Rare variant analysis integrating large public DNA sequencing controls and gene expression data for discovering novel predisposition genes of orofacial clefts

Project Summary/Abstract
Genetic variations significantly contribute to orofacial cleft. Identifying predisposition genes of
orofacial cleft holds promise for early diagnosis, preventive measures, and targeted therapies.
However, pinpointing genes harboring rare causal variants remains a challenge due to limited
statistical power associated with typical sample sizes of hundreds or thousands of cases and
controls. We propose utilizing genetic burden analyses with large control sample size and gene
expression data sets to discover orofacial predisposition genes. This approach leverages
multiple genomics datasets: ~1,400 orofacial cleft samples from Gabriella Miller Kids First
Pediatric Research Program and ~730,000 samples included in the public biobank-level
summary counts from the recently released Genome Aggregation Database V4, ~240 orofacial
cleft samples and ~220K controls from All of Us Genomics data sets. Furthermore,
transcriptomics data sets will be analyzed to enrich potential causal genes, including the
analysis of both bulk and single cell RNA-seq data sets from craniofacial tissues and reference
GTEx tissues. We will perform discovery analysis, followed by further validation and combined
analysis. This comprehensive approach aims to identify novel predisposition genes and variants
associated with orofacial cleft, ultimately facilitating early diagnosis, risk stratification, improved
understanding of disease etiology, and developing targeted treatments.

Grant Number: 1R03OD039975-01
NIH Institute/Center: NIH
Principal Investigator: Wenan Chen