A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism

Abstract

Autism is a childhood neuropsychiatric disorder that, despite exhibiting high heritability, has largely eluded efforts to identify specific genetic variants underlying its etiology. We performed a two-stage genetic study in which genome-wide linkage and family-based association mapping was followed up by association and replication studies in an independent sample. We identified a common polymorphism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily, that is significantly associated with autism susceptibility. Importantly, the genetic variant displays a parent-of-origin and gender effect recapitulating the inheritance of autism.

Figure 1

Genome-wide Linkage and Association Studies in Autism (A) Linkage studies were conducted in 72 multiplex families from the NIMH Repository and yielded a single significant result on chromosome 7q35. (B) Family-based association test (TDT) results in 145 trios, from the families in (A), for the 1-LOD interval (marked by a red bar) under the linkage peak. Genomic position is on the x axis (cM, centiMorgan; Mb, megabase) and the negative base-10 logarithm of the p value on the y axis.

Figure 2

Fine Mapping of CNTNAP2 The top panel shows the results of association tests in 1440 trios with significance for each SNP shown as the negative base-10 logarithm of the p value on the y axis plotted against genomic position in megabase (Mb) on the x axis. The CNTNAP2 exons 2 and 3 are shown in orange. The bottom panel shows all pairwise associations between 11 SNPs at the CNTNAP2 locus. The value within each diamond is the linkage disequilibrium statistic D′. Diamonds without a number correspond to D′ = 1; shading represents the magnitude and significance of pair-wise linkage disequilibrium (LD) with a red-to-white gradient reflecting higher to lower LD values (see Haploview online for further details).

Figure 3

Relative Risk of rs7794745 Genotype Stratified by Sex The first allele of each genotype represents the paternal allele, and the second allele represents the maternal allele. Relative risk is compared to the sex-specific population risk, assuming overall prevalence of 1:500 and males 4 times more likely to be affected than females. The bars indicate 95% confidence intervals.