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Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

ABSTRACT: A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

SUBMITTER: Felix JF

PROVIDER: S-EPMC4854022 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

Felix Janine F JF Bradfield Jonathan P JP Monnereau Claire C van der Valk Ralf J P RJ Stergiakouli Evie E Chesi Alessandra A Gaillard Romy R Feenstra Bjarke B Thiering Elisabeth E Kreiner-Møller Eskil E Mahajan Anubha A Pitkänen Niina N Joro Raimo R Cavadino Alana A Huikari Ville V Franks Steve S Groen-Blokhuis Maria M MM Cousminer Diana L DL Marsh Julie A JA Lehtimäki Terho T Curtin John A JA Vioque Jesus J Ahluwalia Tarunveer S TS Myhre Ronny R Price Thomas S TS Vilor-Tejedor Natalia N Yengo Loïc L Grarup Niels N Ntalla Ioanna I Ang Wei W Atalay Mustafa M Bisgaard Hans H Blakemore Alexandra I AI Bonnefond Amelie A Carstensen Lisbeth L Eriksson Johan J Flexeder Claudia C Franke Lude L Geller Frank F Geserick Mandy M Hartikainen Anna-Liisa AL Haworth Claire M A CM Hirschhorn Joel N JN Hofman Albert A Holm Jens-Christian JC Horikoshi Momoko M Hottenga Jouke Jan JJ Huang Jinyan J Kadarmideen Haja N HN Kähönen Mika M Kiess Wieland W Lakka Hanna-Maaria HM Lakka Timo A TA Lewin Alexandra M AM Liang Liming L Lyytikäinen Leo-Pekka LP Ma Baoshan B Magnus Per P McCormack Shana E SE McMahon George G Mentch Frank D FD Middeldorp Christel M CM Murray Clare S CS Pahkala Katja K Pers Tune H TH Pfäffle Roland R Postma Dirkje S DS Power Christine C Simpson Angela A Sengpiel Verena V Tiesler Carla M T CM Torrent Maties M Uitterlinden André G AG van Meurs Joyce B JB Vinding Rebecca R Waage Johannes J Wardle Jane J Zeggini Eleftheria E Zemel Babette S BS Dedoussis George V GV Pedersen Oluf O Froguel Philippe P Sunyer Jordi J Plomin Robert R Jacobsson Bo B Hansen Torben T Gonzalez Juan R JR Custovic Adnan A Raitakari Olli T OT Pennell Craig E CE Widén Elisabeth E Boomsma Dorret I DI Koppelman Gerard H GH Sebert Sylvain S Järvelin Marjo-Riitta MR Hyppönen Elina E McCarthy Mark I MI Lindi Virpi V Harri Niinikoski N Körner Antje A Bønnelykke Klaus K Heinrich Joachim J Melbye Mads M Rivadeneira Fernando F Hakonarson Hakon H Ring Susan M SM Smith George Davey GD Sørensen Thorkild I A TI Timpson Nicholas J NJ Grant Struan F A SF Jaddoe Vincent W V VW

Human molecular genetics 20151124 2

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in ...[more]

PMID: 26604143

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Project description:OBJECTIVE:To identify common loci and potential genetic variants affecting body mass index (BMI, kg m(-2)) in study populations originating from Europe. DESIGN:We combined genome-wide linkage scans of six cohorts from Australia, Denmark, Finland, the Netherlands, Sweden and the United Kingdom with an approximately 10-cM microsatellite marker map. Variance components linkage analysis was carried out with age, sex and country of origin as covariates. SUBJECTS:The GenomEUtwin consortium consists of twin cohorts from eight countries (Australia, Denmark, the Netherlands, Finland, Italy, Norway, Sweden and the United Kingdom) with a total data collection of more than 500,000 monozygotic and dizygotic (DZ) twin pairs. Variance due to early-life events and the environment is reduced within twin pairs, which makes DZ pairs highly valuable for linkage studies of complex traits. This study totaled 4401 European-originated twin families (10,535 individuals) from six countries (Australia, Denmark, the Netherlands, Finland, Sweden and the United Kingdom). RESULTS:We found suggestive evidence for a quantitative trait locus on 3q29 and 7q36 in the combined sample of DZ twins (multipoint logarithm of odds score (MLOD) 2.6 and 2.4, respectively). Two individual cohorts showed strong evidence independently for three additional loci: 16q23 (MLOD=3.7) and 2p24 (MLOD=3.4) in the Dutch cohort and 20q13 (MLOD=3.2) in the Finnish cohort. CONCLUSION:Linkage analysis of the combined data in this large twin cohort study provided evidence for suggestive linkage to BMI. In addition, two cohorts independently provided significant evidence of linkage to three new loci. The results of our study suggest a smaller environmental variance between DZ twins than full siblings, with a corresponding increase in heritability for BMI as well as an increase in linkage signal in well-replicated regions. The results are consistent with the possibility of locus heterogeneity for some genomic regions, and indicate a lack of major common quantitative trait locus variants affecting BMI in European populations.

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Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

Publications

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

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