Morgan James Morgan

Age at onset of walking is an important early childhood milestone which is used clinically and in public health screening. In this genome-wide association study meta-analysis of age at onset of walking (N = 70,560 European-ancestry infants), we identified 11 independent genome-wide significant loci. SNP-based heritability was 24.13% (95% confidence intervals = 21.86–26.40) with ~11,900 variants accounting for about 90% of it, suggesting high polygenicity. One of these loci, in gene RBL2, co-localized with an expression quantitative trait locus (eQTL) in the brain. Age at onset of walking (in months) was negatively genetically correlated with ADHD and body-mass index, and positively genetically correlated with brain gyrification in both infant and adult brains. The polygenic score showed out-of-sample prediction of 3–5.6%, confirmed as largely due to direct effects in sib-pair analyses, and was separately associated with volume of neonatal brain structures involved in motor control. This study offers biological insights into a key behavioural marker of neurodevelopment.

Objective

Genetic factors play a substantial role in the etiology of autism and its co-occurrence with other conditions and traits. The primary objective of this study was to clarify the associations between the autism polygenic score and autism diagnosis, autistic traits, and related behavioral and neurobiological traits.

Method

We included peer-reviewed studies written in English reporting univariate associations. We systematically searched PubMed, Web of Science, PsycINFO, and Scopus on November 2, 2022, and January 6, 2023. We assessed the quality of included studies using the QUIPS tool, applied systematic review with best-evidence synthesis, and performed meta-analyses if >5 studies were performed on similar phenotypes.

Results

Of 72 eligible studies (pooled N = 720,087), 61 received high-quality rating. Meta-analysis of nine studies revealed strong evidence for an association between the autism polygenic score and autism diagnosis (meta-analytic r = 0.158 (95% CI 0.067 – 0.249)). Our systematic review revealed strong evidence for an association with social behavior, depression, and motor skills and weak evidence for physical activity. Associations with other outcomes were inconclusive and effect sizes generally small (median r = 0.03).

Conclusion

The autism polygenic score is consistently associated with autism diagnosis and a small number of co-occurring traits. Associations with many other traits and conditions are not significant. Due to its inconsistent associations and limited generalizability, we underscore that the autism polygenic score does not have clinical utility and should only be applied for scientific purposes, with improvements needed for a deeper understanding of autism’s polygenic underpinnings.