Association Between 5-HTTLPR Polymorphism and the Risk of Autism: A Meta-Analysis Based on Case-Control Studies

Abstract

Background: Recently, many case-control studies have reported the association between 5-HTTLPR polymorphism and autism risk. However, the results are inconclusive and conflicting. To investigate the genetic association of 5-HTTLPR polymorphism and autism risk, we conducted a comprehensive meta-analysis based on previous case-control studies. Methods: Literature search was performed through PubMed, Embase, Web of Knowledge and CNKI databases until June 27, 2018. The strength of the association was assessed by relative risk (RR) and its corresponding 95% confidence interval (CI). Fixed or random effect model was selected based on the results of heterogeneity test. Further, subgroup analyses were conducted to explore the association of 5-HTTLPR polymorphism and autism risk in different population. Results: Eleven studies with 930 cases and 1234 controls were identified. Although there was a significant association between 5-HTTLPR polymorphism and autism risk under the dominant model after removing the studies causing heterogeneity, the significance did not exist after Bonferroni's correction. Subgroup analyses also showed similar results after Bonferroni's correction. In addition, there was no obvious publication bias in our meta-analysis. Conclusions: Our present meta-analysis does not support a direct effect of 5-HTTLPR polymorphism on autism risk according to present results. Further analyses of the effect of genetic networks and more well designed studies with larger sample size are required.

The role of 5-HTTLPR in autism spectrum disorder: New evidence and a meta-analysis of this polymorphism in Latin American population with psychiatric disorders

“…Replication of results across ethnicities has been postulated as a good strategy to discover true risk variants or to understand if the lack of replication reflects the complexity in the genetic architecture of some complex disorders as ASD [ 64 , 65 ]. Although two meta-analyses recovering case-control studies mainly from European, American, and Asian population did not find association of this polymorphism with ASD, they also confirmed high heterogeneity in the included studies probably explained by population ethnicity [ 27 , 28 ]. These results suggest that the 5-HTTLPR polymorphism varies across ethnicities and the genetic background of each population may have a role in the risk conferred by this polymorphism [ 64 , 65 ].…”

“…The role of 5-HTTLPR polymorphism in the ASD pathophysiology evaluated through casecontrol studies and family-based association have reflected conflicting results. For instance, two studies suggested S allele as risk variant for ASD [15,16], while three meta-analysis did not find association [26][27][28]. We assessed this polymorphism through a case-control approach failing to find association between 5-HTTLPR and idiopathic ASD, and also through a familybased assessment that did not find a preferential transmission of either S or L allele.…”

“…Recognizing the under-representation of Latin American population in studies aimed to understand the role of 5-HTTLPR on worldwide [26,27,29], here we present a meta-analysis including articles which evaluate this polymorphism in Latin American individuals with psychiatric disorders as ASD, bipolar disorder, major depressive disorder, obsessive compulsive disorder, attention deficit hyperactive disorder, schizophrenia, dysthymia, anxiety disorder and suicide [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. Although the S allele has been associated with increased risk for psychiatric disorders [16][17][18][19][20][21]55], our meta-analysis revealed no significant heterogeneity among studies, no publication bias and failed to find an association between 5-HTTLPR and a risk for psychiatric disorders.…”

“…Despite three meta-analysis suggesting that the short/long alleles are not risk factors for ASD [26][27][28], the ethnical heterogeneity among included studies has been proposed as a factor that may affect the overall result. A comprehensive transmission disequilibrium test (TDT) meta-analysis including eighteen studies from diverse populations, demonstrated a non-preferential S/L transmission at the global scale, but preferential transmission of the S and L alleles in the American and Asian populations, respectively [29].…”

Significant associations between 5-hydroxytryptaminetransporter-linked promoter region polymorphisms of the serotonin transporter (solute carrier family 6 member 4) gene and Thai patients with autism spectrum disorder

“…[ 16 – 19 ] Various meta-analyses on this region also failed to identify any correlations to ASD. [ 20 – 22 ] Apart from the L and S alleles, there is an A/G single nucleotide polymorphism in 5-HTTLPR named rs25531 which is a functional polymorphism. Two earlier studies reported that 5-HTTLPR with the L allele and A single nucleotide polymorphism on rs25531 (LA haplotype) had higher expression compared to other haplotypes, [ 23 , 24 ] which could affect serotonin levels.…”