Other groups also reported overtransmission of the G allele of either rs2056202 or rs2292813, or undertransmission of the A-A haplotype of rs2056202-rs2292813 in autism families. For instance, two independent groups reported overtransmission of the G alleles of two SLC25A12 SNPs in intron 3 (rs2056202) and intron 16 (rs2292813) in autism families. SLC25A12 was initially identified as an autism-susceptibility gene through a linkage-directed association study and replication. SLC25A12 (solute carrier family 25 member 12 OMIM *603667) on chromosome 2q24 encodes aralar, a mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) protein.
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The heterogeneity of ASDs makes it difficult to identify risk alleles, but also supports the validity of a model that requires more than one genetic variant to contribute to the full syndrome of autism. ASDs are highly heritable complex genetic disorders with rare variants, oligogenic inheritance, and interactions between susceptibility alleles. This could be due to the examined SLC25A12 SNPs being in linkage disequilibrium with another risk allele, and/or genetic/phenotypic heterogeneity of the ASD samples across studies.Īutism spectrum disorders (ASDs) are characterized by qualitative impairments in reciprocal social interaction and communication, and by the presence of restricted repetitive behavior (RRB). This study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. Taken together, the A alleles of rs2056202 and rs2292813 were consistently and positively associated with RRB traits in both the UIC-UF and SSC samples, but the most significant SNP with phenotype association varied in each dataset. The SSC sample had positive associations between the A allele of rs2056202 and four RBS-R scores (stereotyped, sameness, restricted, sum) (p = 0.006-0.010), between the A allele of rs908670 and three RBS-R scores (stereotyped, self-injurious, sum) (p = 0.003-0.015), and between the rs2056202-rs2292813 haplotype and six RBS-R scores (stereotyped, self-injurious, compulsive, sameness, restricted, sum)(omnibus test, p = 0.002-0.028). In the UIC-UF sample, three RBS-R scores (ritualistic, sameness, sum) had positive associations with the A allele of rs2292813 (p = 0.006-0.012) and with the rs2056202-rs2292813 haplotype (omnibus test, p = 0.025-0.040). We examined associations in our University of Illinois at Chicago-University of Florida (UIC-UF) sample (179 unrelated individuals with an ASD), and then attempted to replicate our findings in the Simons Simplex Collection (SSC) sample (720 ASD families). We used the Repetitive Behavior Scale-Revised (RBS-R) as a quantitative RRB measure, and conducted linear regression analyses for individual SNPs and a previously identified haplotype (rs2056202-rs2292813). In this study, we investigated the relationship between three SLC25A12 single nucleotide polymorphisms (SNPs) (rs2056202, rs908670 and rs2292813) and restricted repetitive behavior (RRB) traits in autism spectrum disorders (ASDs), based on a positive correlation between the G allele of rs2056202 and an RRB subdomain score on the Autism Diagnostic Interview-Revised (ADI-R).
SLC25A12 was previously identified by a linkage-directed association analysis in autism.
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