Supplementary datasets - Autism D-score

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Supplementary datasets accompanying the paper:

Zhang, C. & Shen, Y. 2016. A cell type-specific expression signature predicts haploinsufficient autism-susceptibility genes.  Human Mutation. in press.


Recent studies have identified many genes with rare de novo mutations in autism, but a limited number of these have been conclusively established as disease-susceptibility genes due to lack of recurrence and confounding background mutations. Such extreme genetic heterogeneity severely limits recurrence–based statistical power even in studies with a large sample size. Here we use cell-type specific expression profiles to differentiate mutations in autism patients from those in unaffected siblings. We report a gene expression signature in different neuronal cell types shared by genes with likely gene disrupting (LGD) mutations in autism cases. The signature reflects haploinsufficiency of risk genes enriched in transcriptional and post-transcriptional regulators, with the strongest positive associations with specific types of neurons in different brain regions, including cortical neurons, cerebellar granule cells, and striatal medium spiny neurons. When used to prioritize genes with a single LGD mutation in cases, a D-score derived from the signature achieved a precision of 40% as compared to the 15% baseline with a minimal loss in sensitivity. An ensemble model combining D-score with mutation intolerance metrics from Exome Aggregation Consortium further improved the precision to 60%, resulting in 117 high-priority candidates. These prioritized lists can facilitate identification of additional autism-susceptibility genes.

Prioritized gene list

download: (3.3 MB)

Spreadsheet containing D score and ensemble score of all genes.