(P41-01-26) Genetic Risk for Human Milk Volume and B-Vitamin Concentrations in the MILQ Study

Objectives: To investigate genetic associations with human milk B-vitamins and milk volume.

Methods: Genetic data from 956 well-nourished women from 4 countries in the Mothers, Infants and Lactation Quality (MILQ) study were combined with phenotypic data collected at 2-3 months post-partum; the final sample sizes were n=758 for B-vitamins and n=642 for milk volume. Genome-wide association studies for each outcome were conducted with PLINK v2.0 and adjusted for maternal age, parity, BMI, infant age, milk fat, and 20 principal components. Threshold analyses and mediation analyses were used to elaborate and interpret GWAS results.

Results: GWAS identified 16 lead SNPs (p < 5×10⁻⁸), revealing novel associations for vitamins B1, B2, B5, and B12. For each of these SNPs, alternate allele carriers consistently had milk vitamin concentrations below the MILQ 50th percentile. For example, carrying the alternate allele at rs7066698 strongly associated with lower vitamin B2: 81.0% of carriers fell below the reference value compared to only 45.1% of non-carriers. GWAS of milk volume identified 14 lead candidate SNPs (p < 1×10⁻⁵), and cumulative genetic risk scores were associated with milk volume (p= 9.0×10^⁻48). Women in the highest vs lowest genetic risk quartile (Q4 vs Q1) had ~239 mL/d less milk (p= 3.7×10⁻²⁶), lower milk B6 concentrations (mean difference: -13.7μg/L, p= 7.9×10⁻⁴) and lower infant weight (mean difference: -401.7g, p= 6.7×10⁻⁵). Infant weight partially mediated the relationship between maternal genotype and milk volume for 8 of 14 SNPs (proportion mediated range: 17.8-27.1%, p < 0.05); however, the direct genetic effect remained predominant across all SNPs suggesting these maternal genotypes influence milk volume primarily through pathways independent of infant size.

Conclusions: Novel genetic variants strongly associated with milk B-vitamin concentrations and cumulative genetic risk predicted substantial differences in milk volume, primarily through direct maternal pathways rather than infant-mediated mechanisms. These findings advance understanding of the genetic architecture of human lactation and may inform personalized approaches to identifying women at risk for inadequate milk nutrients or low milk volume.

Funding Sources: Gates Foundation grants OPP1148405 and INV-002300 and USDA-Agricultural Research Service #2032-51530-026-00D.