GWAS integrating maternal and child genetics reveals novel risk-modifying loci for fetal alcohol spectrum disorders (FASD)

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.