Widespread signatures of positive selection in common risk alleles associated to autism spectrum disorder

Abstract

The human brain is the outcome of innumerable evolutionary processes; the systems genetics of psychiatric disorders could bear their signatures. On this basis, we analyzed five psychiatric disorders, attention deficit hyperactivity disorder, autism spectrum disorder (ASD), bipolar disorder, major depressive disorder, and schizophrenia (SCZ), using GWAS summary statistics from the Psychiatric Genomics Consortium. Machine learning-derived scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). ASD GWAS results positively correlated with incomplete-selection (p = 3.53*10−4). Variants with ASD GWAS p<0.1 were shown to have a 19%-increased probability to be in the top-5% for incomplete-selection score (OR = 1.19, 95%CI = 1.11–1.8, p = 9.56*10−7). Investigating the effect directions of minor alleles, we observed an enrichment for positive associations in SNPs with ASD GWAS p<0.1 and top-5% incomplete-selection score (permutation p<10−4). Considering the set of these ASD-positive-associated variants, we observed gene-expression enrichments for brain and pituitary tissues (p = 2.3*10−5 and p = 3*10−5, respectively) and 53 gene ontology (GO) enrichments, such as nervous system development (GO:0007399, p = 7.57*10−12), synapse organization (GO:0050808, p = 8.29*10−7), and axon guidance (GO:0007411, p = 1.81*10−7). Previous genetic studies demonstrated that ASD positively correlates with childhood intelligence, college completion, and years of schooling. Accordingly, we hypothesize that certain ASD risk alleles were under positive selection during human evolution due to their involvement in neurogenesis and cognitive ability.

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

“…It has been hypothesized that human and/or primate-specific adaptations, such as bipedalism, have resulted in the accelerated evolution of birth-timing phenotypes along these lineages 2,93,94 . Accelerated evolution has also been implicated in other complex disorders—especially those like schizophrenia 95,96 and autism 97 which affect the brain, another organ that is thought to have undergone adaptive evolution in the human lineage.…”

How Do We Explain ‛Autistic Traits’ in European Upper Palaeolithic Art?

“…In contrast to the conclusion presented by Pickard et.al (2011) most cases of autism spectrum conditions (about 70%) occur through inherited genetics and are typically cases without intellectual impairment, previously often termed Asperger Syndrome Ronemus et al, 2014). Autism without intellectual disability is coded by common variants called single nucleotide polymorphisms (SNPs) that have been shown to be under positive selection and are not necessarily disabling (Warrier et al, 2016;Polimanti & Gelernter, 2017). Potentially thousands of SNPs that increase risk are scattered throughout the genome, which are thought to act additively (Klei et al, 2012).…”

“…Firstly, the genetic evidence confirms that individuals with autism were present in the Palaeolithic. Secondly evidence is growing that some advantageous elements related to genes associated with autism have been subject to positive selection (Warrier et al, 2016;Polimanti & Gelernter, 2017). Thirdly the phenotypes of those who have autism spectrum conditions without intellectual disability carry a number of strengths including significant perceptual abilities and special skills (Meilleur et al, 2015) improved concentration, ability to recognise patterns, and strong factual memory (Lorenz & Heinitz, 2014) all likely to be of benefit in Upper Paleolithic environments (Spikins, Wright & Hodgson, 2015).…”

Abnormal features of human self-domestication in bipolar disorder

“…One promising approach to make more tractable the genetic study of complex diseases like BD is adopting an evolutionary perspective. A robust link exists between evolution and abnormal development, with genes positively selected in our species being enriched in candidates for high-prevalence, complex cognitive conditions like SZ (Srinivasan et al, 2016) or autism spectrum disorders (ASD) (Polimanti and Gelernter, 2017). Even in conditions with a neat genetic origin, like Williams syndrome (WS), abnormally expressed genes outside the WS region are enriched in protein-coding genes that have been positively selected in modern humans compared to extinct hominins (Benítez-Burraco, 2020a).…”