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Autism and genetics

The study of genetics and autism is by far the most prevalent area of autism biology research. As autism has thus far been shown to be highly heterogenous, we cannot adequately cover all the findings here.  A consensus has emerged across numerous studies in the past decade; that autism is a most likely a combination of genetic and environmental factors

Hundreds, possibly even thousands of genes, may be implicated in autism.

Some general findings:

     - large numbers of copy number variants (CNV) have           been found

     - de novo mutations are common

     - mutations or epigenetic changes in genes impacting

       brain structure, synapse formation, neuronal                      signaling, increased oxidative stress, and multiple            metabolic and biological functions.

Thousands of published papers on autism and genetic findings can be found on Pub Med. Please see links below to gene based research collections for more in-depth information.

Selected Studies

"In conclusion, bio-collections have been shown as valuable resources and enabled large-scale studies on ASD. The recent genetic studies have begun to reveal de novo mutations on major cellular pathways [17177]. There is also emerging evidence that ASD continuum contains subgroups with discrete mutations in specific genes such as CDH8 [88], DYRK1A [71] and POGZ [90] and gene mutations like NRXN1 [286073178179] and SHANKs [7298114123] recurring in broad populations. There is a vast amount of clinical and biological information available in these bio-collections, and the data are in the need for concrete guidelines on ethics and governance. The communication and trust shall be maintained between the researchers and families who have given biological and personal information. Finally, the availability of iPSC resources dedicated to idiopathic and syndromic forms of ASD could be a tremendous boon to the research community and such models are anticipated to be complementary with animal models and to speed up the development of therapeutic interventions for ASD."

Reilly J, Gallagher L, Chen JL, Leader G, Shen S. Bio-collections in autism research. Molecular Autism. 2017;8:34. doi:10.1186/s13229-017-0154-8.

 "We have pinpointed several novel co-expression signals that show strong evidence for replicable dysregulation across datasets [2021]. Rather than pinpointing a single synaptic or immune-related module, we have identified several dysregulated synaptic and immune modules. These modules are differentiated in terms of cell type/compartment enrichment and/or show different biological process enrichment within the broader class of synaptic and immune-related processes. For example, while both M3 and M9 modules are downregulated in ASD and enriched in similar synaptic processes, their cell type/compartment enrichments differ. M3 is primarily enriched in neuronal markers, whereas M9 is specifically enriched in synaptic and postsynaptic density markers. Synaptic M3 and M9 modules also differentiate in how they interact with other modules (see Fig. 7c, d for example). These results provide an example of how subtle distinctions may be present within the class of downregulated synaptic signals.

We have also identified multiple types of ASD-upregulated immune/inflammation modules that are novel distinctions from past work. Although prior work has implicated interferon signaling, particularly with respect to M2 microglia markers [20], here, we find evidence for two upregulated interferon signaling modules (M24, M27). These modules differentiate by M1 and M2 microglia activation states, with M27 enriched in M1 microglia markers while M24 is enriched in M2 microglia markers. Between-module connectivity evidence also suggests that these two interferon signaling modules are disrupted in different ways. M27 is abnormally connected to an important ASD-upregulated translation initiation (M25) and ASD-downregulated synaptic module (M9). Given the enrichment in M27 for M1 microglia activation markers, this evidence suggests that cytotoxic M1 microglia processes may be affecting synaptic proteins in ASD. On the other hand, M24 shows intact connectivity between M25 and M9 but aberrant connectivity between other modules (M2, M22). These results suggest that while upregulated interferon signaling can be linked to both M1 and M2 microglia phenotypes, such aberrant processes may have differing impact on ASD brain function and structure."

