Ladd-Acosta and coworkers measured over , CpG loci in post-mortem brain tissue from 40 individuals and identified four differentially methylated regions. The last site, an alternative promoter for succinate dehydrogenase complex flavoprotein subunit A pseudogene 3 SDHAP3 , was found in cerebellar tissue Ladd-Acosta et al.
Affected pathways implied in these studies and others include synaptic transmission, immune function, ion transport, and GABAergic genes Nardone and Elliott, ; Sun et al. Mor et al. This finding was supported by a study that found fetal membranes from preterm birth had hypermethylated OXTR , potentially linking an environmental risk factor to a pathological mechanism Behnia et al.
Another risk gene with epigenetic functions is engrailed homeobox 2 EN2 , a homeobox gene with an unusual methylation pattern in ASD that has been hypothesized to cause abnormal cerebellar Purkinje growth James et al.
The list of ASD risk genes with epigenetic functions is vast, suggesting a mechanism by which few mutations can result in widespread misregulation of gene expression. Because of this, genes with epigenetic functions and their substrates may be promising targets of therapies. For example, mutations in FMRP , a chromatin remodeler, result in widespread gene expression abnormalities, but a recent study found that inhibition of FMRP target bromodomain containing 4 BRD4 alleviated many of the disease characteristics Korb et al.
Proteins with epigenetic-regulating function may also be key targets of disease modifiers, a concept that will be discussed later in this review. Large-scale sequencing studies of major psychiatric diseases have revealed extensive overlap in risk loci, challenging the classification of these conditions as distinctive disorders.
Glessner et al. Schork et al. Studies also report shared susceptibility genes across a more restricted set of psychiatric diseases. Wang et al. Khanzada et al. Hit genes were primarily involved in dopamine and serotonin homeostasis, suggesting a potential mechanism for abnormal emotional regulation observed across all three disorders Khanzada et al.
The immense crossover revealed in these studies intriguingly suggests some level of shared etiology across psychiatric conditions, despite having clinically distinct presentations.
Previous epidemiological studies had suggested their linkage, reporting increased risk of ASD in children with schizophrenic parents and significant co-morbidity of child-onset schizophrenia and autism Rapoport et al.
In addition to susceptibility genes involved in neurodevelopment, other studies have also reported shared susceptibility in genes affecting chromatin remodeling, oxidative stress response, and lipid metabolism McCarthy et al. Many studies have also found a significant correlation between autistic and ADHD scored traits. Nijmeijer et al. A study investigating the overlap of pathological structural variants in ADHD and ASD found significant overlap in genes related to a wide variety of processes, including the nicotinic receptor signaling pathway and cell division Martin et al.
Since ASD is a multigenic and highly heterogeneous disease that often co-occurs with other conditions, it can be difficult to distinguish which genes truly have overlapping risk for multiple psychiatric conditions, and which variations are responsible for the common disease phenotypes.
For example, the ubiquitin ligase gene UBE3A is implicated in both autism and Angelman Syndrome, a condition distinct from ASD but with similar symptoms, such as movement and speech defects. Interestingly, Angelman Syndrome is generally associated with UBE3A deletions, while ASD can be caused by duplications — yet the same individual can be diagnosed with both syndromes Peters et al.
Multiple studies have found that ASD and intellectual disability share risk loci Pinto et al. Similarly, other risk genes for ASD are epigenetic regulators whose effectors are associated with different diseases Samaco et al.
The interaction and overlap between psychiatric disorders is complex, and much is left to discern regarding shared disease mechanisms. Though significant progress has been made in determining genetic causes of ASD, many aspects of how pathogenic variants regulate genetic susceptibility remain unknown.
Individuals with the same variants can have widely heterogeneous disease presentations and levels of disability. Presence of second modulating variants that may interact with other susceptibility loci are one possible explanation of this heterogeneity. To date, genetic evidence supporting a multiplex theory of autism has primarily been found for germline second-hits. These investigations of how non-causative variants may modify the ASD phenotype are challenging to undertake, as few autistic individuals have the same pathogenic variants.
One way to circumvent these issues is to investigate an autism subtype with a monogenic cause, such as Rett Syndrome. Artuso et al. Another valuable approach is to assess monozygotic twins with a discordant phenotype. Several studies have assessed potential differences in CNVs or epigenetic regulation in discordant monozygotic twins, revealing potential methylation pattern differences in one case and anomalies in the 2p However, a study involving twin pairs failed to find differences in CNVs that could explain the discordant phenotypes Stamouli et al.
