Autism Heterogeneity Related to Preterm Birth: Multi-Ancestry Results From the Simons Foundation Powering Autism...

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 31,947 autistic individuals using data from the SPARK (Simons Foundation Powering Autism Research for Knowledge) sample. We conducted 3 ancestry-specific genome-wide association studies for African/African American, admixed American, and non-Finnish European ancestries, followed by a meta-analysis of 3308 preterm cases and 28,639 controls using METAL. Functional mapping and gene-based analyses were performed using FUMA, and genetic correlations were estimated using LDSC and Popcorn. Polygenic risk scores (PRSs) were computed with BridgePRS, using PRS of preterm birth in the general population.

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 single nucleotide polymorphism heritability was 14%, indicating a meaningful contribution of common genetic variants. Across ancestry groups, preterm birth status was not significantly associated with PRSs for any psychiatric or medical conditions analyzed. However, polygenic liability to preterm birth in the general population was linked to several congenital anomalies after multiple testing adjustments.

These findings highlight the importance of diverse ancestries and early-life exposures in understanding 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.