Genetic admixture predictors of fetal alcohol spectrum disorders (FASD) in the South African Cape Coloured population

Ancestrally admixed populations are underrepresented in genetic studies of complex diseases, which are still dominated by European-descent populations. This is relevant not only from a representation standpoint but also because of admixed populations unique features, including being enriched for rare variants, for which effect sizes are disproportionately larger than common polymorphisms. Furthermore, results from these populations may be generalizable to other populations. The South African Cape Coloured (SACC) population is genetically admixed, with one of the highest prevalences of fetal alcohol spectrum disorders (FASD) worldwide. We profiled its admixture and examined associations between ancestry profiles and FASD outcomes using two longitudinal birth cohorts (N=308 mothers, 280 children) designed to examine effects of prenatal alcohol exposure on development. Participants were genotyped via MEGA-ex array to capture common and rare variants. Rare variants were overrepresented in our SACC cohorts, with numerous polymorphisms being monomorphic in other reference populations (e.g., [~]30,000 and [~]221,000 variants in gnomAD European and Asian populations, respectively). The cohorts showed global African (51%; Bantu and San); European (26%; Northern/Western); South Asian (18%); and East Asian (5%; largely Southern regions) ancestries. The cohorts exhibited high rates of homozygosity (6%), with regions of homozygosity harboring more deleterious variants when lying within African local-ancestry genomic segments. Both maternal and child ancestry profiles were associated with FASD risk and altered severity of prenatal alcohol exposure-related cognitive deficits in the child. Our findings indicate that the SACC population may be a valuable asset to identify novel disease-associated genetic loci for FASD and other diseases.