Lombardo, M. et al "Hierarchical cortical transcriptome disorganization in autism" Molecular Autism

Brain, Cognition and Behavior June 2017 8:29

"Our analyses of both human brain and experimental models constitutes the largest WGBS study of ASD to date, providing over 5 billion uniquely alignable reads across 41 brain and 23 cell culture samples, analyzed by complementary bioinformatics approaches for identifying differential methylation (summarized in Supp Data 1, Table S15). As a focused investigation on the brain and neuronal DNA methylome, this study provides several important insights into genes, gene pathways, genome stability, and chromatin modulation in the complex etiology of ASD. First, by investigating an interaction between Dup15q syndrome and PCB 95 exposures, we identify differentially methylated genes in common between brain and different experimental models, as well as with genes in common with rare genetic variants observed in ASD. Second, through long-term cloning of Dup15q neuronal cell lines with PCB 95 exposure, we investigated the impact of global hypomethylation on genome instability in the acquisition of a second genetic hit of chromosome 22q duplication on the epigenome. Third, we explore a possible mechanistic connection for maternal UBE3A overexpression and PCB 95 on RING1B and histone H2A.Z epigenetic modifications. Together, these results demonstrate a cumulative effect of large chromosome duplications and PCB 95 exposure on genes with functions at neuronal synapses, transcriptional regulation, and signal transduction pathways."

Dunaway, Keith W. et al. “Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes.” Cell reports 17.11 (2016): 3035–3048. PMC.

"Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1)...Overall, through an integrative analysis of de novo mutations in ASD, we further clarify the genomic architecture of ASD, estimating that 50% of dnCNVs/dnLoFs mediate ASD risk, that more than 200 CNV risk loci and 800 risk genes are vulnerable to de novo mutation, and that de novo mutations contribute to the ASD phenotype in at least 11% of simplex ASD cases."

Sanders, Stephan J. et al. “Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.” Neuron 87.6 (2015): 1215–1233. PMC. 

"However, genome-wide association studies have amassed evidence suggesting involvement of hundreds of genes and a variety of associated genetic pathways. Recently, investigators have turned to epigenetics, a prime mediator of environmental effects on genomes and phenotype, to characterize changes in ASD that constitute a molecular level on top of DNA sequence. Though in their infancy, such studies have the potential to increase our understanding of the etiology of ASD and may assist in the development of biomarkers for its prediction, diagnosis, prognosis, and eventually in its prevention and intervention. This review focuses on the first few epigenome-wide association studies of ASD and discusses future directions...To date, hundreds of genes have been linked to ASD using such approaches. However, reproducible genetic variants have been linked with a very small percentage of cases of non-syndromal ASD. Although this underscores the phenotypic heterogeneity of ASD, we now know that common variants of small effect and rare and de novo variants of large effect can combine to influence risk for ASD (12)...Epigenetic load (from prenatal environment and stochastic variation) and genetic load (from familial and de novo variation) interact to compromise neurodevelopmental, immune, oxidative stress, and mitochondrial pathways identified through studies of ASD genetics, physiology, expression, and/or methylation... Further interactions will occur between specific genes and specific prenatal environments. Over a certain threshold of genetic and epigenetic dysfunction, development is decanalized and neurodevelopment disrupted. This includes defects in synaptic function, connectivity, and morphogenesis and would lead to abnormal brain maturation, neural circuity dysfunction, characteristic endophenotypes of ASD. Further, postnatal environments may also contribute to severity of symptoms."

Loke, Yuk Jing, Anthony John Hannan, and Jeffrey Mark Craig. “The Role of Epigenetic Change in Autism Spectrum Disorders.” Frontiers in Neurology 6 (2015): 107. PMC.

"Our analysis of ASD and ID suggests two fundamentally distinct modules with different properties and phenotypic manifestations. The M1_Extended module is significantly enriched in genes with chromatin remodeling function and includes many genes encoding the SWI/SNF complex as well as genes associated with NCOR/HDAC3, Notch, and Wnt signaling pathways. Genes within this module show the highest level of expression early in development (8–16 pcw). In contrast, the M2_Extended module is enriched in synaptic genes associated with long-term potentiation/calcium signaling and shows the highest level of expression postnatally (birth to 1 yr) as has been observed for other networks (Willsey et al. 2013). Patients with LoF mutations within M2 are much more likely to be intellectually disabled (IQ < 70) when compared to M1. Although the M1_Extended module is more strongly associated with autism, the proportion of de novo truncating mutations in that module (27%) among high-functioning autism individuals (IQ > 70) decreases compared to those that are intellectually disabled (40%)"

Hormozdiari, Fereydoun et al. “The Discovery of Integrated Gene Networks for Autism and Related Disorders.” Genome Research 25.1 (2015): 142–154. PMC. 

