AMBRA1, Autophagy, and the Extreme Male Brain Theory of Autism.

Bernard Crespi,Silven Read,Amy Ly,Peter Hurd

doi:10.1155/2019/1968580

Bernard Crespi, Silven Read + Show 2 more

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https://doi.org/10.1155/2019/1968580

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Abstract

The extreme male brain theory of autism posits that its male bias is mediated by exaggeration of male-biased sex differences in the expression of autism-associated traits found in typical populations. The theory is supported by extensive phenotypic evidence, but no genes have yet been described with properties that fit its predictions. The autophagy-associated gene AMBRA1 represents one of the top genome-wide “hits” in recent GWAS studies of schizophrenia, shows sex-differential expression, and has been linked with autism risk and traits in humans and mice, especially or exclusively among females. We genotyped the AMBRA1 autism-risk SNP in a population of typical humans who were scored for the dimensional expression of autistic and schizotypal traits. Females, but not males, homozygous for the GG genotype showed a significant increase in score for the single trait, the Autism Quotient-Imagination subscale, that exhibits a strong, significant male bias in typical populations. As such, females with this genotype resembled males for this highly sexually dimorphic, autism-associated phenotype. These findings support the extreme male brain hypothesis and indicate that sex-specific genetic effects can mediate aspects of risk for autism.

Highlights

Autism exhibits a strong male bias in its incidence, that increases from about 2 : 1 in relatively severe, monogenic cases to about 5–10 : 1 among autistic individuals with relatively high intelligence [1, 2]. e expression of autism phenotypes shows evidence of differences between females and males, the patterns of sex differences remain unclear
High prenatal testosterone in turn drives altered expression of a suite of sexdifferential phenotypes, especially those related to empathizing and systemizing
The genes that contribute to high systemizing in males tend to show male-biased expression in the brain [7]. ese results support aspects of the Autism Research and Treatment extreme male brain theory in a genome-wide context, the links of specific genes with sex differences and autism risk remain to be discerned

Summary

Introduction

Autism exhibits a strong male bias in its incidence, that increases from about 2 : 1 in relatively severe, monogenic cases to about 5–10 : 1 among autistic individuals with relatively high intelligence [1, 2]. e expression of autism phenotypes shows evidence of differences between females and males, the patterns of sex differences remain unclear. E expression of autism phenotypes shows evidence of differences between females and males, the patterns of sex differences remain unclear. Ese results support aspects of the Autism Research and Treatment extreme male brain theory in a genome-wide context, the links of specific genes with sex differences and autism risk remain to be discerned.

Results

Conclusion