Genetic Test for Autism

Predicting the diagnosis of autism spectrum disorder using gene pathway analysis

Full Paper Link.

Autism spectrum disorder (ASD) depends on a clinical interview with no biomarkers to aid diagnosis. The current investigation interrogated single-nucleotide polymorphisms (SNPs) of individuals with ASD from the Autism Genetic Resource Exchange (AGRE) database. SNPs were mapped to Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived pathways to identify affected cellular processes and develop a diagnostic test.

This test was then applied to two independent samples from the Simons Foundation Autism Research Initiative (SFARI) and Wellcome Trust 1958 normal birth cohort (WTBC) for validation. Using AGRE SNP data from a Central European (CEU) cohort, we created a genetic diagnostic classifier consisting of 237 SNPs in 146 genes that correctly predicted ASD diagnosis in 85.6% of CEU cases. This classifier also predicted 84.3% of cases in an ethnically related Tuscan cohort; however, prediction was less accurate (56.4%) in a genetically dissimilar Han Chinese cohort (HAN).

Eight SNPs in three genes (KCNMB4, GNAO1, GRM5) had the largest effect in the classifier with some acting as vulnerability SNPs, whereas others were protective.

Prediction accuracy diminished as the number of SNPs analyzed in the model was decreased. Our diagnostic classifier correctly predicted ASD diagnosis with an accuracy of 71.7% in CEU individuals from the SFARI (ASD) and WTBC (controls) validation data sets.

In conclusion, we have developed an accurate diagnostic test for a genetically homogeneous group to aid in early detection of ASD. While SNPs differ across ethnic groups, our pathway approach identified cellular processes common to ASD across ethnicities. Our results have wide implications for detection, intervention and prevention of ASD.



From the study –

“The SNPs contributing most to diagnosis in our classifier corresponded to genes for KCNMB4, GNAO1, GRM5, INPP5D and ADCY8.

KCNMB4 is a potassium channel that is important in neuronal excitability and has been implicated in epilepsy and dyskinesia.*

GNAO1 has also been shown to have a role in nervous development.

Function: There are 55 articles specifically referring to this gene in PubMed. Functionally, the gene has been tested for association to diseases (Carcinoid Tumor; Carcinoma, Small Cell; Lung Neoplasms; Pregnancy Complications), proposed to participate in pathways (Chagas disease, Long-term depression, Melanogenesis) and processes (aging, cellular process, dopamine receptor signaling pathway, forebrain development, locomotory behavior and 10 others). (

GRM5 is highly expressed in hippocampus, inferior temporal gyrus, inferior frontal gyrus and putamen, regions implicated in ASD brain MRI studies. GRM5 has a role in synaptic plasticity, modulation of synaptic excitation, innate immune function and microglial activation

With regard to GRM5’s involvement with neuroimmune function, this receptor is expressed on microglia,with microglial activation demonstrated by us and others in frontal cortex in ASD.

INPP5D – ( also named as SHIP, SHIP1, SIP-145 and hp51CN… INPP5D acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells.

INPP5D regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance.**


– membrane-bound, calcium inhibitable adenyl cyclase involved in learning, memory, drug dependance

– with ADCY1, are the only cyclases stimulated by calcium and calmodulin, making them uniquely poised to regulate neuronal development and neuronal processes such as learning and memory

– plays a particularly important role in rapidly resetting the balance of active to silent synapses after adaptation to strong activity

– Ca2+-stimulable adenylate cyclase, interacting with an AKAP and role for AKAP5 in the attenuation of Ca2+-dependent ADCY8 activity

– essential component of a signaling pathway that opposes repellent signaling, and helps regulate retinal sensitivity to midline guidance cues


* Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.


We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable.


The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.


*Dyskinesia ( is a movement disorder which consists of adverse effects including diminished voluntary movements[1] and the presence of involuntary movements, similar to tics or chorea. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but can also be seen in the lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognised.[2] Dyskinesia is a symptom of several medical disorders and is distinguished by the underlying cause.


