we know that these genes are associated with autism because we find that these variants are more frequently inherited by children with autism. We hypothesized that people with autism who have these inherited genetic variants are not as likely to have seizures and cognitive differences as people with de novo genetic variants. So far our data strongly support[s] this hypothesis," said Feliciano.

THE SPARK COHORT'S REACH

A second study also published in Nature Genetics, "Rare coding variation provides insight into the genetic architecture and phenotypic context of autism," led by a team of investigators supported by the Simons Foundation Autism Research Initiative (SFARI) and the Autism Sequencing Consortium (ASC), performed analyses on genetic data from 20,627 people with autism, with new genetic data derived primarily from SPARK. The team developed new methods to discover gains and losses of DNA, or copy number variants (CNVs), from exome sequencing, and methods to integrate data from these CNVs with other classes of de novo and rare inherited variants, and identified 72 genes associated with autism. Most evidence came from de novo variants, with smaller but significant contributions from rare inherited variants. The researchers then combined data from the autism studies with a large dataset of 31,000 families in which the child was diagnosed with developmental delay and/or other neurodevelopmental conditions. These analyses discovered 373 genes associated with these diverse neurodevelopmental outcomes, and allowed the team to identify genes more associated with autism than with other neurodevelopmental conditions, and vice versa. They found that genes associated predominantly with developmental delay tend to be important in early neuronal development, whereas autism genes tend to play a role in more mature neurons.

The study's senior author, Michael Talkowski, Ph.D., director, Center for Genomic Medicine at Massachusetts General Hospital and member of the Broad Institute, noted that "the scale of the data collections from SPARK, the ASC and other sources – as well as the newly developed methods – has allowed us to explore the relative contribution of the diverse classes of genetic variants that contribute to a continuum of neurodevelopmental variability across these datasets. These analyses suggested that most of the genes identified play a role very early in brain development, though the genes with higher mutation rates in autism displayed slightly greater enrichment in more mature excitatory neurons. There are so many new genes and insights into neurodevelopment to be pursued from these findings, and all of these discoveries were only possible due to the accessibility of [the] rich data that SPARK and

other studies provide for the field."

Finally, two other studies (Antaki et al, 2022, Warrier et al, 2022) appearing in a recent issue of Nature Genetics analyzed the SPARK datasets. These two studies made use of the ASC and SPARK whole genomes, exomes and single nucleotide polymorphism (SNP) genotypes to determine the contributions of multiple genetic factors to ASD, including de novo mutations, inherited rare variants, common polygenic variants, and sex. The study by Antaki et al. found that different forms of genetic contributors are associated with different ASD symptoms, and that the wide variety of clinical presentations of individuals across the autism spectrum can be explained by the combinations of genetic factors they carry. Antaki also found that genetic contributors to ASD influence behavior in all family members, including parents and typically developing siblings.

Jonathan Sebat, Ph.D., professor of psychiatry and cellular and molecular medicine at UCSD and senior author on Antaki et al, said, "The spectrum of symptom severity in ASD is attributable to a spectrum of genetic influence. People who meet diagnostic criteria for autism may have the most genetic factors for autism, but these types of factors are present to varying degrees in all of us. We are all somewhere on a continuum."

Together, the four papers provide new insights into the genetic basis of autism, a condition so varied in its characteristics that it has been difficult to understand its neurobiological basis. Although researchers have yet to identify the fuller picture of brain molecules and pathways that underlie autism, these new studies will lead the way toward an improved understanding of this complicated and common condition.

ABOUT SPARK

SPARK (Simons Powering Autism Research), the world's largest autism research study, has mobilized almost 300,000 participants including more than 100,000 people with autism to participate directly in scientific research, with more than 150,000 of their family members also enrolled as participants. The SPARK community brings together people with autism and the world's leading autism researchers to drive research that is uncovering the genetic causes of autism and informing the development of targeted treatments and support. SPARK's ultimate goal is to power research to help people with autism live their fullest lives. Learn more at sparkforautism.org