A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity
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 ,   Struan F A Grant for the Early Growth Genetics Consortium
Published: July 2019

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 &lt;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.