Synthesis of genetic association studies on autism spectrum disorders using a genetic model-free approach

Abstract

Background Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous group of neurodevelopmental disorders. Despite the extensive efforts of scientists, the etiology of ASD is far from completely elucidated. In an effort to enlighten the genetic architecture of ASDs, a meta-analysis of all available genetic association studies (GAS) was conducted. Methods We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available case–control GAS of ASDs. The threshold for meta-analysis was two studies per genetic variant. The association between genotype distribution and ASDs was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. Results Overall, 57 candidate genes and 128 polymorphisms were investigated in 159 articles. In total 28 genetic polymorphisms have been shown to be associated with ASDs, that are harbored in 19 genes. Statistically significant results were revealed for the variants of the following genes adenosine deaminase (ADA), bone marrow stromal cell antigen-1 (CD157/BST1), Dopamine receptor D1 (DRD1), engrailed homolog 2 (EN2), met proto-oncogene (MET), methylenetetrahydrofolate reductase (MTHFR), solute carrier family 6 member 4 (SLC6A4), Synaptosomal-associated protein, 25kDa (SNAP-25) and vitamin D receptor (VDR). In the allele contrast model of cases versus healthy controls, significant associations were observed for Adrenoceptor Alpha 1B (ADRA1B), acetyl serotonin O - methyltransferase (ASMT), complement component 4B (C4B), dopamine receptor D3 (DRD3), met proto-oncogene (MET), neuroligin 4, X-linked (NLGN4), neurexin 1 (NRXN1), oxytocin receptor (OXTR), Serine/Threonine-Protein Kinase PFTAIRE-1 (PFTK1), Reelin (RELN) and Ras-like without CAAX 2 (RIT2). Conclusion These significant findings provide further evidence for genetic factors’ implication in ASDs offering new perspectives in means of prevention and prognosis.

The importance of genetics in an advanced integrative model of autism spectrum disorder

“…Recently, the heterogeneity of ASD was confirmed in a large study by Kuo et al [38] . However, genetic ASD research continues as if the role of genes in ASD is causal and not contributive [39] .…”

Association between RIT2 rs16976358 Polymorphism and Autism Spectrum Disorder in Asian Populations: A Meta‐analysis

“…In two distinct GWAS reports, RIT2 gene was identified as a new locus for both Parkinson's disease (PD) and autism spectrum disorder (ASD) [ 9 , 11 , 12 ]. SNP analysis results in each study showed that rs12456492 and rs16976358 were associated with the risk of PD and ASD, respectively.…”

The role of vitamin D deficiency in the development of paediatric diseases

“…In the embryonic brains of individuals with DVD deficiency, the gene expressions of Nurr1 and P57kip2a were reduced, the maturation of DA neurons and DA distribution within the midbrain were inhibited [ 41 ]. The study found that 28 gene polymorphisms were associated with ASD, including the dopamine receptor D1 [ 42 ]. Among 2084 children with ASD (age under six-year-old) in Vineland, 35% were found to have obvious movement difficulties.…”