Autism heterogeneity related to preterm birth: multi-ancestry results from the SPARK sample

Autism Spectrum Disorder (ASD) shows significant clinical variability, likely due to a combination of genetic and environmental factors. Preterm birth is a known risk factor for ASD, occurring in approximately 13% of diagnosed individuals. While genetic factors contribute to preterm birth in the general population, the relationship between genetic variation, preterm birth, and ASD heterogeneity remains unclear.

We investigated the genetic factors associated with preterm birth in autistic individuals using data from the SPARK sample. We conducted three ancestry-specific, genome-wide association studies for African/African American, Admixed American, and Non-Finnish European ancestries, followed by a meta-analysis using METAL. Functional mapping and gene-based analyses were performed using FUMA, and genetic correlations were estimated using LDSC and Popcorn. Polygenic risk scores (PRS) were computed with BridgePRS.

Our study identified ancestry-specific genetic loci associated with preterm birth in ASD cases. Although the meta-analysis results were not statistically significant, the estimated SNP heritability was 14%, indicating a meaningful contribution of common genetic variants. Across ancestry groups, preterm birth status was not significantly associated with PRS for any psychiatric or medical conditions analyzed. However, polygenic liability to preterm birth was linked to several congenital anomalies after multiple testing adjustments.

These findings underline the importance of including diverse ancestries in genetic studies of preterm birth in ASD and underscore the potential for utilizing early-life exposure information to understand ASD heterogeneity. Future research should replicate these findings in larger samples and explore rare variants associated with preterm birth to better understand the relationship between gestational duration and clinical and genetic differences in ASD.