Genome-wide linkage analyses of quantitative and categorical autism subphenotypes

Abstract

Background: The search for susceptibility genes in autism and autism spectrum disorders (ASD) has been hindered by the possible small effects of individual genes and by genetic (locus) heterogeneity. To overcome these obstacles, one method is to use autism-related subphenotypes instead of the categorical diagnosis of autism since they may be more directly related to the underlying susceptibility loci. Another strategy is to analyze subsets of families that meet certain clinical criteria to reduce genetic heterogeneity.

Methods: In this study, using 976 multiplex families from the Autism Genome Project consortium, we performed genome-wide linkage analyses on two quantitative subphenotypes, the total scores of the reciprocal social interaction domain and the restricted, repetitive, and stereotyped patterns of behavior domain from the Autism Diagnostic Interview-Revised. We also selected subsets of ASD families based on four binary subphenotypes, delayed onset of first words, delayed onset of first phrases, verbal status, and IQ > or = 70.

Results: When the ASD families with IQ > or = 70 were used, a logarithm of odds (LOD) score of 4.01 was obtained on chromosome 15q13.3-q14, which was previously linked to schizophrenia. We also obtained a LOD score of 3.40 on chromosome 11p15.4-p15.3 using the ASD families with delayed onset of first phrases. No significant evidence for linkage was obtained for the two quantitative traits.

Conclusions: This study demonstrates that selection of informative subphenotypes to define a homogeneous set of ASD families could be very important in detecting the susceptibility loci in autism.

Figure 1

Genome-wide linkage analysis results for the seven subphenotypes. The vertical reference lines separate the chromosomes. The horizontal reference lines are at LOD score = 2.2 as the suggestive linkage threshold and LOD score = 3.6 as the significant linkage threshold. LOD, logarithm of odds; other abbreviations as in Table 1.

Figure 2

Highlighted linkage analysis results for chromosomes 11 and 15. The horizontal reference lines are at LOD score = 2.2 as the suggestive linkage threshold and LOD score = 3.6 as the significant linkage threshold. ASD, autism spectrum disorders; BEH, behavior domain total scores; LOD, logarithm of odds; SOC, social interaction domain total scores.