Statistical and functional convergence of common and rare variant risk for autism spectrum disorders at chromosome 16p
Bibliographic record
Abstract
Abstract The dominant human genetics paradigm for converting association to mechanism (“variant-to-function”) involves iteratively mapping individual associations to specific SNPs and to the proximal genes through which they act. In contrast, here we demonstrate the feasibility of extracting biological insight from a very large (>10Mb) region of the genome, and leverage this approach to derive insight into autism spectrum disorder (ASD). Using a novel statistical framework applied in an unbiased scan of the genome, we identified the 33Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of common polygenic risk for ASD. This region includes the recurrent 16p11.2 copy number variant (CNV) – one of the largest single genetic risk factors for ASD, and whose pathogenic mechanisms are undefined. Analysis of bulk and single-cell RNA-sequencing data from post-mortem human brain samples revealed that common polygenic risk for ASD within 16p associated with decreased average expression of genes throughout this 33-Mb region. Similarly, analysis of isogenic neuronal cell lines with CRISPR/Cas9-mediated deletion of 16p11.2 revealed that the deletion also associated with depressed average gene expression across 16p. The effects of the rare deletion and diffuse common variation were correlated at the level of individual genes. Finally, analysis of chromatin contact patterns by Hi-C revealed patterns which may explain this transcriptional convergence, including elevated contact throughout 16p, and between 16p11.2 and a distal region on 16p (Mb 0-5.2) which showed the greatest gene expression changes in both the common and rare variant analyses. These results demonstrate that elevated 3D chromatin contact may coordinate genetic and transcriptional disease liability across large genomic regions, exemplifying a novel approach for extracting biological insight from genetic association data. As applied to ASD, our analyses highlight the 33Mb p-arm of chromosome 16 as a novel locus for ASD liability and provide insight into disease liability originating from the 16p11.2 CNV.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.013 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".