Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci

Human ear morphology, a complex anatomical structure represented by a multidimensional set of correlated and heritable phenotypes, has a poorly understood genetic architecture. In this study, we quantitatively assessed 136 ear morphology traits using deep learning analysis of digital face images in 14,921 individuals from five different cohorts in Europe, Asia, and Latin America. Through GWAS meta-analysis and C-GWASs, a recently introduced method to effectively combine GWASs of many traits, we identified 16 genetic loci involved in various ear phenotypes, eight of which have not been previously associated with human ear features. Our findings suggest that ear morphology shares genetic determinants with other surface ectoderm-derived traits such as facial variation, mono eyebrow, and male pattern baldness. Our results enhance the genetic understanding of human ear morphology and shed light on the shared genetic contributors of different surface ectoderm-derived phenotypes. Additionally, gene editing experiments in mice have demonstrated that knocking out the newly ear-associated gene (Intu) and a previously ear-associated gene (Tbx15) causes deviating mouse ear morphology. Author summaryHuman ear morphology varies widely, with largely inherited differences. However, the genetic basis for these differences is not well understood. To better understand the genetics of human ear morphology, we analyzed 136 ear traits from digital facial images of 14,921 individuals from three continents using GWAS meta-analysis and the recently developed C-GWAS method. We identified 16 genetic loci associated with ear morphology, eight of which had not been previously associated with ear features. These genetic loci can serve as candidates for future research to understand the function of these genes. Additionally, we have demonstrated the impact of two ear-associated loci on ear morphology in gene-edited mice. This study provides new insights into the complex genetics of the human ear.