Genetic evidence of gender difference in autism spectrum disorder supports the female-protective effect

Yi Zhang,Zhongsheng Sun,Jinchen Li,Huajing Teng,Kun Zhang,Tingting Zhao,Yan Wang,Ze Zhang,Chao Li,Na Li,Leisheng Shi,Kun Xia

doi:10.1038/s41398-020-0699-8

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a male-to-female prevalence of 4:1. However, the genetic mechanisms underlying this gender difference remain unclear. Mutation burden analysis, a TADA model, and co-expression and functional network analyses were performed on de novo mutations (DNMs) and corresponding candidate genes. We found that the prevalence of putative functional DNMs (loss-of-function and predicted deleterious missense mutations) in females was significantly higher than that in males, suggesting that a higher genetic load was required in females to reach the threshold for a diagnosis. We then prioritized 174 candidate genes, including 60 shared genes, 91 male-specific genes, and 23 female-specific genes. All of the three subclasses of candidate genes were significantly more frequently co-expressed in female brains than male brains, suggesting that compensation effects of the deficiency of ASD candidate genes may be more likely in females. Nevertheless, the three subclasses of candidate genes were co-expressed with each other, suggesting a convergent functional network of male and female-specific genes. Our analysis of different aspects of genetic components provides suggestive evidence supporting the female-protective effect in ASD. Moreover, further study is needed to integrate neuronal and hormonal data to elucidate the underlying gender difference in ASD.

Highlights

Autism spectrum disorder (ASD) represents a series of complex neurodevelopmental disabilities, characterized by deficits in social communication and restricted behaviors or interests[1]
Our analysis revealed that the probands carried significantly more loss-of-function and deleterious missense mutations than the matched controls, with no difference in tolerant missense mutations
We found all of the three subclasses of candidate genes being more frequently co-expressed in female-brain regions than in male-brain regions across multiple brain regions during prenatal development, which were reported as the most significant period associated with ASD by us[45] and other group[39,40], including the dorsolateral prefrontal cortex (DFC), anterior cingulate cortex (MFC), orbital frontal cortex (OFC), ventrolateral prefrontal cortex (VFC), amygdaloid complex (AMY), hippocampus (HIP), mediodorsal nucleus of thalamus (MD), striatum (STR), primary auditory cortex (A1C), primary motor cortex (M1C), primary somatosensory cortex (S1C), primary visual cortex (V1C), posteroinferior parietal cortex (IPC), inferolateral temporal cortex (ITC), posterior superior temporal cortex (STC), Putative functional de novo mutations (DNMs) per person female male p = 1.21E-02

Summary

Introduction

Autism spectrum disorder (ASD) represents a series of complex neurodevelopmental disabilities, characterized by deficits in social communication and restricted behaviors or interests[1] It is characterized by a strong sexual dimorphism, as males are about four times more likely to be diagnosed with ASD than females[2]. The multiple threshold liability model has been most frequently discussed, which hypothesizes that multiple genetic factors contribute to the liability for developing ASD, and a higher threshold of genetic liability is required for females as compared with males; this is known as the “female protective model”[4,5,6] This hypothesis has been supported by studies demonstrating that female cases have an excess of deleterious copy number variants, which disrupt more genes compared with those found in males[7,8,9,10]. Steroidogenic activity was shown to be elevated

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