Association of Allelic Variants of the Reelin Gene with Autistic Spectrum Disorder: A Systematic Review and Meta-Analysis of Candidate Gene Association Studies

Abstract

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disability with a genetic basis, and several studies have suggested a potential role of the reelin gene (RELN) in ASD susceptibility. Accordingly, genetic association studies have explored this potential association, but the results have been controversial thus far. For this reason, we assessed the association of four genetic variants of RELN (the 5′UTR CGG triplet repeat and polymorphisms rs736707, rs362691, and rs2229864) with ASD by means of a systematic review and meta-analysis. We retrieved studies comparing the distribution of the above-mentioned genetic variants between ASD patients and healthy controls. A meta-analysis was conducted using a random effects model, and calculations of the odds ratios (ORs) and confidence intervals (CIs) were performed. A sensitivity analysis and tests to determine the heterogeneity of the results were also performed. Eleven previous studies fulfilled the inclusion criteria and analyzed the association of the above-mentioned genetic variants and ASD. We did not find any significant association between the allele or genotype frequencies of the analyzed polymorphisms and ASD, and large heterogeneity was found for the rs736707 polymorphism. Moreover, no significant differences were found between the 5′UTR triplet repeat and this disorder. In light of current evidence, no single genetic variant within this gene is clearly associated with the development of ASD, and ethnic differences may explain part of the observed heterogeneity. Larger studies among different ethnic groups are needed to establish the role of specific genetic variants within RELN in the etiology of this disorder.

Genetics of autism spectrum disorder: an umbrella review of systematic reviews and meta-analyses

“…The characteristics of the selected studies are presented in Table 1 . Of the 28 included reviews, eight were on methylenetetrahydrofolate reductase ( MTHFR ) [ 29 – 36 ]; four each on solute carrier family 6 member 4 ( SLC6A4 ) [ 37 – 40 ] and contactin associated protein 2 ( CNTNAP2 ) [ 41 – 44 ]; three each on oxytocin receptor ( OXTR ) [ 45 – 47 ] and reelin ( RELN ) [ 48 – 50 ]; two each on gamma-aminobutyric acid type A receptor subunit beta3 ( GABRB3 ) [ 51 , 52 ], solute carrier family 25 member 12 ( SLC25A12 ) [ 53 , 54 ], and vitamin D receptor ( VDR ) [ 55 , 56 ]; and one on catechol-o-methyltransferase ( COMT ) [ 39 ] (one meta-analysis was on both COMT and SLC6A4 ). These studies were published from 2008 to 2021 and considered the associations between 41 SNPs in nine candidate genes and ASD risk.…”

“…Genetic association studies have been conducted to investigate the associations between SNPs within RELN and ASD with conflicting results. None of the three meta-analyses found significant associations [ 48 – 50 ]. The meta-analysis by Hernández-García et al was retained for further analysis of the original studies after comparing publication years and sample sizes of the three meta-analyses [ 50 ].…”

“…None of the three meta-analyses found significant associations [ 48 – 50 ]. The meta-analysis by Hernández-García et al was retained for further analysis of the original studies after comparing publication years and sample sizes of the three meta-analyses [ 50 ]. Hernández-García et al did not find a significant association between RELN and ASD risk [ 50 ].…”

“…The meta-analysis by Hernández-García et al was retained for further analysis of the original studies after comparing publication years and sample sizes of the three meta-analyses [ 50 ]. Hernández-García et al did not find a significant association between RELN and ASD risk [ 50 ]. In our analysis, because there was no substantial statistical heterogeneity under the five genetic models (all P > 0.10, I 2 ≤ 50%), a fixed model was applied to pool the effect size.…”

Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

“…Increased sera concentrations of MIF are correlated with worsening behavioral assessments in individuals with ASD compared with their unaffected siblings [ 44 ]. Moreover, genes that can affect immune responses, such as PTEN and reelin, have been associated with ASD [ 45 , 46 , 47 , 48 , 49 ], suggesting that multiple susceptibility genes related to innate immune activation and/or the loss of adaptive immune regulation may be involved in the etiology of ASD.…”