The authors still acknowledge postzygotic mosaicism as a potential modifier and encourage more studies to help develop a clearer understanding of CNV modulating activity. For example, Girirajan et al. In the same year, a study of SHANK2 pathogenic variants found abnormalities in both individuals with neuropsychiatric disease and controls, suggesting the presence of additional variants in order to cause disease.
Barber et al. Included in these hypothesized modifier regions were genes G protein regulated inducer of neurite outgrowth 2 GPRIN2 — previously implicated as a modifier in the study by Artuso et al. More recently, an analysis of 20, patient records revealed 19 patients with CNVs in contactin 6 CNTN6 , a gene hypothesized to be involved in neurodevelopmental disorders including ASD Repnikova et al. The authors were not able to find any significant genotype-phenotype relationships and concluded that CNV in CNTN6 were likely benign or modifying, but not causative of disease.
In addition to CNVs, there may be thousands of smaller pathogenic variants — such as SNPs and indels — that also modulate severity. For example, in a study of developmental delay, individuals that only carried a specific 16p One study of individuals with 22q Bonnet-Brilhault et al. Therefore, other variants which are not causative by themselves are not often emphasized or even reported. The emerging study of all types of genetic modifiers is a relatively recent development, and continuing advancements in sequencing technology, analyzing software, and expansion of databases should lay the framework for significant advancements in the near future.
Environmental factors — likely acting through epigenetic regulation as the major mechanism — presumably compromise the remainder of the risk. Hundreds of potential environmental factors have been suggested to contribute to risk, such as increased parental age especially paternal , maternal complications or infections during pregnancy, or prenatal exposure to anticonvulsants Rasalam et al. In-depth reviews of these findings can be found elsewhere Gardener et al.
In this review, we will only discuss the epigenetic modifying effects of valproic acid — an anticonvulsant — as one example of the widespread modifications that an environmental factor can induce.
Valproic acid has been hypothesized to modify gene expression through histone deacetylase inhibition activity and is sometimes used to induce an autistic phenotype in animal models Kataoka et al. In more thorough studies of the mechanism of action, Go et al. Finally, Kolozsi et al. Examples of other proposed environmentally modulated mechanisms of ASD risk exist, but the literature supporting valproic acid is an excellent example of the heterogeneous effects one environmental factor can induce.
Further research is strongly needed to determine how the environment modulates ASD risk. Clearly, epigenetics can have a profound impact on the transcriptome of an organism. Pathogenic variants in even one epigenetic-regulating gene or effects from the environment can cause widespread gene dysregulation.
Epigenetic modulators can themselves be causative of disease, but they may also exacerbate or ameliorate the disease phenotype by influencing expression of risk genes. More genome-wide studies are needed to understand the common ASD epigenome, and whether certain epigenetic markings might be protective or detrimental to individuals who are genetically susceptible.
In addition, more studies are needed to decipher epigenetics as a link between environmental risk factors and genetic susceptibility. There is a possibility that certain environmental factors could have protective epigenetic effects, providing potential avenues for therapy. It is well established that ASD affects males at much higher rates than females. The reasons for this are not yet completely clear. Some studies argue that differential expression between genders may result in an under-diagnosis of females, as males tend to present more external behavior e.
This may be due to influence from hormones, genetics, or other unknown factors. The genetically heterogeneous nature of ASD makes it likely that all these elements are involved — sex bias varies drastically based on factors such as which CNVs are causative or which comorbidities are present, suggesting diverse means by which a sex bias may occur Amiet et al.
Potential mechanisms of sex-specific modulation will be discussed briefly, although more thorough reviews are available elsewhere Ferri et al. Multiple studies argue that the female sex is protective toward ASD susceptibility Robinson et al. For example, the average mutational burden in diagnosed females is much higher than in males, suggesting that males have a lower mutational burden threshold Jacquemont et al.
Another study by Robinson et al. Many investigations have also found that unaffected mothers may carry the same mutation as their affected male children. One particularly well-documented example for this is the 15q duplication Cook et al.
It is also possible that the female sex is not protective, but males are particularly vulnerable. Three studies of gene expression patterns noted males generally had a higher expression of genes implicated in ASD, such as chromatin regulators and genes related to immune involvement Ziats and Rennert, ; Shi et al.
