Autism prodrome 44 of 89
likely to be influenced by a combination of rare and common alleles, but with many
more rare variants than common variants.
The complex inheritance of ASD and the fact that ASD is relatively common
has first led to the suggestion that ASD is a polygenic disease, contributed by risk
alleles of relatively high frequencies in multiple genes. The Common
Disease/Common Variant (CDCV) hypothesis predicts that the genetic risk is
contributed by a combination of loci, each locus harboring a single or a very limited
number of common predisposing alleles (Reich & Lander, 2001). The high frequency
alleles are expected to be relatively old and thus shared across various populations.
Genetic association studies are based on the CDCV hypothesis, and they have limited
power if multiple rare genetic variants are the primary cause of ASD. A recent
published genome-wide association study (Wang et al., 2009) involving 943 ASDs
families (4,444 subjects) and another sample of 1,453 unrelated subjects with ASDs
and 7,070 control subjects identified an association between ASD and a SNP
(rs4307059) located on 5p14.1. The association was replicated in two other cohorts,
including 1,390 subjects from 447 families with autism and another independent
cohort of 108 ASD cases and 540 matched control subjects. The associated SNP is
located in an intergenic region between CDH10 (cadherin 10) and CDH9 (cadherin
9). Both CDH10 and CDH9 encode type II classical cadherins from the cadherin
superfamily, which represent transmembrane proteins that mediate calcium-dependent
cell-cell adhesion. These results represent the first consistently replicated associations
of common variation with ASD.
The alternative hypothesis is that genetic susceptibility to ASD is conferred by
rare deleterious mutations in any of a large number of genes, with substantial allelic
heterogeneity between patients. In addition, ASD could result from none inherited -
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