Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is more common in boys, possibly due to biological and social factors. Research suggests that the “female protective effect” may require a higher genetic load for females to manifest symptoms. Recent studies on the X chromosome have identified important genes associated with ASD, highlighting the need to include sex chromosomes in genomic research to better understand sex differences in ASD and explore new therapeutic approaches.
Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects social communication and is characterized by restricted interests and repetitive behaviors.
Approximately 1% of the global population is diagnosed with ASD, with a higher prevalence in boys, at a ratio of 3–4:1 compared to girls.
However, this disparity may be partly attributed to social and demographic factors, such as underreporting of cases in girls due to the normalization of certain behaviors.
Research suggests that the gender gap in the prevalence of Autism Spectrum Disorder (ASD) has a significant biological basis. Studies indicate that females with Autism Spectrum Disorder (ASD) often have a higher number of harmful genetic changes.
These changes include copy number variants (CNVs), where parts of the DNA may be missing or duplicated, and single nucleotide variants (SNVs), which involve changes to a single “letter” of the genetic code.
These genetic changes increase susceptibility to ASD, but they appear to be needed in greater numbers or with greater impact in females to result in symptoms similar to those seen in males.
In addition to genetic differences, steroid hormones, such as testosterone, and the expression of genes that differ between men and women may play a crucial role in the development of ASD.
Testosterone, for example, may influence brain development and the neuroimmune system differently in the sexes, affecting dendritic arborization (the formation of connections between neurons) and the number of microglial cells and neurons.
A sister is less likely to have ASD than a brother, even in families where the disorder is already present.
This points to the so-called “female protective effect,” a theory that suggests that women need a heavier genetic load or more severe risk factors to manifest symptoms of ASD.
This effect indicates that women are somehow more protected against the development of ASD, requiring a greater accumulation of adverse genetic or environmental factors to present the disorder.
The X chromosome has been the focus of several studies due to its implication in genetic variants associated with ASD. Studies indicate that certain genes located on the X chromosome, such as MECP2 and DDX3X, are linked to the development of ASD.
Analysis of the X chromosome, however, faces challenges, such as its lower genetic diversity compared to autosomes and X inactivation in women, which can complicate the interpretation of results.
Recent research has advanced the study of X chromosome variants, overcoming previous limitations and revealing new genetic associations with ASD.
In a comprehensive study, more than 400,000 variants on the X chromosome were analyzed, identifying 59 variants associated with ASD, linked to 17 genes that may be crucial to better understand the biology of ASD and develop new therapeutic approaches:
GRPR (Gastrin-Related Peptide Receptor): This gene encodes a receptor that binds to a peptide called GRP (Gastrin-Releasing Peptide). GRPR plays a role in modulating neural function, and studies suggest that it may influence social behavior and communication, characteristics often impaired in ASD. Alterations in this gene may affect cognitive and social processes.
AP1S2 (AP-1 Subunit 2, Adaptor Complex): The AP1S2 gene is related to the intracellular transport system, more specifically to the formation of vesicles that transport proteins between cellular compartments. This transport is essential for normal nerve cell function, and mutations in this gene can impair neural function, contributing to developmental disorders such as ASD.
DDX53 (RNA Helicase): DDX53 encodes an RNA helicase, a protein involved in the processing of RNA, which is essential for the production of proteins. Defects in this gene can alter gene expression and neuronal development, potentially affecting cognitive and behavioral functions associated with autism.
HDAC8 (Histone Deacetylase 8): This gene is involved in the regulation of gene expression through chemical modifications to histones, proteins that help package DNA. Histone dysregulation can affect neuronal development and has been implicated in several neurological disorders, including ASD.
PCDH19 (Protocadherin Cadherin 19): PCDH19 encodes a protein that facilitates communication between nerve cells. Alterations in this gene are particularly associated with a type of autism-related epilepsy known as PCDH19 syndrome. It is essential for synapse formation and neuronal communication.
