Expanding the Genetic Landscape of Craniofacial Anomalies Through Transcriptome-Wide Association Studies

Craniofacial anomalies are common congenital anomalies that significantly contribute to infant mortality and life-long health problems. Studies of craniofacial anomalies have identified several genetic causes, but focus on rare, Mendelian presentations. Despite this, current diagnostic genetic testing only identifies a causal genomic variant in ~ 25% of affected individuals. This low diagnostic yield for Mendelian conditions may relate to oligogenic and polygenic risks for craniofacial anomalies. In this study we sought to use large electronic health record systems including many patients with craniofacial anomalies to determine whether we could identify patterns of genetic associations with craniofacial anomalies and known associated genes.

We performed transcriptome-wide association studies that evaluated the association between genetically predicted gene expression and craniofacial anomalies in two cohorts: Vanderbilt University Medical Center's BioVU and Electronic Medical Records and Genomics Network (eMERGE). Using a list of 391 previously identified craniofacial anomaly-associated genes we determined whether there was a greater proportion of significant associations with these genes than others. We also evaluated whether these genes were associated with other congenital anomalies.

We determined the predicted expression of 12 (3.1%) of the known craniofacial anomaly genes were associated with craniofacial anomalies (p < 0.05) in BioVU and 18 (4.6%) in eMERGE. In both cohorts, the majority of significant genes and those demonstrating the strongest significance were not previously associated with craniofacial anomalies. In total, we identified 53 genes not previously associated with craniofacial anomalies. Interestingly fewer than 15% of the known craniofacial associated genes were associated with craniofacial anomalies (p < 0.05) while 262 (76.8%) were associated with congenital anomalies of the heart, 133 (39.0%) anomalies of the nervous system and 142 (41.6%) of the urinary system.

Our results support that both rare and common variation in Mendelian disease-associated genes may contribute to craniofacial anomalies and are broadly involved in congenital anomaly development.