A genome-wide linkage and association scan reveals novel loci for autism

Abstract

Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Figure 1

Genome-wide Linkage Results. The genome-wide linkage results are shown in 1a, with the orange line indicating LOD 3. The four chromosomes with LOD > 2 are shown in 1b. The black and blue lines indicate results from families with both parents genotyped and all families, respectively. The green line indicates information content. The red circle indicates the position of the centromere.

Figure 2

SEMA5A Expression in Autism Brains SEMA5A gene expression is shown relative to MAP2. Yellow diamonds indicate individual expression levels for each sample; error bars indicate standard error (SE).