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Integrative kraniofaziale Genomik - von genomweiten Assoziationsstudien zu ihrer funktionellen Bedeutung

Fachliche Zuordnung Humangenetik
Entwicklungsbiologie
Förderung Förderung von 2016 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 289822512
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

Nonsyndromic cleft lip with/without cleft palate (nsCLP) is one of the most common human birth defects. The main aim of the Emmy-Noether (EN) group “Integrative craniofacial genomics – from GWAS to function” was to advance our understanding of the biological pathways underlying embryonic craniofacial development and nsCL/P. At time of project start, sixteen risk loci harboring common risk variants had been identified by GWAS, but our understanding of the underlying biological mechanisms remained limited. Towards this goal the EN group was set up to further complete the map of genetic risk factors by identifying and annotating susceptibility variants of the entire allelic spectrum, including common variants generated by array-based genotyping as part of GWAS, and rare risk variants in coding and non-coding regions through analysis of targeted and systematic sequencing data in large cohorts. We further applied computational approaches to integrate functional, expression and epigenetic data sets with those genetic data, to identify and characterize pathways and cellular networks that underlie nsCL/P risk, with the aim to generate novel hypotheses that could be tested at functional level. We first generated the largest nsCL/P-GWAS-data set of Central European individuals at that time, which enabled us to perform systematic annotation of genetic data at unprecedented statistical power. At the functional level, we identified high-throughput datasets that are of relevance to craniofacial development, including chromatin modification data from craniofacial cell types during human development, and established pipelines for their joint analyses. The new large scale GWAS data combined with the chromatin state annotations of regulatory elements in relevant tissues allowed for systematic selection of non-coding candidate regions for follow-up, including resequencing approaches to study rare variants in these regions. We have successfully established a robust smMIPs-based sequencing and analysis pipeline, which was used for nsCL/P cohorts as well as additional samples in other project. We have complemented our risk variant identification with the analysis of de novo mutations (DNMs) in whole genome sequence data of 220 trios with nsCL/P. We identified a strong enrichment of DNMs variants at two GWAS loci (4q28, 2p21), showing that rare and common variants converge at these loci and suggesting those variants as high priority candidates for further functional work-up. Furthermore, using novel computational strategies that incorporate allele-specific transcription factor binding information, we identified an enrichment of rare non-coding mutations at binding sites for Msc and showed that its murine homologue is expressed in relevant tissues during craniofacial development. We have also used our expertise in multifactorial traits, high-throughput genomics and sequencing technology, to support national and global efforts to encounter the SARS-CoV-2 pandemic, the latter of which substantially affected the planned work of the EN group in their second half. Specifically, we founded the “Bonn study of COVID genetics” (BoSCO) and collaborated with different hospitals across Germany, to establish one of only a few German host genetic datasets that was contributed to international efforts such as the COVID19-HGI. These global consortia were able to identify numerous risk loci for severe COVID-19, and further large-scale analysis efforts involving the EN-PI are still ongoing to understand the post-acute sequelae of SARS-CoV-2 infection. In summary, the EN research group has significantly advanced our knowledge on the genetic and functional architecture of nsCL/P development, through identification of novel risk loci/variants and molecular factors, and has substantially contributed to global efforts encountering the SARS-CoV-2 pandemics.

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