Intellectual disability is associated with increased runs of homozygosity in simplex autism

Abstract

Intellectual disability (ID), often attributed to autosomal-recessive mutations, occurs in 40% of autism spectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runs of homozygosity (ROH) in simplex ASD-affected families consisting of a proband diagnosed with ASD and at least one unaffected sibling. In these families, probands with an IQ ≤ 70 show more ROH than their unaffected siblings, whereas probands with an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do support an association between ROH burden and autism diagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autism candidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autism or (2) a gene that is within an autism ROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecture for participants with autism and co-occurring intellectual disability and that this architecture could involve a role for recessively inherited loci for this autism subgroup.

Figure 1

The Burden of Autosomal ROH Is Higher in Autism-Affected Individuals with IQ ≤ 70 than in Unaffected Siblings in Simplex Pedigrees Autosomal ROH burden was higher in probands with an IQ ≤ 70 (blue) than in unaffected siblings in the SSC data set. This effect was not observed in probands with an IQ > 70 (red). Each ratio is plotted for different minimum segment sizes used for determining a block of ROH. Asterisks represent the statistical test if the point is different from a ratio of 1, i.e., the proband and unaffected sibling have equal values (p value < 0.05). Specific p values are presented in Table S1. Conditional-logistic-regression analysis in STATA version 11.1 was performed for comparing probands to their designated siblings. Error bars represent the SEM. Ratios were computed in STATA version 11.1 with standard errors. ‡ symbols represent the statistical test if the IQ ≤ 70 curve is different from the IQ > 70 curve (p value < 0.05). A one-way ANOVA was performed for comparing all data points for IQ ≤ 70 and > 70. The ANOVA p value was 0.01 for (A) and (B). The number of discordant sibling pairs, indicated by n, contributed to the data. Further information regarding this association analysis can be found in Table S1. (A) The ratio of total length of ROH per individual for probands compared to designated unaffected siblings is plotted. (B) The ratio of the average number of blocks per individual for probands compared to designated unaffected siblings is plotted. (C) The ratio of the average block size per individual for probands compared to designated unaffected siblings is plotted. (D) The ratio between the proportion of probands with at least one ROH block and the proportion of designated unaffected siblings with at least one ROH block is plotted.

Figure 2

Genome-wide Distribution of ROH Blocks for the Minimum Final Segment Size of 2,500 kb According to Disease Status Genome-wide distribution of ROH blocks for the minimum final segment size of 2,500 kb is shown and was created with Idiographica (see Web Resources). Chromosomes X and Y were excluded from the analysis. All ROH blocks, which occur at least once in a subject, are shown.

Figure 3

Children with Autism and Autosomal ROH Have Lower Cognitive Function and Adaptive Function (A) Comparison of IQ tests for autism probands with and without autosomal ROH (minimum final segment size of 2,500 kb). The y axis indicates the mean score, and error bars represent the SEM. (B) Comparison of adaptive functioning based on Vineland scores for autism probands with and without ROH (minimum final segment size of 2,500 kb). The y axis indicates mean composite scores for each group, and error bars represent the SEM. (C) Comparison of autistic symptoms based on ADOS scores for autism probands with and without ROH (minimum final segment size of 2,500 kb). The y axis indicates mean ADOS scores for each group, and error bars represent the SEM. (D) Comparison of autistic symptoms based on ADI-R scores for autism probands with and without ROH (minimum final segment size of 2,500 kb). The y axis indicates mean ADI-R scores for each group, and error bars represent the SEM. All tests were conducted in SAS version 9.2. Statistically significant p values (<0.05) are shown in the graphs. Further information regarding phenotype-genotype analysis can be found in Table S5.