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Genetic Risk for Autism Associated With Neurodevelopmental Progress, Condition-Linked Traits

NEW YORK – Infants with high polygenic risk scores for autism spectrum disorder exhibit traits associated with the condition, a new study has found.

Autism spectrum disorder is highly heritable and both rare and common variants are associated with it. Signs of autism spectrum disorder typically begin to manifest by three or four years of age, but as that is after a time of accelerated brain development, scientists are searching for ways to spot those at risk at an early age when interventions may be the most effective.

Researchers led by Hamamatsu University School of Medicine's Kenji Tsuchiya examined whether a polygenic risk score for autism spectrum disorder was associated with neurodevelopmental progress and autism-related traits in a cohort of 734 infants from the general population. 

"[T]he association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood," Tsuchiya and colleagues wrote in their paper.

As they reported Friday in JAMA Network Open, they found these risk scores to be associated with infant neurodevelopment, especially gross motor and receptive language development, and their analysis implicated gene sets involved in glutamate signaling and the immune system. 

To generate their polygenic risk score for autism, the researchers used data from the Lundbeck Foundation Initiative for Integrative Research GWAS study and the software program PRSice-2. They applied the score to genotyping data gathered from 734 infants from the Hamamatsu Birth Cohort for Mothers and Children without developmental delay. They also used the Mullen Scales of Early Learning to measure the infants' neurodevelopmental progress at 18 months of age and the Autism Diagnostic Observation Schedule 2 to measure autism traits at six years of age.

Overall, they found that participants' polygenic risk scores were associated with autism-linked traits, as gauged by the ADOS-2 measure, and social affect. Additionally, polygenic risk scores were also linked with infant neurodevelopment, especially gross motor skills and receptive language skills, as captured by the Mullen scale. 

A gene set enrichment analysis tied a number of biological pathways to these autism-linked traits. In particular, they linked cell maturation, adenylyl cyclase activity and cyclic adenosine monophosphate concentration, and glutamate secretion regulation with autism traits. At the same time, they noted ties between protein metabolism and MSEL gross motor scores and between receptive language scores and broader pathways like midbrain development or RNA localization. Inflammation-linked gene sets, like chemokine motif ligand 2 production, regulation of monocyte differentiation, and B-cell differentiation, were associated with both autism-linked traits and gross motor skills

The association between autism-linked traits and glutamatergic signaling and neurotransmitter signaling is in line with previous findings, according to the researchers, who noted that excitability and inhibitory balance has been linked to autism etiology and could also be involved in the development of autism-linked traits in the general population. Glutamate signaling is also associated with delayed progression in receptive language, suggesting that it is associated with both autism spectrum disorder and early language development, they added.

The ties between the immune system — such as the regulation of monocyte differentiation — and autism-linked traits is also supported by previous studies that indicated a role for the immune system in autism, the researchers noted in their paper. They added that immunomodulatory therapies have been suggested for autism spectrum disorder.

However, the researchers noted that this study has a number of limitations, including that it focuses on a general population sample and that their polygenic risk score was developed using a white population, as there has not been a large genome-wide association study of autism among East Asians.