Paternally inherited cis-regulatory structural variants are associated with autism

Abstract

The genetic basis of autism spectrum disorder (ASD) is known to consist of contributions from de novo mutations in variant-intolerant genes. We hypothesize that rare inherited structural variants in cis-regulatory elements (CRE-SVs) of these genes also contribute to ASD. We investigated this by assessing the evidence for natural selection and transmission distortion of CRE-SVs in whole genomes of 9274 subjects from 2600 families affected by ASD. In a discovery cohort of 829 families, structural variants were depleted within promoters and untranslated regions, and paternally inherited CRE-SVs were preferentially transmitted to affected offspring and not to their unaffected siblings. The association of paternal CRE-SVs was replicated in an independent sample of 1771 families. Our results suggest that rare inherited noncoding variants predispose children to ASD, with differing contributions from each parent.

Figure 1.. Selection of target functional categories based on deletion intolerance.

Bar charts illustrating functional elements that show depletions in deletions relative to random permutations, stratified by deciles of gene variant-intolerance (pLI) as estimated by the ExAC consortium. A) Protein-coding deletions. B) Cis regulatory elements deletions. Odds ratios calculated based on observed counts versus expected based on permutation. Stars indicate the level of significance in the permutation analysis; whiskers represent 95% confidence intervals. TSS = transcription start site.

Figure 2.. Parental transmission of private cis-regulatory and exonic SVs to cases and sibling controls

Rate of transmission from parents to offspring was tested for SVs that disrupt cis-regulatory elements or exons of variant-intolerant genes (pLI > 90^th percentile). Whiskers represent the 95% confidence intervals. Effect sizes for CRE-SVs in all four cohorts individually is provided in figure S7).

Figure 3.. Recurrent promoter deletions of LEO1 derepress expression

A) Paternally inherited deletions of the LEO1 promoter were detected in three affected individuals, one trio (14-59) and one concordant sib pair (F0182). A common deletion polymorphism (parent allele frequency = 0.011) is also present in this locus. B) Chromatin interactions associated with transcription factors RNA Polymerase II and CTCF based on ChIA-PET data suggests that the cis-regulatory element upstream of LEO1 disrupted by both rare deletions (F0182 deletion shown here) serves as a focal point for the spatially organized transcription of LEO1 and MAPK6. C) mRNA expression of LEO1 and MAPK6 in fibroblast lines derived from two deletion carriers (REACH00319 and REACH000322) compared to three control lines. Whiskers represent 95% Confidence Intervals. Layered H3K27Ac = Histone 3 lysine 27 acetylation (an active promoter associated mark) in seven cell types from ENCODE. ChromHMM Tss = predicted transcription start site based on chromatin signatures in multiple cell types from the Epigenomics Roadmap Project (20).