Studies Spell Out Rare, Common Variant Contributions to Autism Spectrum Disorder

Studies by independent research teams have more clearly defined the distinct contributions of rare and common risk variants in autism, along with their ties to core or more variable features of the condition.

"The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear," co-senior and co-corresponding authors Jonathan Sebat, a psychiatric genomics, psychiatry, cellular and molecular medicine, and genomic medicine researcher at the University of California at San Diego, and Caroline Nievergelt, with UCSD's psychiatry department, and their colleagues wrote in the first of these studies, published in Nature Genetics on Thursday.

Based on whole-genome sequence, exome sequence, or SNP profiles for 12,270 ASD cases, more than 19,900 parents, and nearly 5,200 siblings without ASD enrolled through three research cohorts, the team found that rare variants tended to be lower in ASD cases marked by higher-than-usual levels of common polygenic risk variants and vice versa.

"We show that the genetic architecture of ASD varies as a spectrum of rare and common variation, each having distinct phenotypic correlates and differential effects in males and females," the authors reported, adding that the "growing cohorts of ASD as well as individual rare diseases promise to improve knowledge of the effects of risk alleles on psychiatric traits and how their combined effects determine clinical outcome."

Findings from that study pointed to rare or common variant patterns linked to ASD symptoms, severity, and parental age features, for example. The researchers also saw differences in genetic contributors to ASD in males and females with the condition including enhanced genetic risk variant loads in the female ASD cases considered.

When the team analyzed the sequence data in the context of available genome-wide association study data, brain cell gene expression profiles, and results from rare variant transmission and association tests, it saw signs that rare ASD-related variants tended to fall in genes involved in neuronal functions and development, while common variants implicated in ASD were peppered across regulatory networks and other sequences.

"The results described in the present study highlight how an integrated analysis of multiple genetic factors can improve our understanding of the genetic basis of ASD," authors of that study concluded. "Although most of the heritability of ASD remains unexplained, the expanding arsenal of sequencing platforms and methods of variant detection promise to expand the range of genetic factors that can be captured from a genome."

For another paper in Nature Genetics, a University of Cambridge-led team analyzed array-based genotypes or exome sequences across almost 12,900 individuals with ASD, searching for genetic variants linked to core ASD phenotypes or to features such as intellectual disability found in just a subset of individuals with ASD.

"Individual differences among autistic individuals in core and associated features are complex and genetically multifactorial," co-senior and corresponding author Simon Baron-Cohen, a developmental psychopathology researcher and director of the University of Cambridge's Autism Research Centre, and colleagues wrote, noting that "[h]igh-impact de novo variants and PGS have differential and often independent effects on these features."

After defining half a dozen core autism features using behavioral and phenotypic data collected using parental reports for more than 24,400 individuals with autism, the team performed association analyses, searching for rare or common variants linked to 19 core or associated ASD features.

While common variants tended to coincide with core ASD features, the investigators found that rare, de novo risk variants were more often documented in ASD cases marked by developmental disabilities and/or ASD cases occurring in females.

Among other findings, their results indicated that developmental disability features tend to be less common in individuals classified at high risk using a polygenic risk score (PGS) for ASD, the researchers reported. They also highlighted sex-related differences in ASD genetics, suggesting that autism PGS variants are more common in females with ASD than in their male counterparts.

"There is additivity between common and high-impact de novo variants in autism," the authors reported, further explaining that the two risk variant types "do not have the same effects on either the core or associated autism phenotypes nor on co-occurring developmental disabilities."

While the latest results "have important implications for using genetics to understand autism," they noted, "[w]e need deeper phenotyping at scale and need to account for the evolving diagnostic criteria for autism."