Lack of evidence for an association between WNT2 and RELN polymorphisms and autism

Abstract

Autism is a pervasive neurodevelopmental disorder characterized by deficits in language development and social interaction, as well as stereotypical, repetitive behaviors. The etiology of autism is largely unknown. Family and twin studies have provided compelling evidence for a strong genetic component in most idiopathic cases. Several recent candidate gene studies have suggested that alleles of WNT2 and the reelin gene (RELN), two genes involved in distinct aspects of neurodevelopment, confer greater susceptibility to autism. We screened WNT2 for DNA polymorphisms by sequencing all exons and adjacent intronic regions in 24 autistic patients, and identified not only the WNT2 variants reported previously (two common single-nucleotide polymorphisms (SNPs) in the 5' upstream region and the 3' untranslated region (UTR), respectively), but also two new SNPs in its 3' UTR. We genotyped all four WNT2 polymorphisms and a polymorphic trinucleotide repeat in the 5' UTR of RELN in 107 families with multiple autistic children, and evaluated evidence for association between these variants and autism by the transmission disequilibrium test (TDT). Our results revealed no deviation from the null hypothesis of no association. Our interpretation of these findings is that it is unlikely that DNA variations in RELN and WNT2 play a significant role in the genetic predisposition to autism.

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.…”

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

“…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. However, in another study, 178 the most common repeat 10 was over-represented in AD.…”

“…189 The first study 17 reported a nominal association of a 3 0 UTR 783C > T SNP detected by mutation analysis in two affected siblings with AD. Subsequent studies 182,190 could not replicate this finding. Despite an established role of WNT2 in the development of the vertebrate central nervous system, its function in human brain development has not yet been proven.…”

Advances in behavioral genetics: mouse models of autism

“…[150][151][152] Fatemi et al 153,154 have shown that levels of RELN mRNA and Reelin protein are significantly deficient in the brain of autistic subjects. RELN plays multiple roles in brain, including cell guidance during embryonic development, and mediation of neurotransmission and synaptic plasticity in adulthood.…”