Analysis of the RELN gene as a genetic risk factor for autism

Abstract

Several genome-wide screens have indicated the presence of an autism susceptibility locus within the distal long arm of chromosome 7 (7q). Mapping at 7q22 within this region is the candidate gene reelin (RELN). RELN encodes a signaling protein that plays a pivotal role in the migration of several neuronal cell types and in the development of neural connections. Given these neurodevelopmental functions, recent reports that RELN influences genetic risk for autism are of significant interest. The total data set consists of 218 Caucasian families collected by our group, 85 Caucasian families collected by AGRE, and 68 Caucasian families collected at Tufts University were tested for genetic association of RELN variants to autism. Markers included five single-nucleotide polymorphisms (SNPs) and a repeat in the 5 0 -untranslated region (5 0 -UTR). Tests for association in Duke and AGRE families were also performed on four additional SNPs in the genes PSMC2 and ORC5L, which flank RELN. Familybased association analyses (PDT, Geno-PDT, and FBAT) were used to test for association of single-locus markers and multilocus haplotypes with autism. The most significant association identified from this combined data set was for the 5 0 -UTR repeat (PDT P-value ¼ 0.002). These analyses show the potential of RELN as an important contributor to genetic risk in autism.

The genetics of autistic disorders and its clinical relevance: a review of the literature

“…[179][180][181][182][183] The first positive finding 176 reported an association with the relatively rare longer alleles ( > 10) of the 5 0 UTR trinucleotide polymorphism with AD. However, in another study, 178 the most common repeat 10 was over-represented in AD. One study 177 reported an association of the more common allele of SNP rs736707, which has not yet been replicated by other studies and might not be of functional relevance, as it is located in intron 59 of RELN.…”

“…The most commonly assessed variant in RELN is a trinucleotide repeat polymorphism in the 5 0 UTR with unknown functional relevance. Three studies did find an association, [176][177][178] five other studies of comparable size and power did not find an association of the 5 0 UTR trinucleotide or other variants with AD. [179][180][181][182][183] The first positive finding 176 reported an association with the relatively rare longer alleles ( > 10) of the 5 0 UTR trinucleotide polymorphism with AD.…”

A heterogeneity-based genome search meta-analysis for autism-spectrum disorders

“…region before the start codon, have reached conflicting results. [43][44][45][46][47][48][49] This may reflect only the common pattern of nonreplication of early claims from small studies 50 or a modest effect may still be present. A large study should be conducted on this association.…”

Immune Dysfunction in Autism: A Pathway to Treatment

“…In addition, a number of other immunerelated genes have been implicated in ASD, including macrophage migration inhibitory factor (MIF), 43 MET encoding tyrosine kinase, 44 the serine and threonine kinase C gene PRKCB (alias PRKCB1), 45 protein phosphatase and tensin homolog (PTEN), 46 and the reelin gene (RELN). [47][48][49] It is not known whether immune activation plays an initiating or ongoing role in the pathology of ASD. Immune activation leading to inflammation can have serious detrimental effects and could lead to destruction of tissues.…”