Deepface: Deep-Learning-Based Framework to Contextualize Orofacial-Cleft-Related Variants During Human Embryonic Craniofacial Development

Authors

Yulin Dai
Toshiyuki Itai
Guangsheng Pei
Fangfang Yan
Yan Chu
Xiaoqian Jiang
Seth M Weinberg
Nandita Mukhopadhyay
Mary L Marazita
Lukas M Simon
Peilin Jia
Zhongming Zhao

Publication Date

7-18-2024

Journal

Human Genetics and Genomic Advances

Abstract

Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the "casual" variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50-0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.

Keywords

Humans, Deep Learning, Cleft Palate, Cleft Lip, Polymorphism, Single Nucleotide, Neural Networks, Computer, Epigenomics, Embryonic Development

Comments

Supplementary Materials

PMID: 38796699

This article has been corrected. See HGG Adv. 2024 July 18; 5(3): 100322.