A polymorphic trinucleotide repeat (CGG/GCC) within the human Reelin gene (RELN) was examined as a candidate gene for autism spectrum disorders (ASDs). This gene encodes a large extracellular matrix protein that orchestrates neuronal positioning during corticogenesis. The CGG-repeat within the 5′ untranslated region of RELN exon 1 was examined in 126 multiple-incidence families. The number of CGG repeats varied from three to 16 in affected individuals and controls, with no expansion or contraction observed during maternal (n = 291) or paternal (n = 287) transmissions in families with autistic probands. Although the frequencies of the RELN alleles and genotypes in affected children were not different from those in the comparison group, a family-based association test (FBAT) showed that the larger RELN alleles (≥11 repeats) were transmitted more often than expected to affected children (S = 43, E(S) = 34.5, P = 0.035); this was particularly the case for the 13-repeat RELN allele (S = 22, E(S) = 16, P = 0.034). Affected sib-pair (ASP) analysis found no evidence of excess sharing of RELN alleles in affected siblings. The impact of genotypes with large alleles (≥11 repeats) on the phenotypes in individuals with ASD was analyzed by ANOVA in a subset of the families for which results of the Autism Diagnostic Interview-Revised were available. Children with large RELN alleles did not show any difference in scores for questions related to the core symptoms of autistic disorder, but there was a tendency for children with at least one large RELN allele to have an earlier age at first phrase (χ2 = 3.538, P = 0.06). Thus, although the case-control and affected sib-pair findings did not support a role for RELN in susceptibility to ASD, the more powerful family-based association study demonstrated that RELN alleles with larger numbers of CGG repeats may play a role in the etiology of some cases of ASD, especially in children without delayed phrase speech.
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The authors are very grateful to the families who participated in this research and we acknowledge the resources provided by the AGRE (Autism Genetics Resource Exchange) consortium (www.AGRE.org) and the participating AGRE families. We also thank The Autism Research Consortium and the ‘Think-Tank’ session members who led to the current study (Director: Margaret Bauman, MD, Massachusetts General Hospital. Members: George M Anderson, PhD, Yale University School of Medicine; Gene Blatt, PhD, Boston University School of Medicine; Edwin H Cook, MD, University of Chicago; Jeanette JA Holden, PhD, Queen's University, Ontario; Thomas L Kemper, MD, Boston University School of Medicine; Marcie MacDonald, PhD, Massachusetts General Hospital; Francesca Persichetti, PhD, Massachusetts General Hospital; Jonathan LR Rubenstein, PhD, Univ of California at San Francisco; Stephen Vincent, PhD, Human Brain Tissue Resource Center; Gary L Wenk, PhD, The University of Arizona; Andrew Zimmerman, MD, Kennedy Krieger Institute & Johns Hopkins University.
This work was supported by research grants from the Ontario Mental Health Foundation (to JJAH) and the Canadian Institutes of Health Research Interdisciplinary Health Research Team grant RT-43820 to the Autism Spectrum Disorders Canadian-American Research Consortium (ASD-CARC) (JJAH, principal investigator; www.autismresearch.ca) and a scholarship from the Ontario Mental Health Foundation (to HZ).
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Zhang, H., Liu, X., Zhang, C. et al. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol Psychiatry 7, 1012–1017 (2002). https://doi.org/10.1038/sj.mp.4001124
- autism spectrum disorders
- allelic association
- family-based association test
- affected sib-pair method
- phenotype–genotype correlation
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