fat at birth is unique to humans among primates , suggesting that a recently evolved genetic component accounts for this difference .
body fat accumulated during intrauterine development in humans is thought to serve as an energy source to support growth of the large human newborn brain in the early neonatal period . as such , subcutaneous
however , high or low body fat at birth is associated with increased morbidity in the first year of life as well as an increased susceptibility to poor metabolic and/or cardiovascular health later in life .
while maternal fuels such as glucose and triglycerides impact fetal fat accretion , genetic factors also contribute . a locus between ccnl1 and lekri on chromosome 3 ( 3q25.31 )
was previously shown to be associated with birthweight , but our recent genome - wide association study ( gwas ) performed in a multi - ancestry cohort of newborns revealed this locus was much more strongly associated with newborn sum of skinfolds ( p=1.52  10 ) , a measure of newborn adiposity , than with birthweight ( p=5.72  10 ) .
the goal of the present study was to determine whether this same locus is associated with adiposity at later points during childhood .
the hyperglycemia and adverse pregnancy outcome ( hapo ) study was an international multi - center epidemiologic study that examined levels of maternal glucose tolerance and risk of adverse pregnancy outcomes .
briefly , eligible women underwent a 75  g oral glucose tolerance test between 24 and 32 weeks gestation . using standardized methods and procedures , maternal height , weight , and blood pressure
cord blood was collected for measurement of newborn glucose , c - peptide and dna extraction . using standardized methods and equipment ,
neonatal anthropometric measurements were obtained within 72  h of birth , including head circumference , birth length , birthweight and skinfold thickness measured at the flank , triceps and subscapular regions .
hapo participants and their offspring from the belfast , northern ireland center were invited to participate in the hapo family study in which offspring were examined at the ages of 2 and 6 years .
measurements included weight , height , head circumference , mid - arm circumference , and triceps , subscapular , and suprailiac skinfold thickness . for genetic analyses , individual skinfold measurements and their sum
examining newborn size , hapo newborns from four ancestries were genotyped using illumina genomewide single nucleotide polymorphism ( snp ) arrays ( illumina , inc . , san diego , ca , usa ) .
details of genotyping platform selection , genotype calling algorithms , quality control and imputation procedures , and estimating population substructure were previously reported .
we examined the association of four snps at this locus with sum of skinfolds , a measure of adiposity , among belfast hapo offspring at 2 and 6 years of age using linear regression analyses ( snptestv2 ) with an additive model , adjusting for ancestry ( principal components 1 and 2 ) , newborn gender , gestational age at delivery , parity , and maternal age , body mass index ( bmi ) , height , mean arterial blood pressure , smoking status and alcohol intake at the time of oral glucose tolerance test .
all other analyses were conducted in sas 9.3 ( sas institute , cary , nc , usa ) .
genotype and phenotype data were available at birth and age 2 for 293 children and at birth and age 6 for 350 children ( table 1 ) ; 270 children were common between the two cohorts .
four snps at the chromosome 3q25.31 locus that are in strong linkage disequilibrium ( lowest pairwise r=0.93 ) , rs10049088 , rs1482853 , rs17451107 and rs900400 , were previously shown to be the snps most highly associated with sum of skinfolds in a cohort of hapo newborns .
the association and direction of effect between one of these snps , rs900400 , and sum of skinfolds as well as individual skinfold thicknesses in the cohorts of 2- and 6-year - olds from the belfast hapo family study are shown in table 2 .
a positive association was observed between rs900400 and newborn sum of skinfolds among the 293 children in the cohort of 2-year olds ( p=4.8  10 ; =0.025 ) , and 350 children in the cohort of 6-year olds ( p=2.8  10 ; =0.024 ) .
in contrast , at age 2 years and 6 years no association was observed between sum of skinfolds and rs900400 ( p=0.06 , =0.015 at age 2 ; p=0.86 ,  = 0.002 at age 6 ) .
although rs900400 demonstrated a marginal , albeit non - significant , association with sum of skinfolds at age 2 years , the direction of effect was opposite to that observed in the newborns .
similar analyses were performed examining the association of rs900400 with measurements of the flank / suprailiac , triceps and subscapular skinfolds ( table 2 ) .
a positive association was observed between rs900400 and individual skinfold measurements at birth among the 293 children in the cohort of 2-year olds ( triceps , p=3.4  10 ; subscapular , p=2.0  10 ; flank , p=5.0  10 ) , and 350 children in the cohort of 6-year olds ( triceps , p=1.8  10 ; subscapular , p=5.0  10 ; flank , p=1.0  10 ) . for the suprailiac and subscapular skinfold thicknesses , an association with rs900400
was not seen at either age 2 ( p=0.14 and p=0.52 , respectively ) or age 6 ( p=0.70 and p=0.98 , respectively ) .
however , in the cohort of 2-year olds , rs900400 was weakly associated with triceps skinfold thickness at age 2 ( p=0.03 ) .
