RECENT PUBLICATIONS

The molecular genetic landscape of human brain size

Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. But the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage postmortem brain RNA sequencing and estimates of brain size in 2,531 individuals and identified 928 genes that showed genome-wide significant associations. These genes showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto developmental, functional and cellular axes of brain organization. We found that transcriptomic regulation of these genes influences cortical surface area and volume, as well as behavioral traits related to brain function and disease.

Genetic overlap between psychopathology and brain structure

Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remains elusive. In this study, we employed pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area, and seven psychiatric disorders in approximately 700,000 individuals. We identified 50 genetic loci shared between psychiatric disorders and surface area, as well as 26 genetic loci shared with cortical thickness.

Sex Differences in Association Network Topography

We identified normative developmental sex differences in the functional topography of personalized association networks including the ventral attention network and default mode network. Furthermore, chromosomal enrichment analyses revealed that sex differences in multivariate patterns of functional topography were spatially coupled to the expression of X- linked genes as well as astrocytic and excitatory neuronal cell-type signatures. These results highlight the role of sex as a biological variable in shaping functional brain development in youth.

Brain growth charts of “clinical controls”

Clinically acquired brain MRI scans represent a valuable but underused resource for investigating neurodevelopment due to their technical heterogeneity and lack of appropriate controls. To address this challenge, we generated brain growth charts from clinically acquired brain MRI scans with limited imaging pathology from the Children's Hospital of Philadelphia Electronic Health Record. We found that brain growth charts derived from clinical controls with limited imaging pathology were highly correlated with brain charts from research controls, suggesting the potential of curated clinical MRI scans to supplement costly prospectively acquired research scans.

Brain charts for the human lifespan

For decades, growth charts for human traits such as head circumference, body weight, and height have served as a prime example of personalized precision medicine. Unfortunately, no equivalent reference charts exist the brain. In this paper, we developed computational models to quantify individual differences in brain structure from any brain imaging scan benchmarked against normative age-related trends, based on one of the largest and most inclusive brain MRI datasets ever aggregated. Individual deviations from normative trends were highly sensitive to both genetic and environmental factors, which have interconnected influences on risk and resilience to brain disorders over the whole human life-cycle.

Copy number variant risk scores affect brain and cognition

How do copy number variants (CNVs) combine with common genetic variants and environmental factors to help explain variability in cognition and psychopathology in our community? For 9498 youths in the Philadelphia area, elevated CNV risk scores were associated with lower cognitive ability, higher overall psychopathology, and higher psychosis-spectrum symptoms. Predictive models of clinical outcomes were improved my integrating rare genetic, common genetic, and environmental factors.

Imaging local genetic influences on cortical folding

Major gaps remain in our understanding of mechanisms that underlie the folding of the human cerebral cortex. Stereotyped folding in specific cortical locations could be explained by a corresponding anatomical pattern of genetic influences on cortical development, but no direct evidence supports this explanation. Here, we use high-resolution brain MRI to show the existence of the predicted pattern of genetic influences on the thickness of the cerebral cortex, leveraging the prediction that shared genetic influences during development create covariability of cortical thickness in adult neuroanatomy. We found that anatomically local covariability in cortical thickness has a genetic basis, is symmetric between cortical hemispheres, shows consistency across independent datasets, and may influence patterns of surface folding on the human brain.

Polygenic Risk Underlies Youth Psychopathology and Personalized Functional Brain Network Topography

Functional brain networks are associated with both behavior and genetic factors. To uncover clinically translatable mechanisms of psychopathology, it is critical to define how the spatial organization of these networks relates to genetic risk during development. The current study sought to determine the relationship between transdiagnostic polygenic risk scores (PRSs), personalized functional brain networks (PFNs), and overall psychopathology (p-factor) during early adolescence. Findings indicate that polygenic risk for transdiagnostic adulthood psychopathology is associated with both p-factor and PFN topography during early adolescence.

The copy number variant architecture of psychopathology and cognitive development in the ABCD® study

While common genetic variants account for a large proportion of inherited genetic risk, rare genetic variations, particularly copy number variants (CNVs), play a significant role in the genetic architecture of neurodevelopmental disorders. Despite their importance, the relevance of CNVs to child psychopathology and cognitive function in the general population remains underexplored. Our findings shed light on the contributions of CNVs to interindividual variability in complex traits related to neurocognitive development and child psychopathology.

ComBatLS: A location- and scale-preserving method for multi-site image harmonization

We introduce a new extension of the popular ComBat harmonization method, ComBatLS, that preserves biological variance in features' locations and scales. We use UK Biobank data to show that ComBatLS robustly replicates individuals' normative scores better than other ComBat methods when subjects are assigned to sex-imbalanced synthetic “sites”. Additionally, we demonstrate that ComBatLS significantly reduces sex biases in normative scores compared to traditional methods. Finally, we show that ComBatLS successfully harmonizes consortium data collected across over 50 studies.

Normative trajectories of extra-axial cerebrospinal fluid during childhood and adolescence defined in a clinically-acquired MRI dataset

Benign enlargement of the subarachnoid space (BESS), a condition marked by increased extra-axial cerebrospinal fluid (eaCSF) thickness, has been associated with macrocephaly and may be associated with subdural collections. However, diagnosis of BESS is complicated by the lack of age-specific normative data which hinders rigorous investigation of its clinical associations. rowth charts of eaCSF could shed light on normal CSF dynamics while also providing a normative benchmark to assist the diagnosis of BESS and other associated conditions. Our findings indicate that eaCSF thickness evolves in a dynamic pattern throughout childhood and adolescence, and that patients with BESS can be differentiated from clinical controls using computational measurements of eaCSF thickness paired with normative modeling.