A study with rat models of ASD reported male-specific downregulation of MeCP2 leading to abnormal glutamate activity, providing another potential mechanism for male-specific vulnerability Kim et al. Interestingly, multiple studies have found decreased levels of aromatase — an enzyme that catalyzes the conversion of testosterone to estradiol — in the brains of adolescent ASD individuals Sarachana et al.
Hu et al. Of course, there may also be a combination of female-specific protective and male-specific deleterious effects. For example, Jung et al. While male mice demonstrated abnormal social behaviors such as isolation-induced self-grooming, female behavior was similar to controls. Neuronal excitability was also enhanced in males and suppressed in females. Transcriptomes were distinct, with female mice revealing an enrichment for ECM molecules, likely providing a protective effect.
A likely mechanism of divergent modulation is from differential effects of sex hormones, which have been hypothesized to play an important role in ASD pathology for both males and females Baron-Cohen et al.
For example, testosterone and estrogen have been shown to have contrasting effects on the immune system Lenz et al. Schwarz et al. Spine density, another phenotype strongly implicated in autism Comery et al. It is not yet clear whether the majority of differences between male and female presentation of ASD arise from differential regulatory actions of sex hormones or from other modifiers, but the presence of a sexually dimorphic phenotype is well established.
Future research will likely elucidate a clearer picture of the identity and mechanisms of sex-specific modifiers. When autism was first described, it was hypothesized to be an environmentally caused disease. Decades of research have since revealed that autism is a highly heterogeneous and extremely complex genetic condition.
Even though great progress had been made in identifying hundreds of risk genes, very little is known about the different types of modifiers that may exacerbate or ameliorate disease severity. Such modifiers could include epigenetics, sex-linked modifiers, CNVs, double-hit mutations, or environmental factors see Figure 1.
Figure 1. Genetic modifiers in autism spectrum disorder. However, both genetic and non-genetic factors modulate the penetrance of risk genes, resulting in a highly heterogeneous disease phenotype for similar pathogenic variants. Examples of genetic modulators include CNV, epigenetics, and double-hit mutations. Examples of non-genetic modifiers include environmental exposures and sex-linked modifiers.
It may take many more decades of research before the scientific community has an accurate picture of how these modulators contribute to the etiology of ASD. However, this understanding is critical for the development of effective therapies. Due to the extremely diverse genetic phenotype of patients, personalized medicine may be a future avenue for maximally effective treatment. A condensed series of genetic tests — such as a microarray with identified risk loci — could be an expedient and cost-effective solution to determining genetic etiology.
Alternatively, therapies may be developed to address convergent disease phenotypes that encompass multiple genetic etiologies, such as neuronal hyperexcitability and abnormal synaptic function. Autism research has come astonishingly far in just a half a century. There is much more work to be done, but continued investigation will eventually lead to a cohesive understanding of the interplay between causative genetic factors and disease modifiers in the etiology of ASD.
LR contributed to writing the main text and gathering all references. AG-G contributed to editing the manuscript drafts and providing insight into structure and material that should be included. This work was supported by start-up funds from the Feinberg School of Medicine, Northwestern University. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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If they can match a gene to the missing section of the chromosome, they may be able to uncover how the gene changes the body to cause autism. These findings may also lead to treatments that correct the changes caused by the missing chromosome piece. Researchers at the University of Rochester School of Medicine and Dentistry in Rochester, New York, found that nearly 40 percent of people with autism in their study had a change in their gene linkage that could be a factor in causing their autism Ingram The sequence or pattern of your genes controls how your body builds its parts.
An alteration in that sequence changes how your body and mind are built, which may lead to autism. Specifically, 39 percent of the people with autism in the study had a change in one of the two copies of the HOXA1 gene, which is located on Chromosome 7. Remember that chromosomes come in pairs, which means your cells have two copies of every gene.
The percentage of people who had the change in one of their genes, but did not have autism and were not related to anyone with autism, was much lower only 22 percent. Because twice as many people with autism had the gene change when compared with people who did not have autism but had the gene change, the HOXA1 gene could play a role in causing autism. In addition, 33 percent of people in the study, who did not have autism, but were related to someone with autism, also had the change in their gene, which supports the idea that the HOXA1 gene plays a role in causing autism.
