Goovaerts, S. | bioRxiv Science

bioRxiv2022

Joint Multi-Ancestry and Admixed GWAS Reveals the Complex Genetics behind Human Cranial Vault Shape

The cranial vault - the portion of the skull surrounding the brain and cerebellum - is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conducted a joint multi-ancestry and admixed multivariate GWAS on 3D cranial vault shape extracted from magnetic resonance images of 6,772 children from the ABCD study cohort, identifying 30 genome-wide significant genetic loci and replicating 20 of these signals in 16,947 additional individuals of the UK Biobank. This joint multi-ancestry GWAS was enriched for genetic components of cranial vault shape shared across ancestral groups and yielded a greater discovery than a European-only GWAS. We present supporting evidence for parietal versus frontal bone localization for several of the identified genes based on expression patterns in E15.5 mice. Collectively, our GWAS loci were enriched for processes related to skeletal development and showed elevated activity in cranial neural crest cells, suggesting a role during early craniofacial development. Among the identified genes, were RUNX2 and several of its upstream and downstream actors, highlighting the prominent role of intramembranous ossification - which takes place at the cranial sutures - in influencing cranial vault shape. We found that mutations in many genes associated with craniosynostosis exert their pathogenicity by modulating the same pathways involved in normal cranial vault development. This was further demonstrated in a non-syndromic sagittal craniosynostosis case-parent trio dataset of 63 probands (n = 189), where our GWAS signals near BMP2, BBS9, and ZIC2 contributed significantly to disease risk. Moreover, we found strong evidence of overlap with genes influencing the morphology of the face and the brain, suggesting a common genetic architecture connecting these developmentally adjacent structures. Overall, our study provides a comprehensive overview of the genetics underlying normal cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.

genetics↗

bioRxiv2022

Hybrid Autoencoder with Orthogonal Latent Space for Robust Population Structure Inference

BackgroundAnalysis of population structure and genomic ancestry remains an important topic in human genetics and bioinformatics. Commonly used methods require high-quality genotype data to ensure accurate inference. However, in practice, laboratory artifacts and outliers are often present in the data. Moreover, existing methods are typically affected by the presence of related individuals in the dataset. ResultsIn this work, we propose a novel hybrid method, called SAE-IBS, which combines the strengths of traditional matrix decomposition-based (e.g., principal component analysis) and more recent neural network-based (e.g., autoencoders) solutions. I.e., it yields an orthogonal latent space enhancing dimensionality selection while learning non-linear transformations. The proposed approach achieves higher accuracy than existing methods for projecting poor quality target samples (genotyping errors and missing data) onto a reference ancestry space and generates a robust ancestry space in the presence of relatedness. ConclusionWe introduce a new approach and an accompanying open-source program for robust ancestry inference in the presence of missing data, genotyping errors, and relatedness. The obtained ancestry space allows for non-linear projections and exhibits orthogonality with clearly separable population groups.

bioinformatics↗