A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.
Bradfield, Jonathan P. 1, 2, +; Vogelezang, Suzanne 3, 4, 5, +; Felix, Janine F. 3, 4, 5; Chesi, Alessandra 6, 7; Helgeland, Oyvind 8, 9; Horikoshi, Momoko 10, 11, 12; Karhunen, Ville 13; Lowry, Estelle 14; Cousminer, Diana L. 6, 7, 15; Ahluwalia, Tarunveer S. 16, 17, 18; Thiering, Elisabeth 19, 20; Boh, Eileen Tai-Hui 21; Zafarmand, Mohammad H. 22, 23; Vilor-Tejedor, Natalia 4, 25, 26, 27, 28; Wang, Carol A. 29; Joro, Raimo 30; Chen, Zhanghua 31; Gauderman, William J. 31; Pitkanen, Niina 32, 33; Parra, Esteban J. 34; Fernandez-Rhodes, Lindsay 35, 36; Alyass, Akram 37; Monnereau, Claire 3, 4, 5; Curtin, John A. 38; Have, Christian T. 18; McCormack, Shana E. 39, 40; Hollensted, Mette 18; Frithioff-Bojsoe, Christine 18, 41; Valladares-Salgado, Adan 42; Peralta-Romero, Jesus 42; Teo, Yik-Ying 21, 43, 44, 45, 46; Standl, Marie 19; Leinonen, Jaakko T. 47; Holm, Jens-Christian 18, 41, 48; Peters, Triinu 49; Vioque, Jesus 26, 50, 51; Vrijheid, Martine 24, 25, 26; Simpson, Angela 38; Custovic, Adnan 52; Vaudel, Marc 8; Canouil, Mickael 53; Lindi, Virpi 54; Atalay, Mustafa 30; Kahonen, Mika 55, 56; Raitakari, Olli T. 32, 33, 57; van Schaik, Barbera D. C. 23; Berkowitz, Robert I. 58; Cole, Shelley A. 59; Voruganti, Saroja V. 60; Wang, Yujie 61; Highland, Heather M. 61; Comuzzie, Anthony G. 62; Butte, Nancy F. 63; Justice, Anne E. 61, 64; Gahagan, Sheila 65; Blanco, Estela 65; Lehtimaki, Terho 66, 67; Lakka, Timo A. 30, 68, 69; Hebebrand, Johannes 49; Bonnefond, Amelie 53, 70; Grarup, Niels 18; Froguel, Philippe 53, 70; Lyytikainen, Leo-Pekka 66, 67, 71; Cruz, Miguel 42; Kobes, Sayuko 72; Hanson, Robert L. 72; Zemel, Babette S. 39, 73; Hinney, Anke 49; Teo, Koon K. 37, 74; Meyre, David 37, 75; North, Kari E. 61, 76; Gilliland, Frank D. 31; Bisgaard, Hans 16; Bustamante, Mariona 24, 25, 26; Bonnelykke, Klaus 16; Pennell, Craig E. 29; Rivadeneira, Fernando 3, 4, 77; Uitterlinden, Andre G. 4, 77; Baier, Leslie J. 72; Vrijkotte, Tanja G. M. 22; Heinrich, Joachim 19, 78, 79; Sorensen, Thorkild I. A. 18, 80, 81; Saw, Seang-Mei 21, 82; Pedersen, Oluf 18; Hansen, Torben 18; Eriksson, Johan 83, 84, 85; Widen, Elisabeth 47; McCarthy, Mark I. 10, 11, 86; Njolstad, Pal R. 8, 87; Power, Christine 88; Hypponen, Elina 88, 89, 90; Sebert, Sylvain 14, 91, 92; Brown, Christopher D. 93; Jarvelin, Marjo-Riitta 13, 14, 91, 94, 95; Timpson, Nicholas J. 81; Johansson, Stefan 8, 96, +; Hakonarson, Hakon 1, 97; Jaddoe, Vincent W. V. 3, 4, 5, ++; F.A. Struan Grant for the Early Growth Genetics Consortium
[Article]
Human Molecular Genetics.
28(19):3327-3338, October 1, 2019.
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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.
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