; Curtin, John A; Have, Christian T; McCormack, Shana E; Hollensted, Mette; Frithioff-Bøjsøe, Christine; Valladares-Salgado, Adan; Peralta-Romero, Jesus; Teo, Yik-Ying; Standl, Marie; Leinonen, Jaakko T; Holm, Jens-Christian; Peters, Triinu; Vioque, Jesus; Vrijheid, Martine; Simpson, Angela; Custovic, Adnan; Vaudel, Marc; Canouil, Mickaël; Lindi, Virpi; Atalay, Mustafa; Kähönen, Mika; Raitakari, Olli T; van Schaik, Barbera D C; Berkowitz, Robert I; Cole, Shelley A; Voruganti, V Saroja; Wang, Yujie; Highland, Heather M; Comuzzie, Anthony G; Butte, Nancy F; Justice, Anne E; Gahagan, Sheila; Blanco, Estela; Lehtimäki, Terho; Lakka, Timo A; Hebebrand, Johannes; Bonnefond, Amélie; Grarup, Niels; Froguel, Philippe; Lyytikäinen, Leo-Pekka; Cruz, Miguel; Kobes, Sayuko; Hanson, Robert L; Zemel, Babette S; Hinney, Anke; Teo, Koon K; Meyre, David; North, Kari E; Gilliland, Frank D; Bisgaard, Hans; Bustamante, Mariona; Bonnelykke, Klaus; Pennell, Craig E; Rivadeneira, Fernando; Uitterlinden, André G; Baier, Leslie J; Vrijkotte, Tanja G M; Heinrich, Joachim; Sørensen, Thorkild I A; Saw, Seang-Mei; Pedersen, Oluf; Hansen, Torben; Eriksson, Johan; Widén, Elisabeth; McCarthy, Mark I; Njølstad, Pål R; Power, Christine; Hyppönen, Elina; Sebert, Sylvain; Brown, Christopher D; Järvelin, Marjo-Riitta; Timpson, Nicholas J; Johansson, Stefan; Hakonarson, Hakon; Jaddoe, Vincent W V;
• Is Part Of: Human molecular genetics. Volume 28:Number 19(2019)
• Page Start: 3327
• Page End: 3338
• Publication Date: 2019-06-07
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddz161
• Languages: English
• ISSNs: 0964-6906

Abstract

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.