398V Poster Online - Virtual Posters
Tuesday June 07, 11:00 AM - 3:00 PM

Authors:
Kelsey Johnson ¹; Timothy Heisel ¹; Dan Knights ¹; Katherine Jacobs ¹; Michael Rudolph ²; David Fields ²; Cheryl Gale ¹; Frank Albert ¹; Ellen Demerath ¹; Ran Blekhman ¹

Affiliations:
1) University of Minnesota, Minneapolis, MN; 2) University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Keywords:
Complex traits

Breast milk provides complete nutrition and confers immune protection to the neonate, and plays a critical role in infant gut microbiome development. The dependence of human--and more broadly, mammal-- reproduction on milk across evolutionary history suggests strong selective pressure on milk production and composition. The role of maternal genetics in the production of human milk and in the expression of most milk components is almost entirely unknown. Understanding the genetic and genomic basis of variation in lactation is critical for identifying the mechanisms linking milk composition and production to infant and maternal health.

Here, we report the first expression quantitative trait locus (eQTL) analysis of human milk, using one-month postpartum milk samples from 171 exclusively breastfeeding women. RNA in milk is primarily derived from the milk-producing mammary gland cells. We identified cis-acting eQTLs for 2,686 genes, of which eQTLs at 668 genes were specific to milk (i.e. not observed in other tissues). Milk-specific eQTLs affected genes encoding major milk proteins (e.g. kappa-casein, CSN3) and ubiquitously expressed genes (e.g. the circadian gene CLOCK). Milk eQTLs present in other tissues were most often shared with other exocrine gland tissues, like the salivary gland. Colocalization analyses highlighted 7 milk eQTLs that may underlie risk loci for breast cancer. These included a milk eQTL affecting the transcription factor gene LMX1B at a breast cancer GWAS locus without a previous candidate gene.

To probe connections between the lactating mammary gland and infant health, we tested for associations between maternal genotype at milk eQTLs and the gut microbiome of exclusively breastfed infants. The strongest association was between the lead SNP of the LCT (lactase) eQTL in milk and Collinsella, a beneficial microbe in the infant gut. This eQTL is on the haplotype that confers lactase persistence in European adults. The lactase expression-increasing allele was correlated with decreased infant gut Collinsella at both 1 and 6 months postpartum. We propose that this relationship may be due to genetically-determined differences in milk composition.

Our results uncover new biology linking the lactating breast with maternal and infant health. An improved understanding of milk genetics will reveal new insights into the evolution of lactation and mammary biology.