Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism

Abstract

The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well.

Fig. 1

Genome-wide linkage analyses in a omnibus, b LIQ, c MIQ, and d NIQ groups. The PPL (posterior probability of linkage) represents the probability of an ASD gene at each position. The x-axis represents chromosomes 1–23 (X) on the Kosambi cM scale; the y-axis is on the probability scale. The horizontal line at PPL = 0.02 corresponds to the prior probability of linkage. Values below this line represent evidence against linkage, while values above the line represent evidence for linkage, at the given position

Fig. 2

Genome-wide combined linkage and association results from a omnibus, b LIQ, and c NIQ analyses. The PPLD (posterior probability of LD) represents the probability of allelic association with ASD due to LD for each SNP in turn, and utilizes both linkage information from the multiplex families and association information from the trios. The x-axis represents the physical map for chromosomes 1–23 (X); the y-axis is on the probability scale. An additional 151 markers from the pseudoautosomal region of X are not shown on the graph; none had PPLD exceeding the prior probability of LD

Fig. 3

Omnibus PPL and PPLD for chromosomes a 4, b 11, c 16. Units on the x-axis are in cM

Fig. 4

PPL and PPLD for LIQ, NIQ groups respectively, for chromosomes a 3, b 8, c 11, d 16, e X containing SNPs shown in Table 1. Units on the x-axis are in cM