"In this study, we provide transcriptomic evidence for type I interferon and M2-activation state abnormalities in autism that may lead to a variety of pathologic and phenotypic consequences. We further note that there is a strong negative correlation between two differentially co-expressed modules, mod5 (activated M2-state microglia genes) and mod1 (synaptic transmission genes; r=−0.92, Supplementary Data 14). Recently, microglia have been identified as cells capable of restoring neural function in the ASD-model MECP2 knockout mice37. We observe, for the first time, that M2-activation state microglia genes, in particular, are altered in autism, potentially driven by type I interferon responses. This process may drive changes in neural progenitor cell proliferation and connectivity with resultant altered activity-dependent neural expression profiles in post-natal development38,39. The linkage of this pathway to autism may lead to more accurate and predictive models of idiopathic disease that might contribute to the identification of effective therapeutic approaches."

Gupta, Simone et al. “Transcriptome Analysis Reveals Dysregulation of Innate Immune Response Genes and Neuronal Activity-Dependent Genes in Autism.” Nature Communications 5 (2014): 5748. PMC.

"To further study the relationship between DNA methylation and gene expression, we performed RT–PCR analysis on a subset of genes that displayed dysregulated methylation at multiple CpG sites. We found that out of 17 genes that we tested, 12 displayed differential expression between control and autism groups (Figure 3Supplementary Figure 5). Among these, C1qA, C3, ITGB2, TNF-α, IRF8, SPI1, PTPN6 and HLA-DMB were significantly overexpressed and showed highly significant inverse correlation between DNA methylation and gene expression (Figure 3Supplementary Table 11). From the 17 genes we tested, 48 out of 93 CpG sites displayed a significant correlation between methylation levels and gene expression (Supplementary Table 11). However, of the 12 genes that displayed dysregulated gene expression in our RT–PCR analysis, the DNA methylation of 42 out of 61 CpGs was significantly correlated with gene expression. Therefore a subset of CpGs may have a significant influence on gene expression. Our expression data strongly indicates the presence of an altered immune response in the autistic brain that correlates well with epigenetic modulation of genomic regions relevant to immune function. To strengthen this hypothesis, we further explored the inflammatory status of the autistic brain by checking for expression of classic inflammatory markers. We found IL-1b and IBA-1, a marker of microglia activation, increased in autism brain."

Nardone, S et al. “DNA Methylation Analysis of the Autistic Brain Reveals Multiple Dysregulated Biological Pathways.” Translational Psychiatry 4.9 (2014): e433–. PMC. 

"While the etiopathogenesis of ASDs remains elusive and controversial, it is now well recognized that ASDs involve the complex interaction of several genes and environmental risk factors [9,10,11]. As ASDs result from a complex combination of genetic, epigenetic, environmental (i.e., infections, toxins, air pollution, organophosphates, heavy metals, stressors), and immunological factors, these pathologies could be referred as multifactorial and polygenic disorders [12,13,14]. It seems likely that epigenetic dysregulation might contribute to significant proportion of ASD cases [15]. Even if specific chromosomal regions have been identified in autism-susceptibility loci, the results have been inconclusive, and the identification of the underlying genes has failed to produce a substantial causal linkage [16]. No single gene can account for more than 1% of the cases of ASDs."

Siniscalco, Dario et al. “Epigenetic Findings in Autism: New Perspectives for Therapy.” International Journal of Environmental Research and Public Health10.9 (2013): 4261–4273. PMC.

"The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models..., whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism."

Pu, D., Shen, Y. and Wu, J. (2013), Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis. Autism Res, 6: 384–392. doi:10.1002/aur.1300

"Multiple studies have confirmed the contribution of rare de novo copy number variations (CNVs) to the risk for Autism Spectrum Disorders (ASD).1-3 While de novo single nucleotide variants (SNVs) have been identified in affected individuals,4 their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations has not been well characterized in matched unaffected controls, data that are vital to the interpretation of de novo coding mutations observed in probands. Here we show, via whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with ASD and carry large effects (OR=5.65; CI: 1.44-22.2; p=0.01 asymptotic test). Based on mutation rates in unaffected individuals, we demonstrate that multiple independent de novo SNVs in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (Sodium Channel, Voltage-Gated, Type II, Alpha Subunit), a result that is highly unlikely by chance (p=0.005)."

