Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases

Abstract

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9136 children. We uncovered 440 genome-wide significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca’s area, which is important for speech, were enriched for human-specific genomic elements. Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

Clinical opportunity awaits at the intersection of genomics and brain imaging

“…Focal polymicrogyria is an example of a genetically determined cortical malformation that develops only in specific regions of the cortex, strongly supporting the notion of regional genetic influences on cortical area development. 27 Among the identified genes in our recent work, 8 TUBB was linked to posterolateral temporal surface area. Tubulin gene subclasses are widely expressed in the developing brain, 28 and have also been linked to cortical morphology and asymmetry in previous GWASs.…”

“…The genetically based atlas of the human cortex depicted in Figure 1B, 8 initially derived from the MRI data of more than 400 twins using a data-driven fuzzy clustering algorithm, 13,14 set the foundation for the discovery of 440 genetic loci (and nearly 800 significant loci in a meta-analysis combining total samples) underlying cortical surface area and thickness of the human brain, which we will hereafter refer to as cortical morphology for brevity. As mentioned, some of the boundaries in our genetically based atlas follow traditional gyral-based patterns (e.g., inferior and parietal area), whereas some diverge (e.g, no distinction between dorsomedial frontal and orbitofrontal regions for the area atlas).…”

“…These genes are then annotated for significant biologic al pathways to help with the functional interpretation of significant loci that have identified pathways related to development and morphogenesis in cortical GWASs. 5,6,8 It is important to bear in mind that these mapped genes are putative causal genes only, given that GWAS associations do not directly yield a gene target or mechanistic insight. 19,20 Mapping strategies to identify causal genes from GWAS has proven to be challenging, but is an active area of research, for instance by leveraging gene expression data to bring us a step closer to causal genetic mechanisms.…”

“…There is notable overlap between disease-related genes reported previously and genes associated with cortical phenotypes. Our recent work 8 nonexhaustively included these links based on their genetic discovery in a supplementary table based on the Genetics Home Reference database. This is a data source similar to Online Mendelian Inheritance in Man (OMIM) in which many gene-phenotype associations are from monogenic disorders or conditions attributable to genes with large effects.…”

“…6,29 There was also genetic overlap with holoprosencephaly, a common developmental defect where the cerebral hemispheres fail to separate properly. 30 Holoprosencephaly has been attributed to a gain-of-function mutation or duplication of PTCH1, a gene found to be associated with occipital, posterolateral temporal, dorsomedial and orbitofrontal cortical morphology 5,8,31 as well as microstructure of the uncinate fasciculus. 10 Additionally, ZIC1 and ZIC4 have been mapped to the surface area of frontoparietal cortices.…”