Shared heritability of face and brain shape distinct from cognitive traits

Abstract

Evidence from both model organisms and clinical genetics suggests close coordination between the developing brain and face1–8, but it remains unknown whether this developmental link extends to genetic variation that drives normal-range diversity of face and brain shape. Here, we performed a multivariate genome-wide association study of cortical surface morphology in 19,644 European-ancestry individuals and identified 472 genomic loci influencing brain shape at multiple levels. We discovered a substantial overlap of these brain shape association signals with those linked to facial shape variation, with 76 common to both. These shared loci include transcription factors with cell-intrinsic roles in craniofacial development, as well as members of signaling pathways involved in brain-face crosstalk. Brain shape heritability is equivalently enriched near regulatory regions active in either brain organoids or in facial progenitor cells. However, brain shape association signals shared with face shape are distinct from those shared with behavioral-cognitive traits or neuropsychiatric disorder risk. Together, we uncover common genetic variants and candidate molecular players underlying brain-face interactions. We propose that early in embryogenesis, the face and the brain mutually shape each other through a combination of structural effects and paracrine signaling, but this interplay may have little impact on later brain development associated with cognitive function.

Discovering non-additive heritability using additive GWAS summary statistics

“…However, many previous studies have extensively shown that modeling multiple phenotypes can often dramatically increase power 43,44 . Therefore, it would be interesting to extend the i-LDSC framework to multiple traits to study nonlinear genetic correlations in the same way that LDSC was recently extended to uncover additive genetic correlation maps across traits 45 .…”

Beyond Volume: Unraveling the Genetics of Human Brain Geometry

“…There is evidence for a high inter-individual variance in these intricate details, with a substantial proportion being heritable (6)(7)(8). Initial efforts to delve into the genetic underpinning of this heritable aspect used techniques like voxel-based analysis in combination with dimension reduction methods (9,10), or global-to-local representations of brain shapes (11,12). Each of these techniques carries its own challenges, including reduced robustness and accuracy due to suboptimal image registration, high computational effort, or a lack of physical interpretability due to dimensionality reduction or a prohibitive dimensionality of imagederived features.…”