Sanders, Stephan J. et al. “De Novo Mutations Revealed by Whole Exome Sequencing Are Strongly Associated with Autism.” Nature 485.7397 (2012): 237–241. PMC. Web.

"Our system-level analysis of the ASD brain transcriptome demonstrates the existence of convergent molecular abnormalities in ASD for the first time, providing a molecular neuropathological basis for the disease, whose genetic, epigenetic, or environmental etiologies can now be directly explored. The genome-wide analysis performed here significantly extends previous findings implicating synaptic dysfunction, as well as microglial and immune dysregulation in ASD 6 by providing an unbiased systematic assessment of transcriptional alterations and their genetic basis. We show that the transcriptome changes observed in ASD brain converge with GWAS data in supporting the genetic basis of synaptic and neuronal signaling dysfunction in ASD, while immune changes have a less pronounced genetic component and thus are most likely either secondary phenomena or caused by environmental factors. Since immune molecules and cells such as microglia play a role in synaptic development and function26, we speculate that the observed immune up-regulation may be related to abnormal ongoing plasticity in ASD brain."

Voineagu, Irina et al. “Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology.” Nature 474.7351 (2011): 380–384. PMC.  

"The 82 upregulated probes in ASD corresponded to 59 known genes, the majority of which have been ascribed to leukocyte function, more specifically NK cell cytotoxic function (Table 3). Thirty of the 59 genes (42 of the 82 probes) were associated with leukocytes, and 22 of these 59 (37%) were associated with cytolytic cells, predominantly NK cells. There was increased expression for 11 probes for killer cell immunoglobulin receptors (KIR), and 9 of these were probes for inhibitory KIR (long cytoplasmic domains). Additionally, expression of CD94 (2 probes) and CD160 (1 probe), which are both involved in MHC-I recognition and cytolytic activity increased (Barakonyi et al., 2004Terrazzano et al., 2002). The expression of KSP37, a gene restricted to NK cells and co-expressed with perforin during viral infection (Ogawa et al., 2001), increased 2.5-fold. Similarly, the RNA levels for perforin (2 probes), a pore forming protein secreted by activated NK cells, also increased 2.5 fold. The expression of three probes specific for granzymes, which enter the pore formed by perforin to induce apoptosis, were also increased. Thus, a profile indicating paradoxically increased expression of both inhibitory (KIR long cytoplasmic domain) and cytolytic (CD94, CD160, granzymes, perforin) natural killer cell-related genes were identified. Using the up-regulated genes as inputs, functional annotation clusters from the DAVID database strongly supported these findings showing that pathways and functions associated with NK cell-mediated cytotoxicity and antigen presentation were altered in ASD (Table 4). 

Enstrom, A M et al. “Altered Gene Expression and Function of Peripheral Blood Natural Killer Cells in Children with Autism.” Brain, behavior, and immunity 23.1 (2009): 124–133. PMC. 

"The two pathways of transmethylation and transsulfuration are metabolically interdependent such that chronic deficit in glutathione will feed back to inhibit SAM synthesis (Corrales at al. 1991) and create a chronic self-perpetuating cycle that progressively decreases GSH levels. The fact that both pathways were adversely affected in many parents suggests that the initiating factors were chronic in nature.

In summary, we have uncovered a significant metabolic imbalance in transmethylation and transsulfuration pathways in many parents that is similar to the imbalance previously observed in many autistic children."

James, S. Jill et al. “Abnormal Transmethylation/transsulfuration Metabolism and DNA Hypomethylation among Parents of Children with Autism.” Journal of autism and developmental disorders 38.10 (2008): 1966–1975. PMC.

