Admixture mapping identifies African and Amerindigenous local ancestry loci associated with fetal growth

Abstract

Fetal growth is an important determinant of cardiometabolic disease risk during childhood and adulthood. The genetic architecture of fetal growth remains largely understudied in ancestrally diverse populations. We conducted genome-wide admixture mapping scan and analysis of genetic ancestry among Hispanic American, African American, European American, and Asian American pregnant women to identify genetic loci associated with fetal growth measures across 13-40 weeks gestation. Fetal growth measures were associated with genome-wide average African, European, Amerindigenous and East Asian ancestry proportions (P ranged from10^-3 to 4.8 × 10^-2). Admixture mapping analysis identified ten African ancestry loci and three Amerindigenous ancestry loci significantly associated with fetal growth measures at Bonferroni-corrected levels of significance (P ranged from 2.18 × 10^-8 to 3.71 × 10^-6). At the chr2q23.3-24.2 locus in which higher African ancestry was associated with long bone (femur and humerus) lengths, the T allele of rs13030825 (GALNT13) was associated with longer humerus length in African Americans (β = 0.44, P = 6.25 × 10^-6 at week 27; β = 0.39, P = 7.72 × 10^-5 at week 40). The rs13030825 SNP accounted for most of the admixture association at the chr2q23.3-24.2 locus and has substantial allele frequency difference between African and European reference samples (F_ST = 0.55, P = 0.03). Regulatory annotation shows that rs13030825 overlaps with the serum response factor (SRF) transcription factor previously implicated in postnatal bone development of mice. Overall, we identified ancestry-related maternal genetic loci that influence fetal growth, shedding light on molecular pathways that regulate fetal growth and potential effects on health across the lifespan.Clinical trials registration ClinicalTrials.gov, NCT00912132.

Fig 1

Change in fetal weight at 13–40 weeks’ gestation per each percent increase in African, European, Amerindigenous, and East Asian ancestry Black horizontal line along the 0-mark on the vertical axis represents the null. Color shaded areas represent the lower and upper bounds of 95% Confidence Intervals. All models were adjusted for maternal age, education, insurance, employment, height, pre-pregnancy weight, parity, and marital status.

Fig 2

Regional plot of variants in the ch2q23.3-q24.4 African ancestry locus associated with longer bone lengths Data span 500 kb centered at the top associated SNP (rs13030825). The x-axis denotes genomic position (hg19) and the y axis denotes the log10 P-value, and recombination rate (cM/Mb). The purple circle point represents the index SNP. The color of each data point indicates its linkage disequilibrium value (r²) with the index SNP based on HapMap2’s African reference genome.