Investigating the genetic and genomic mechanisms of human lactation disorders

SUMMARY Human milk provides nutrients and important non-nutritive factors for infants that promote growth, development, and protection from infection1,2. Therefore, the World Health Organization (WHO) recommends exclusive breastfeeding for 6 months, then combining breastfeeding with solid foods for 18 months3. Lactation disorders reduce breastfeeding rates, and negatively impact both mothers and children. In mothers, lactation disorders influence mood and maternal well-being, while in children, they affect cognitive and socio-emotional development4, and can cause malnutrition, hypernatremia, hypoglycemia, and death5. Moreover, breastfeeding rates are lower in some ethnic minorities, which may partially reflect poor access to lactation consultants and early initiation of infant formula. Lactation disorders that specifically impair milk production and secretion affect about ~40% of breastfeeding mothers, the major phenotypes including: (i) agalactia: complete absence of milk secretion following birth; and (ii) hypogalactia: insufficient volume for optimal infant nutrition6,7. While post-partum stress, obesity, diabetes, and socioeconomic considerations have been associated with hypogalactia, we and others have demonstrated that hypogalactia has an inherited maternal genetic component6,8,9,10. However, the genetic mechanisms responsible for human lactation disorders are mostly unknown and have not yet been extensively investigated. We hypothesize that variations in genes involved in human milk production and secretion underlie disorders of milk production and secretion, and that these variants and genes can be discovered by interrogating genomic and extensive health and metadata from women with lactation disorders cases compared to unaffected female controls. We therefore propose to conduct a comprehensive study on whole exome sequencing (WES) data of lactation disorders patients. We are uniquely positioned to perform the first such study with the largest lactation disorders cohort to date (1,382 patients and over 60,000 female controls), combining four major biobanks: Vanderbilt University’s BioVU11,12, Mount Sinai Hospital’s BioMe Biobank13,14, All of Us and UK Biobank15,16. We propose a rigorous pipeline combining various state-of-the-art with cutting-edge approaches developed by us and others to: (1) obtain a high-quality WES lactation disorders cohort by variant- and sample-level quality control (QC)17,18, annotations19, and impact predictions20-22; (2) perform computational case-control analyses for high impact variants23,24; (3) prioritize variants and genes by biological relatedness approaches25-27 and use a novel quad-culture organotypic mammary gland model to characterize the molecular pathology of high impact variants; and (4) perform phenome-wide association studies (PheWAS)28 and polygenic risk score (PRS) analyses29. We expect that our findings of human lactation disorders genetics will be vital for understanding the physiology and pathophysiology of human milk systems, directly informing maternal, perinatal, neonatal health decisions, and ultimately guiding precision medicine approaches to improve women’s health. Project Number: 1R01HD119172-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Yuval Itan (+1 co-PI) | Institution: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY | Award Amount: $751,204 | Activity Code: R01 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366592