Admixture mapping and fine-mapping of birth weight loci in the Black Women’s Health Study

Abstract

Several genome-wide association studies (GWAS) have identified genetic variants associated with birth weight. To date, however, most GWAS of birth weight have focused primarily on European ancestry samples even though prevalence of low birth weight is higher among African-Americans. We conducted admixture mapping using 2918 ancestral informative markers in 2596 participants of the Black Women's Health Study, with the goal of identifying novel genomic regions where local African ancestry is associated with birth weight. In addition, we performed a replication analysis of 11 previously identified index single nucleotide polymorphisms (SNPs), and fine-mapped those genetic loci to identify better or new genetic variants associated with birth weight in African-Americans. We found that high African ancestry at 12q14 was associated with low birth weight, and we identified multiple independent birth weight-lowering variants in this genomic region. We replicated the association of a previous GWAS SNP in ADRB1 and our fine-mapping efforts suggested the presence of new birth weight-associated variants in ADRB1, HMGA2, and SLC2A4. Further studies are needed to determine whether birth weight-associated loci can in part explain race-associated birth weight disparities.

Genetic architecture of type 2 diabetes and its shared genetic component with low birth weight in African Americans

“…Results from the Black Women's Health Study show evidence of a shared genetic ancestry component between low birth weight and T2D [15,44]. Genome-wide admixture mapping of both traits found that excess local African ancestry in chromosome 12q14 was associated both with lower birth weight and higher T2D risk (Fig.…”

“…Excess local African ancestry in chromosome 12q14 is associated with T2D risk and low birth weight in African Americans. Admixture mapping results from the Black Women's Health Study (BWHS) [15,44] has shown a shared genetic ancestry component between low birth weight and T2D in the adult file. The BWHS found an inverse association between excess local African ancestry at 12q14 and birth weight (Z ¼ À4.7; P ¼ 2.4 Â 10 À6 ).…”

“…In admixture mapping a threshold of the statistic | Z | ≥ 4.0 is used to declare genome-wide significance. The negative Z -score for birth weight ( Z = −4.7; P = 2.4 × 10 −6 ) indicates an inverse association between local African ancestry and birth weight [44]. The positive Z -score for T2D ( Z = 4.1; P = 4.3 × 10 −5 ) indicates a direct association between local African ancestry and T2D risk [15].…”

The critical needs and challenges for genetic architecture studies in Africa

“…In smaller cohorts that are underpowered for discovering individual loci, gene-based associations can sometimes be useful in conjunction with functional follow up [64]. Studies of traits with elevated prevalence in African Americans, such as BMI, prostate cancer, and low birth weight [65-67] have analyzed genome-wide significant loci by local ancestry or more easily fine-mapped variants with narrower LD.…”