Association of Transcription Factor Gene LMX1B with Autism

Ismail Thanseem,Shiro Suda,Kazuhiko Nakamura,Ayyappan Anitha,Masatsugu Tsujii,Yoshimi Iwayama,Takeo Yoshikawa,Tomoko Toyota,Yasuhide Iwata,Hideo Matsuzaki,Norio Mori,Katsuaki Suzuki,Toshiro Sugiyama,Keiko Iwata,Kazuo Yamada,Kenji Hashimoto

doi:10.1371/journal.pone.0023738

Abstract

Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report.

Highlights

Autism and other developmental disabilities, clinically referred to as autism spectrum disorders (ASDs), are characterized by impairments in communication skills and social interaction, and the presence of repetitive stereotyped behaviors and interests
The results of transmission disequilibrium test (TDT) analysis are shown in Table 1. rs10732392 (p = 0.018; OR = 1.764; 95% CI for OR 1.095–2.842) and rs12336217 (p = 0.022; OR = 1.748; 95% CI for OR 1.076– 2.841) showed significant associations with autism
We examined the association of the transcription factor gene LMX1B with autism in Caucasian population

Summary

Introduction

Autism and other developmental disabilities, clinically referred to as autism spectrum disorders (ASDs), are characterized by impairments in communication skills and social interaction, and the presence of repetitive stereotyped behaviors and interests. It is typically diagnosed by the age of three and has a prevalence rate of 60-70 per 10,000 children in broader diagnostic criteria as per the most recent estimates [1]. Candidate gene and whole genome association studies have suggested several genes and chromosomal regions associated with the disorder None of these known causes individually account for more than 1–2% of the cases, and specific genetic mechanisms underlying the heritability of the disorder still remain largely cryptic. It was found that many different genetic changes in unrelated genes can cause indistinguishable ASD features; this genetic heterogeneity necessitate the need to look for more potential candidate genes associated with the disorder

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Conclusion