Greater than 180 genes have been identified as contributing to autism spectrum disorder (ASD). Historically, nevertheless, researchers have focused on diagnosing the condition reasonably than understanding the spectrum of phenotypes these gene interactions can express.
In a recent study published in Nature Medicine, scientists conducted the biggest meta-analysis to elucidate the phenotypes of ASD-diagnosed individuals and hitherto understudied undiagnosed counterparts.
Study: Phenotypic effects of genetic variants related to autism. Image Credit: SewCreamStudio/Shutterstock.com
Background
This research revealed genetics’ direct influences on ASD diagnosis and the implications of social, economic, and environmental contexts within the externally observable behaviors of people on the ASD spectrum.
‘Autism’ is the abbreviation for ‘autism spectrum disorder (ASD)’, a posh neurological and developmental condition that impairs a person’s social interaction, communication, intelligence, and behavior. The World Health Organization (WHO) estimates that autism affects 10% of the worldwide population.
The phenotypic expression of ASD is exclusive for every individual, and the body of literature exploring the gene-environment interactions which shape these expressions is rapidly growing. Despite many years of research into the genotypic underpinnings of ASD and other neurodevelopmental disorders (NDDs), most research has focused on diagnosed patients.
Undiagnosed individuals have remained largely ignored, even once they possess a number of of the identical loss-of-function (LoF) gene alleles present in ASD patients.
This presents a spot in our understanding of the inter-individual phenotypic variability of members of the ASD spectrum and its impact on the socioeconomic status of the undiagnosed many.
In regards to the study
In the current study, researchers reviewed 4 studies inside a meta-analytic framework to elucidate genes present in patients with ASD and their relative contributions to cognitive impairment in undiagnosed individuals with shared European ancestry.
They began by collecting 226,649 whole exome sequences (WES) comprising 13,091 diagnosed ASD patients, 19,488 of their immediate relatives, and 194,070 undiagnosed others.
100 and eighty-five autosomal genes were chosen based on their having LoF-mutated alleles with confirmed associations with NDDs.
They then collected and compiled a set of two,492 genes without direct NDD association, which research has concluded are ‘intolerant’ to ASD LoF variants. Intolerant genes are those wherein protein-truncating variants (PTVs), or other mutations, are absent or kept at very low frequencies, i.e., natural selection actively filters out or selects against their persistence in a population.
Relationships between autism and biological function were analyzed by evaluating the amount of gene expression at 4 different regions of the brain and across eight different periods of fetal development.
Autism diagnoses based on genome-wide association studies (GWAS) were concurrently condensed to reach at a polygenic rating (PGS) to guage if genetic composition could accurately predict ASD’s presence and intensity in previously undiagnosed humans.
Phenotypic cognition information within the types of social and communication questionnaires (SCQ), intelligence quotients (IQ), and metrics of repetitive behaviors, social interactions, difficulties in communication, and self-injurious behaviors was compiled for participants.
This was done to ascertain conventional diagnostic cutoffs in an otherwise near-continuous spectrum of non-ASD to severely ASD-prone.
Finally, magnetic resonance imaging (MRI) of 21,040 individuals from the UK Biobank, including 1,675 ASD patients, was analyzed to check previous claims that some genes related to autism could alter brain anatomy.
Study findings
Corroborating previous research, all 185 chosen LoF genes were present in various combos in individuals diagnosed with ASD, with gene prevalence matching odds ratios (ORs), i.e., higher OR corresponded with wider prevalence within the ASD group.
Of those, 134 LoF genes were present in not less than one undiagnosed individual, potentially indicative of the complex environmental, societal, and genetic interplays which underpin behavior and diagnosis.
Presence and ORs of genes in undiagnosed individuals were correlated with reduced qualifications and income and reduced intelligence, all of which were statistically significant and highlight the dearth of support provided by society not only to individuals at the acute of the ASD spectrum but in addition those with shallow genetic dispositions to the condition.
Surprisingly, high autism PGS scores in diagnosed individuals, while directly proportional to reduced income, are inversely related to fluid intelligence – the more autistic the person, the more intelligent they’re.
MRI imagery did confirm that significant alterations in brain anatomy were present in individuals positive for ASD LoF genes compared to the individuals devoid of those mutations confirming and corroborating previous research.
Conclusions
This research represents the biggest meta-analysis of autism so far and is the primary to give attention to the undiagnosed carriers of autism-associated genes. Results indicate that the presence and ORs of ASD genes can predict a person’s diagnosis of the condition.
Nonetheless, societal aspects and developmental environment can lead to carriers (individuals having autism-associated genes) living their whole lives with the economic and cognitive demerits of ASD while remaining undiagnosed.
Sex was identified as a confounding factor for some genes – moms were found to transmit some LoF genes greater than fathers. While the gene load in each female and male offspring was found to be a near-identical, phenotypic expression for autism was preferential or exclusive in males, implying that females inherently resist low ORs of rare ASD genes higher than their male counterparts.
“Social environments also influence whether individuals with autistic traits receive a diagnosis, and there continues to be progress to be made on a societal level to enable individuals with all different neurological and developmental diversities to thrive.”
Finally, this research highlights the necessity for education systems to be tailored to individuals with various needs across the NDD spectrum, which could aid them later.
Moreover, the presence of ASD genes in a person stays most of the time hidden in its phenotype, and future research exploring the biological underpinning of multiple such gene interactions is obligatory to enhance future diagnosis.
Such research, when paired with data considering environmental, societal, economic, and genetic aspects, could help profit humanity at large, given the added contributions of its gifted many.