Abstract
BackgroundBirthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood. Birthweight and fetal growth show regional and population variations even under similar maternal conditions, and a large proportion of these differences are not explained by environmental factors. Whether and to what extent population genetic variations at key birthweight-associated loci account for the residual birthweight disparities not explained by environmental determinants is unknown. We hypothesized that the cumulative burden of genetic variants with a birthweight-lowering effect (GRB) is different among ancestrally diverse populations.MethodsGenotype data were extracted from phase 3 of the 1000 Genomes Project for 2504 participants from 26 global populations grouped into five super-populations. GRB was calculated in offspring as the weighted sum of the number of birthweight-lowering genetic variants of 59 autosomal single-nucleotide polymorphisms associated with birthweight, and comparisons were made between Europeans and non-Europeans.ResultsGRB was significantly higher in Africans (mean difference 3.15; 95% confidence interval 2.64, 3.66), admixed Americans (3.02; 2.34, 3.70), East Asians (2.85; 2.29, 3.41), and South Asians (1.07; 0.49, 1.65) compared to Europeans. Birthweight-lowering genetic variants in Africans and East Asians were enriched for rare and frequency-fixed alleles (P < 0.001). African and Asian populations had the greatest deviation from the expectation of the common disease-common variant hyothesis. Compared to Europeans, the GRB of ancestral alleles was significantly higher and that of derived alleles was significantly lower in non-Europeans (P < 0.001).ConclusionsThe burden of birthweight-lowering genetic variants is higher in Africans and East Asians. This finding is consistent with the high incidence of low birthweight in the two populations. The genetic variants we studied may not be causal and the extent to which they tag the causal variants in non-Europeans is unknown; however, our findings highlight that genetic variations contribute to population differences in birthweight.
Highlights
Birthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood
For birthweight-lowering alleles with ancestral state (n = 33 Singlenucleotide polymorphism (SNP)), genetic variants with a birthweightlowering effect (GRB) was significantly higher in Africans, admixed Americans (45.58 ± 4.01), East Asians (45.07 ± 3.06), and South Asians (43.86 ± 3. 37) compared to Europeans (41.84 ± 3.36) (p < 0.001)
For birthweight-lowering alleles with derived state (n = 26 SNPs), GRB was significantly lower in Africans, admixed Americans (18. 82 ± 3.16), and South Asians (18.59 ± 3.01) compared to Europeans (19.53 ± 3.18) (p < 0.001)
Summary
Birthweight is an important predictor of infant morbidity and mortality, and is associated with cardiovascular diseases, obesity, and diabetes in childhood and adulthood. Birthweight and fetal growth show regional and population variations even under similar maternal conditions, and a large proportion of these differences are not explained by environmental factors. Whether and to what extent population genetic variations at key birthweight-associated loci account for the residual birthweight disparities not explained by environmental determinants is unknown. The WHO study found that maternal and fetal characteristics only partially explained these differences [7], consistent with earlier observations in which established non-genetic determinants of birthweight, including socio-demographic and lifestyle-related factors, parental anthropometry, and gestational age, did not fully explain the observed birthweight differences among populations [13]. An important step is to investigate whether and to what extent population genetic differences at key birthweightassociated loci and their interactions with environmental factors account for the residual fetal growth disparities not explained by other determinants. The rs11765649 IGF2BP3 variant associated with lower birthweight is carried by most East Asians compared to three-fourths of Europeans (99% in Han Chinese in Beijing and 74% in Utah residents with Northern and Western European Ancestry from the 1000 Genomes Project, http://www.internationalgenome.org/)
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