Replication and Fine Mapping of Birth Weight Loci in the Black Women's Health Study
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BACKGROUND: African Americans are at highest risk for low birth weight (LBW) and genes are hypothesized to play a role, however to date most genetic association studies of birth weight have focused on individuals of European ancestry. DESIGN: Using data from the Black Women’s Health Study we conducted a genetic replication study of the associations between ten previously GWAS-identified index single nucleotide polymorphisms (SNPs) for LBW in 2596 BWHS participants free of type 2 diabetes. We further conducted fine mapping in ten regions around these SNPs in attempt to further refine the location of purported LBW associated SNPs and to find potential independent SNPs in African Americans. For the fine mapping analysis, additive regression models were run for imputed SNPs +/- 100 kb of each of the ten index SNPs. The additive genetic models for both the replication and fine mapping analyses were adjusted for age, European ancestry, genotype batch, and geographic region. We used the simpleM method for multiple testing adjustment. RESULTS Associations with standardized birthweight were replicated for two of the previously identified loci, ADRB1 (rs1801253; β=0.06, p=0.03) and rs1042725 in HMGA2 (rs1042725; β=0.05, p=0.06), with the latter SNP being marginally significant. Effect sizes for each birth-weight altering allele were between 35-40g. In the fine mapping study, we identified three significant variants associated with LBW when adjusted for multiple testing in three gene regions: ADRB1, HMGA2, and SLC2A4. CONCLUSIONS: Two of the ten candidate regions with birth weight-altering variants showing strong associations with birth weight in European birth cohorts appear to have a fairly large effect in African Americans. Our most significant findings include the ADRB1 region, which has previously been associated with lower blood pressure, and HMGA2, which has been previously shown to be strongly associated with birth head circumference and lower adult height. Further studies are needed to determine whether LBW-associated loci can in part explain race-associated birthweight disparities.