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Evidence from model organisms and clinical genetics suggests coordination between the developing brain and face, but the role of this link in common genetic variation remains unknown. We performed a multivariate genome-wide association study of cortical surface morphology in 19,644 individuals of European ancestry, identifying 472 genomic loci influencing brain shape, of which 76 are also linked to face shape. Shared loci include transcription factors involved in craniofacial development, as well as members of signaling pathways implicated in brain–face cross-talk. Brain shape heritability is equivalently enriched near regulatory regions active in either forebrain organoids or facial progenitors. However, we do not detect significant overlap between shared brain–face genome-wide association study signals and variants affecting behavioral–cognitive traits. These results suggest that early in embryogenesis, the face and brain mutually shape each other through both structural effects and paracrine signaling, but this interplay may not impact later brain development associated with cognitive function. A multivariate genome-wide association study highlighting loci that influence both face and brain shape suggesting shared developmental axes during early embryogenesis. These loci did not overlap with those governing behavioral–cognitive traits or neuropsychiatric risk indicating divergence between early brain development and cognitive function.

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. Homozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

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.