Research sheds light on impact of genetic variants beyond autism diagnosis

Over 180 genes have been identified as contributing to autism spectrum disorder (ASD). Historically, however, researchers have focused on diagnosing disease rather than understanding the spectrum of phenotypes that these gene interactions may express.

In a recent study published in natural medicine, scientists have conducted the largest meta-analysis to elucidate the phenotypes of individuals diagnosed with autism and previously understudied undiagnosed counterparts.

Study: Phenotypic effects of genetic variants associated with autism. Image Credit: SewCreamStudio/Shutterstock.com

Background

This research revealed the direct influences of genetics on the diagnosis of ASD and the consequences of social, economic, and environmental contexts on the externally observable behaviors of individuals on the ASD spectrum.

“Autism” is short for “autism spectrum disorder (ASD),” a complex neurological and developmental condition that impairs an individual’s social interaction, communication, intelligence, and behavior. The World Health Organization (WHO) estimates that autism affects 10% of the world’s population.

The phenotypic expression of ASD is unique for each individual, and the body of literature exploring the gene-environment interactions that shape these expressions is growing rapidly. Despite decades of research into the genotypic underpinnings of ASDs and other neurodevelopmental disorders (NDDs), most research has focused on diagnosed patients.

Undiagnosed individuals have remained largely ignored, even when they possess one or more of the same loss-of-function (LoF) gene alleles found in patients with ASD.

This presents a gap in our understanding of the interindividual phenotypic variability of ASD spectrum members and its impact on the socioeconomic status of the many undiagnosed individuals.

About the study

In the current study, researchers reviewed four studies in a meta-analytic framework to elucidate the genes present in patients with ASD and their relative contributions to cognitive impairment in undiagnosed individuals with common European ancestry.

They started by collecting 226,649 whole exome sequences (WES) comprising 13,091 diagnosed ASD patients, 19,488 from their immediate relatives, and 194,070 undiagnosed others.

One hundred and eighty-five autosomal genes were selected based on their mutated LoF alleles with confirmed associations with NDDs.

They then collected and compiled a set of 2,492 genes with no direct association with NDD, which research concluded are “intolerant” of ASD LoF variants. Intolerant genes are those in which protein truncating variants (PTVs) or other mutations are absent or maintained at very low frequencies, i.e. natural selection actively filters or selects against their persistence in a population.

The relationships between autism and biological function were analyzed by assessing the amount of gene expression in four different regions of the brain and across eight different periods of fetal development.

Autism diagnoses based on genome-wide association studies (GWAS) were simultaneously condensed to arrive at a polygenic score (PGS) to assess whether genetic composition could accurately predict the presence and l ASD intensity in previously undiagnosed humans.

Phenotypic cognition information in the form of social and communication questionnaires (SCQ), intelligence quotients (IQ), and measures of repetitive behaviors, social interactions, communication difficulties, and self-injurious behaviors was compiled for attendees.

This was done to establish conventional diagnostic thresholds in an otherwise nearly continuous spectrum of non-ASD to severely ASD-prone subjects.

Finally, magnetic resonance imaging (MRI) of 21,040 people from the UK Biobank, including 1,675 patients with ASD, was analyzed to test previous claims that certain genes associated with autism could alter the anatomy of the brain.

Study results

Corroborating previous research, the 185 selected LoF genes were found in various combinations in people diagnosed with ASD, with odds ratios (ORs) corresponding to gene prevalence, i.e., an OR higher corresponded to a wider prevalence in the ASD group.

Of these, 134 LoF genes have been found in at least one undiagnosed individual, potentially indicative of the complex environmental, societal, and genetic interactions that underlie behavior and diagnosis.

The presence and ORs of the genes in undiagnosed individuals were correlated with reduced qualifications and income and reduced intelligence, all of which were statistically significant and highlight the lack of support provided by society not only to individuals at the end of the ASD spectrum, but also to those with superficial disorders. genetic dispositions to the condition.

Surprisingly, high autism PGS scores in those diagnosed, while directly proportional to reduced income, are inversely associated with fluid intelligence – the more autistic the individual, the more intelligent they are.

MRI imaging confirmed that significant alterations in brain anatomy were present in individuals positive for ASD LoF genes compared to individuals lacking these mutations, confirming and corroborating previous research.

conclusion

This research represents the largest meta-analysis of autism to date and is the first to focus on undiagnosed carriers of genes associated with autism. The results indicate that the presence and ORs of ASD genes can predict the diagnosis of the disease in an individual.

However, societal factors and the developmental environment can cause carriers (individuals with genes associated with autism) to live their entire lives with the economic and cognitive demerits of ASD while remaining undiagnosed.

Sex has been identified as a confounder for some genes – mothers passed on some LoF genes more than fathers. While the genetic load in female and male offspring was found to be nearly identical, the phenotypic expression of autism was preferential or exclusive in males, implying that females are more resilient than their male counterparts to low ORs of rare ASD genes.

“Social environments also influence whether people with autistic traits are diagnosed, and there is still progress to be made at a societal level to enable people with all different neurological and developmental diversities to thrive.”

Finally, this research highlights the need to adapt education systems to people with varying needs across the NDD spectrum, which may help them later.

Moreover, the presence of ASD genes in an individual most often remains hidden in their phenotype, and future research exploring the biological basis of multiple such genetic interactions is needed to improve future diagnosis.

Such research, when coupled with data that considers environmental, societal, economic, and genetic factors, could help humanity as a whole, given the additional contributions of its many gifted people.