PTCHD1 (Patched Domain Containing 1): The PTCHD1 gene is involved in a signaling pathway called Hedgehog, which regulates cell growth and differentiation. Mutations in this gene can affect the development of the central nervous system and are linked to ASD and sensory processing impairments.
PCDH11X (Protocadherin Cadherin 11X): Similar to PCDH19, PCDH11X is also involved in communication between nerve cells and is essential for synaptic function and brain development. Its dysfunction can affect neural connections and contribute to ASD.
PTCHD1-AS (PTCHD1 Antisense RNA): This gene encodes an RNA that may regulate the expression of the PTCHD1 gene. Because PTCHD1 is involved in cell signaling that is crucial for neuronal development, alterations in PTCHD1-AS may also influence brain development and function.
DMD (Dystrophin): The DMD gene is critical for muscle function and also affects the nervous system. Mutations in this gene are associated with Duchenne muscular dystrophy, but research indicates that dystrophin also plays a role in several neurological conditions, including ASD.
SYAP1 (Synaptic Protein 1): SYAP1 is involved in synaptic signaling, which is crucial for the transmission of signals between neurons. Defects in this gene may alter communication between neurons and affect brain processes necessary for social behavior and learning.
CNKSR2 (Kinase Suppressor of Ras 2): CNKSR2 regulates cell signaling that influences the development of the nervous system. Mutations in this gene may interfere with signals needed for proper cognitive and social function, linking it to ASD.
GLRA2 (Glycine Receptor Alpha 2): GLRA2 is a gene that encodes a receptor involved in the inhibition of neural signals in the brain. Malfunction of this receptor can affect the balance between excitation and inhibition in nerve cells, which may contribute to neurodevelopmental disorders such as ASD.
OFD1 (Oral-Facial-Digital Syndrome 1): OFD1 is associated with genetic syndromes that affect facial, oral, and digital development. Mutations in this gene can lead to cognitive and behavioral impairments, including features of ASD.
CDKL5 (Cyclin-Dependent Kinase-Like 5): CDKL5 is a gene involved in brain signaling and development. Mutations in this gene are associated with a severe type of epilepsy and ASD, primarily affecting cognitive and motor development.
GPRASP2 (GPR Aspartate-Serine Protein 2): GPRASP2 is associated with the cell signaling process and may influence communication between nerve cells. Alterations in this gene may contribute to the social and behavioral deficiencies observed in ASD.
NXF5 (Nuclear Export Factor 5): NXF5 is a gene involved in the export of RNA from the nucleus to the cytoplasm of cells. Defects in RNA processing may interfere with gene expression and affect neural development, which may be relevant to ASD.
SH3KBP1 (SH3 Domain Kinase Binding Protein 1): This gene is related to the regulation of cell growth and the organization of nerve cells. Its dysfunction may compromise cell signaling and affect brain development and function, contributing to the symptoms of ASD.
Finally, the study identified that the FGF13 gene (Fibroblast Growth Factor 13) is involved in the regulation of neuronal growth and development.
Studies indicate that this gene may play a specific role in the gender difference observed in ASD, with variations in its alleles being more frequent in males, which suggests a greater impact of the gene on the manifestation of ASD in males.
These genes are all involved in critical processes of brain development, neural signaling, communication between nerve cells, and neurochemical balance. When altered, they can affect functions essential for behavior, learning, and social interaction, characteristics often compromised in ASD.
These findings reinforce the importance of including the X chromosome in genomic research, revealing new avenues for investigation into how genetic and biological factors contribute to ASD.
READ MORE:
Chromosome X-wide common variant association study in autism spectrum disorder
Mendes, Marla et al.
The American Journal of Human Genetics, Volume 112, Issue 1, 135 - 153
Abstract:
Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The “female protective effect” in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies. Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males). We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9 × 10−6 to 1.51 × 10−5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10−7) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10−6). When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1). FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.
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