"Cholesterol is essential for neuroactive steroid production, growth of myelin membranes, and normal embryonic and fetal development. It also modulates the oxytocin receptor, ligand activity and G-protein coupling of the serotonin-1A receptor. A deficit of cholesterol may perturb these biological mechanisms and thereby contribute to autism spectrum disorders (ASDs), as observed in Smith-Lemli-Opitz syndrome (SLOS) and some subjects with ASDs in the Autism Genetic Resource Exchange (AGRE). A clinical diagnosis of SLOS can be confirmed by laboratory testing with an elevated plasma 7DHC level relative to the cholesterol level and is treatable by dietary cholesterol supplementation. Individuals with SLOS who have such cholesterol treatment display fewer autistic behaviours, infections, and symptoms of irritability and hyperactivity, with improvements in physical growth, sleep and social interactions. Other behaviours shown to improve with cholesterol supplementation include aggressive behaviours, self-injury, temper outbursts and trichotillomania. Cholesterol ought to be considered as a helpful treatment approach while awaiting an improved understanding of cholesterol metabolism and ASD. There is an increasing recognition that this single-gene disorder of abnormal cholesterol synthesis may be a model for understanding genetic causes of autism and the role of cholesterol in ASD."

Alka Aneja & Elaine Tierney "Autism: The role of cholesterol in treatmentInternational Review of Psychiatry Vol. 20 , Iss. 2, 2008

"Among the autistic children, 9.8% inherited the combined homozygous GG genotypes for COMT and TCN2 (4 mutant alleles) compared to 2.5% of control children, raising the odds ratio to 7.0. Homozygous or heterozygous combinations of RFC G allele and the MTHFR 677 T allele (3–4 mutant alleles) also resulted in significant increases in susceptibility to autism: GA/CT, OR 3.2; GA/TT, OR 4.4; and GG/CT, OR 3.1. There was also a significant interaction between the RFC-1 heterozygous GA and homozygous GG alleles and the GST M1 null genotype (3–4 mutant alleles) with odds ratios of 3.78 and 2.67, respectively. An increase in the frequency of compound heterozygous MTHFR 677CT/1298AC reached borderline significance among the autistic children with an OR of 1.78 and also showed an interaction with the RFC 80 G allele...Thus, the abnormal metabolic profile we have discovered in autistic children is an endophenotype that may reflect subtle changes in gene products that regulate flux through methionine transmethylation and transsulfuration pathways. Even small variations in gene expression and enzyme activity, if expressed chronically, could have a significant impact on downstream metabolic dynamics."

James, S. Jill et al. “Metabolic Endophenotype and Related Genotypes Are Associated with Oxidative Stress in Children with Autism.” American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 141B.8 (2006): 947–956. PMC. 

Glossary of genetic terms:

Genetic architecture: the relative contributions of different forms of genetic variation.

Penetrance: the proportion of mutation carriers who also are diagnosed with the disease or carry a given phenotype.

WES. Whole-exome sequencing—reading only the genetic sequence that encodes for proteins in an organism.

WGS Whole-genome sequencing—reading the entirety of the genetic code of an organism.

De novo mutation: A mutation that is present in the offspring but that was not inherited from either parent.

SNV Single-nucleotide variant: a rare (<1%) or common single-bp change in the genome.

CNV Copy-number variation—deletion or duplication of large genomic regions leading to changes in the number of copies of  the genetic e                  elements encoded within those regions.

Polygenic modelmodel that describes the genetic risk factors of a disease as many inherited variants, each of which 

              contributes a small, additive risk for developing a disease.

Oligogenic model: a model that describes the genetic risk factors of a disease as a few variants, each of which contributes a large risk for                            developing a disease.

Major gene model: a model that describes the genetic risk factors of a disease as due to genetic variants, each of which contributes a large r.                    risk for developing a disease. One major gene mutation is typically considered sufficient to cause a disease in an individual.

SNP Single-nucleotide polymorphisma single bp change that is common (>1%) in the population.

Simplex family; a family in which only one individual is affected with a disease.

Multiplex familya family in which multiple individuals are affected with a disease.

--De la Torre-Ubieta, Luis et al. “Advancing the Understanding of Autism Disease Mechanisms through Genetics.” Nature medicine 22.4 (2016): 345–361. PMC.

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