High burden of birthweight-lowering genetic variants in Africans and Asians

Abstract

Background: 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. We hypothesized that the cumulative burden of genetic variants with a birthweight-lowering effect (GRB) is different among ancestrally diverse populations. Methods: Genotype 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. Results: GRB 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). Conclusions: The 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.