** Expression Profiling of Autism Candidate Genes during Human Brain Development Implicates Central Immune Signaling Pathways

“Interestingly, there is also mounting evidence at the cellular and tissue levels that more in depth investigation of an immune component is warranted in ASD [46]. For instance, multiple studies have demonstrated altered cytokine profiles in ASD patients [47], [48], and altered TGF-B concentration in serum and CSF correlates with disease severity [49]. Others have described various autoimmune phenomena including autoantibodies to neural antigens and maternal-fetal cross-reactive neural antibodies [50]. There is also indication of altered innate cellular immunity in ASD, such as differences in gene expression and altered response to immunostimlulatory ligands in both natural killer and monocytic cells from ASD patients [51], [52]. Post-mortem brain tissue from ASD patients shows increased microglial density in grey matter, an activated morphology, and secretion of a cytokine profile consistent with a pro-inflammatory state, most prominent in the cerebellum [53], [54]. Moreover, microglia from MeCP2- null mice—a model of the Autism Spectrum Disorder Rett Syndrome—produce a conditioned media that damages synaptic connectivity via a glutamate-excitotoxicity mechanism [55]. While all of this work provides post-hoc evidence for altered immune response in ASD, our results suggest a direct link between implicated genes in ASD and molecular pathways involved in immune signaling.

This considerable attention to the immune response in previous ASD research has resulted in two prevailing theories: one suggests exogenous factor(s) stimulate neuro-inflammation during development, while the other postulates autoimmune activation causes ASD pathology [56], [57]. However, it is equally possible—as our results support—that the mutations described in ASD result in aberrant signaling regulation of immune cells during neurodevelopment. This could result in cell-autonomous activation and/or improper response to otherwise nominal stimuli, such as occurs in the autoinflammatory syndromes [58]. Alternatively, as glia are increasingly implicated in normal formation of synaptic connectivity [24]—and we have demonstrated a significant proportion of ASD-implicated genes appear to be glial-specific—it is possible that genomic aberrations ultimately funnel through core signaling pathways of glial cells to disrupt formation of neural networks independent of an inflammatory mechanism. In support of this notion, a number of recent reports have demonstrated that these same cytokine signaling pathways are central to proper brain development [59], [60]. Furthermore, signaling through the NFkB pathway has been shown to be important in synaptic plasticity independent of an inflammatory mechanism [61].

Moreover, two of three genome-wide expression studies in Autism brain tissue conclude that the most prominent transcriptome changes are related to neuro-immune disturbances. In the Garbett et al study, the most significant functional pathway implicated was NFκB signaling [31]. The most comprehensive transcriptomics study of ASD post-mortem brain to date (Voineagu et al) concludes that one of two significant co-expression networks is involved in immune function [32]. While our results are only a first step in linking common molecular interaction pathways to the underlying genetic heterogeneity of ASD, they provide integrated genomic evidence, which is supported by these transcriptomics, cell, and tissue level studies that further investigation into cytokine signaling in ASD is needed.

In summary, we report the spatial and temporal expression profile of genes implicated in Autism Spectrum Disorders, in addition to the genetically and phenotypically related neurodevelopmental disorders Schizophrenia and Epilepsy. We found a large proportion of implicated genes are not expressed in the developing human brain, and a significant number appear to be mainly expressed in glial cells. Integrated gene-network analysis, gene ontology enrichment, and canonical pathways investigation of a subset of highly expressed ASD genes all implicate central immune signaling pathways as common to the heterogeneous interactome of the implicated genes. This work serves as a framework to link the genetic findings in ASD with transcriptome, cell, and tissue level evidence for altered immune functions in ASD patients.

This entry was posted in Autism, co-morbid, Epigenetics, Genetics, Immune System, Inflammation, Neurology, Physiology, Schizophrenia and tagged , , , , , , , , , , . Bookmark the permalink.

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