GWAS integrating maternal and child genetics reveals novel risk-modifying loci for fetal alcohol spectrum disorders (FASD)
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Fetal alcohol spectrum disorders (FASD) exhibit wide phenotypic variability not explained by prenatal alcohol exposure (PAE) alone. While genetic factors may modify vulnerability, there are no prior FASD genome-wide association studies (GWAS). We performed genome-wide single-marker and gene-based analyses of two South African prospective birth cohorts (Cape Town Longitudinal Cohorts (CTLC); n=328 mother-child dyads) and the US Collaborative Initiative on Fetal Alcohol Spectrum Disorders cohort (CIFASD n=429 children only). We examined main genetic and gene-by-PAE interaction effects on working memory, recognition memory, height, and FASD diagnosis using single-marker and gene-based analyses and the Haplotype-based Transmission Disequilibrium Test (HTDT), which integrates maternal-child genetics. Genome-wide genotype array data were used; TOPMed-imputed data were used to refine results. Risk-modifying genes were then tested for differential mRNA expression based on PAE in placenta and child blood. Gene*PAE interaction gene-based analyses identified STX6 associated with height-for-age Z-scores (p=2.2×10⁻⁶) and FOXD3 with recognition memory performance (p=4.7×10⁻⁶) in children. Single-marker analysis detected one child SNP approaching significance (rs2833924, p=8.8x10-8) with Gene*PAE interaction for working memory performance. CTLC+CIFASD meta-analysis in children identified one significant locus (HTR1E; pmeta=2.75×10⁻⁶) with Gene*PAE interaction for working memory performance. The HTDT test in CTLC imputed data identified three haplotypes associated with FASD diagnosis risk: COP1 (padj=0.029), WWOX (padj=2×10⁻4), TMEM38B (padj= 0.019). WWOX, STX6, and TMEM38B were differentially expressed in placenta and/or child blood based on PAE. In this first-ever genome-wide investigation of maternal and child genetics in FASD, we identified multiple biologically plausible risk-modifying loci for FASD neurobehavioral, growth, and FASD diagnosis outcomes.
Source: Research Square
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: The Role of Maternal Nutrition in the Teratogenesis of Alcohol in Humans, Neural Bases of Eyeblink Conditioning in FASD, Identification of fetal alcohol-affected children: Alterations in imprinted gene expression and methylation as biomarkers of neurobehavioral and growth impairment., Polygenic Risk Scores for Alzheimer's Disease in Hispanic/Latinx Populations, Identification of FASD in South African Children, Behavioral Characteristics and Neural Correlates of Reading Impairment in FASD, GLASS-AD: Global Latinos Sequencing Study for Alzheimer's Disease, Recruitment and Retention for Alzheimer's Disease Diversity Genetic Cohorts in the ADSP (READD-ADSP)
OpenAlex ID: W7212184673