These findings suggest that the genetic sequence of these families is linked to autism and autism-like symptoms in some way. Scientists need to do more studies to find out just what that link is. But scientists don't think that the change in the HOXA1 gene by itself causes autism.
If the gene change was the only cause, then everyone who had that change would be diagnosed with autism. Because this is not the case, scientists think that the HOXA1 gene is only one of many genes that may contribute to the autism. HOX is short for homeobox, a word that scientists use to describe the group of genes that control growth and development very early in life.
HOX genes act like the director of a movie in that they tell other genes when to act and when to stop during development. You have 38 different HOX genes spread out among your chromosomes that direct the action of your other genes to form your body.
These genes are active very early in human growth, before a baby is born. From studies on growing infants, doctors know that the HOXA1 gene does its directing very early in human development-between the 20th and 24th day of conception. Most women don't even know they are pregnant when the HOXA1 gene is working. HOXA1 controls the genes that make the building blocks for the central nervous system, which includes the brain and the spinal cord.
A change in this gene could also change the way the body builds its nervous system, which in turn could lead to autism. The CPEA Network is looking at other genetic mechanisms that may account for why different genetic defects related to autism seem to be found across different studies. Researchers in the Network will share their information and their methods to see if other researchers get the same results in other people with autism. Having several scientists get the same results "confirms" that discovery.
Every cell in our body has two sex chromosomes. Females have two X chromosomes, and males have one X and one Y. Previous studies have linked mutations in a gene called NLGN4 to autism.
NLGNs are important for establishing and maintaining synapses, the places where communication signals are sent between brain cells called neurons.
A team of researchers led by Drs. Thien A. Affected individuals often dwell on or repeatedly express particular thoughts; this behavior is called perseveration.
People with ASD tend to be rigid about their established routines and may strongly resist disruptions such as changes in schedule.
They may also have difficulty tolerating sensory stimuli such as loud noises or bright lights. While social and communication difficulties and unusual behaviors define ASD, affected individuals can have a wide range of intellectual abilities and language skills. A majority of people with ASD have mild to moderate intellectual disability, while others have average to above-average intelligence. Some have particular cognitive abilities that greatly surpass their overall level of functioning, often in areas such as music, mathematics, or memory.
Some people with ASD do not speak at all, while others use language fluently. However, fluent speakers with ASD often have problems associated with verbal communication. They might speak in a monotone voice, have unusual vocal mannerisms, or choose unusual topics of conversation.
Several diagnoses that used to be classified as separate conditions are now grouped together under the diagnosis of ASD. For example, autistic disorder was a term that was used when affected individuals had limited or absent verbal communication, often in combination with intellectual disability.
By contrast, Asperger syndrome was a diagnosis formerly applied to affected individuals of average or above-average intelligence who were not delayed in their language development. The broader diagnosis of ASD was established because many affected individuals fall outside of the strict definitions of the narrower diagnoses, and their intellectual and communication abilities may change over time. However, some individuals who were previously diagnosed with one of the subtypes now do not meet all the criteria of the new umbrella diagnosis.
ASD is a common condition, and the number of children diagnosed with ASD has been increasing rapidly in the past few decades. The prevalence of the disorder in the United States is estimated at 1 in 59 children.
In the s, before the term ASD was used, the prevalence of autism was reported to be about 1 in 2, However, it is unclear whether this represents a true increase in the prevalence of ASD or reflects changes in the way behaviors characteristic of the disorder have been diagnosed and categorized.
Changes in over 1, genes have been reported to be associated with ASD, but a large number of these associations have not been confirmed. Many common gene variations are thought to affect the risk of developing ASD, but not all people with one or more of these gene variations will be affected. Individually, most of the gene variations have only a small effect. Genetic factors are estimated to contribute 40 to 80 percent of ASD risk. The risk from gene variants combined with environmental risk factors, such as parental age, birth complications, and others that have not been identified, determine an individual's risk of developing this complex condition.
By contrast, in about 2 to 4 percent of people with ASD, rare gene mutations or chromosome abnormalities are thought to be the cause of the condition, often as a feature of syndromes that also involve additional signs and symptoms affecting various parts of the body. In addition to ASD and intellectual disability, this condition involves distinctive facial features and a wide variety of other signs and symptoms. In most individuals with ASD caused by rare gene mutations, the mutations occur in only a single gene.
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