. there was no evidence for association of rs900400 with triceps skinfold thickness at age 6 ( p=0.97 ) .
excess adiposity at birth , which is recognized as a risk factor for peri- and postnatal complications as well as childhood obesity and adverse metabolic health outcomes during adulthood , is influenced by both environmental and genetic factors .
multiple maternal factors influence the intrauterine environment , including maternal bmi , height , blood pressure , nutrition , alcohol consumption , smoking and socioeconomic background , with maternal metabolic factors also having an important impact on fetal adiposity .
in addition to maternal metabolism , fetal genetics also plays an important role in fetal fat accretion . we and others have previously used gwas to identify genes associated with birthweight and/or newborn sum of skinfolds . a highly significant and reproducible finding was the association of snps within the chromosome 3q25.31 locus with newborn adiposity as reflected by newborn sum of skinfolds or ponderal index . in this report
, we now demonstrate that association of this locus with measures of adiposity is no longer evident at ages 2 and 6 years , consistent with the recent observation that this locus is no longer associated with birthweight by age 2 months .
association of this locus with sum of skinfolds , driven primarily by skinfold thickness at the triceps , approached significance in the cohort of 2-year olds , but this association was in the opposite direction to that observed in newborns . in the cohort of 6-year olds , there was no evidence of association of rs900400 with any of the individual skinfolds . together with the results of previous studies , these new findings suggest that genetic variation within the 3q25.31 locus contributes to fetal fat accretion but not to early childhood adiposity . as in newborns ,
both low and normal birthweight newborns with rapid postnatal weight gain during the first 2 years of life have higher body fat and lower lean body mass and , during adulthood , higher body weight and fat .
prevention of rapid postnatal growth in such individuals may prevent development of an obese adult phenotype .
genetic variation is another important determinant of childhood adiposity . through gwas and related approaches , association of variants within 22 different genetic loci with childhood bmi or
body weight has been demonstrated , but snps in the chromosome 3q25.31 locus have not been reported .
consistent with that , meta - analyses performed by the early growth genetics ( egg ) consortium ( www.egg-consortium.org ) in european ancestry children failed to demonstrate association of rs900400 with childhood obesity ( defined as bmi  95 percentile ; p=0.90 ) .
similarly , a previous analysis of data from the giant consortium showed no evidence of association of the 3q25.31 locus with adult bmi . despite the presence of high - quality genotype and phenotype data , our study had certain limitations .
we have examined a small cohort of offspring from only one hapo ancestry and , as a result , our power to demonstrate an association at age 2 and 6 years was limited .
thus , we can not rule out an association of snps at the chromosome 3q25.31 locus with early childhood adiposity ; however , if this locus is associated with childhood adiposity , the association is much weaker than that observed during fetal life and does not alter our conclusion that the chromosome 3 locus primarily influences fetal fat accretion .
similarly , we were not able to assess directly whether this locus is associated with measures of obesity in older children and adolescents , but previous studies of the genetics of childhood obesity have failed to demonstrate an association . in summary , we have demonstrated that snps within the chromosome 3q25.31 locus , which exhibit strong association across multiple ancestry groups with measures of newborn adiposity , do not have a clear association with early childhood adiposity among european ancestry hapo offspring .
 increased newborn adiposity is associated with later adverse metabolic outcomes . 
 previous genome - wide association studies ( gwas ) demonstrated strong association of a locus on chromosome 3 ( 3q25.31 ) with newborn sum of skinfolds , a measure of overall adiposity . whether this locus is associated with childhood adiposity 
 is unknown . 
 genotype and sum of skinfolds data were available for 293 children at birth and age 2 , and for 350 children at birth and age 6 from a european cohort ( belfast , uk ) who participated in the hyperglycemia and adverse pregnancy outcome gwas . 
 we examined single nucleotide polymorphisms ( snps ) at the 3q25.31 locus associated with newborn adiposity . 
 linear regression analyses under an additive genetic model adjusting for maternal body mass index were performed . in both cohorts , a positive association was observed between all snps and sum of skinfolds at birth ( p=2.3  104 , =0.026 and p=4.8  104 , =0.025 ) . at the age of 2 years , a non - significant negative association was observed with sum of skinfolds ( p=0.06 ;  = 0.015 ) . at the age of 6 years 
 , there was no evidence of association ( p=0.86 ; =0.002 ) . 
 the 3q25.31 locus strongly associated with newborn adiposity had no significant association with childhood adiposity suggesting that its impact may largely be limited to fetal fat accretion . 
Introduction
Materials and Methods
Results
Discussion