Autism‐related routines and rituals associated with a mitochondrial aspartate/glutamate carrier SLC25A12 polymorphism

Abstract

Evidence for a genetic association between autism and two single nucleotide polymorphisms (SNPs), rs2056202 and rs2292813, in the mitochondrial aspartate/glutamate carrier (SLC25A12) gene led us to ask whether any of the four previously identified familial traits in autism spectrum disorders (ASD) varied by these SNPs. In 355 ASD cases from 170 sibships we examined levels of the four traits in these SNPs using ANCOVA models. The primary models selected unrelated affected cases and used age and sex as covariates. An ancillary set of models used all affected siblings and included "sibship" as a random effects independent variable. We found significantly lower levels of routines and rituals associated with the presence of the less frequent A allele in rs2056206. No other significant differences were observed. The rs2056202 polymorphism may be associated with levels of routines and rituals in autism and related disorders.

The Mitochondrial Aspartate/Glutamate Carrier AGC1 and Calcium Homeostasis: Physiological Links and Abnormalities in Autism

“…Ramoz et al [62] initially reported a significant association between autism and SLC25A12 gene variants marked by the G allele at the two intronic SNPs rs2056202 (I3-21A>G) and at rs2292813 (I16+70A>G). This result was later confirmed by Segurado et al [63], Turunen et al [64], and in an extended sample recruited by Ramoz and colleagues [65], in addition to suggestive evidence of specific SLC25A12 contributions to repetitive behaviors and rituals in autistic patients [66], which is not confirmed in our sample (Roberto Sacco and Antonio Persico, unpublished observation). On the other hand, no association was found by Blasi et al [67], Rabionet et al [68], Correia et al [69], Chien et al [70], and Palmieri et al [58].…”

Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1

“…14,52,53 In addition to obvious genetic heterogeneity in complex disorders, other factors could have potentially contributed to the repeated nonreplication of the two initial positive reports: 15,16 (1) prominent differences in LD patterns, previously well documented for example at the PRKCB1 locus 27 between our sample and an Irish sample largely overlapping with the one assessed by Segurado et al; 16 (2) spurious positive findings based on the two SNPs (rs2292813 and rs2056202) displaying the lowest heterozygosity (HZ) in the region (see observed HZ in Supplementary Table S6); (3) possible genetic contributions to a clinical endophenotype specifically characterized by prominent routines and rituals. 54 In our sample, the presence of motor stereotypies at intake is not significantly associated with allele G at rs7586207 in haplotype block 1 (w 2 = 1.527, 2 d.f., P = 0.466), or allele T at rs6724337 in haplotype block 2 (w 2 = 2.488, 2 d.f., P = 0.288). Altogether, we do not exclude that rare polymorphisms or functional variants located outside the genomic regions sequenced here could conceivably provide contributions to enhanced SLC25A12 gene expression, although this seems rather unlikely given the tight LD pattern present in the region (Figure 4).…”

“…This cannot be conclusively demonstrated with our sample size of 104 families including one or more unaffected sibling. Unfortunately, no other study has to this date reported on unaffected siblings [14][15][16][52][53][54] and genotyping for the Autism Genetic Resource Exchange (AGRE) data set is only available for the same two SNPs discussed above (rs2292813 and rs2056202), displaying low informatives and in the case of rs2292813 also located outside of the haplotype blocks depicted in Figure 4. It will be important to see whether our results are confirmed in larger samples, for at least two reasons: on one hand, they suggest that the status of 'unaffected sibling' could define an individual possessing genetically determined compensatory mechanisms not available to autistic patients, rather than merely identifying family members who have not inherited the full array of disease-producing alleles.…”

Autoimmune Disorder and Autism

“…rs2056202 and rs2292813) in SLC25A12 [180,182,183], while another three independent groups failed to reveal significant association [184][185][186]. Another group associated one SNP (rs2056202) with ASD but not the other [181]. Thus, the findings so far are inconclusive.…”