Dissecting autism and schizophrenia through neuroimaging genomics

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Autism spectrum disorder (ASD) and schizophrenia research often uses a 'top-down' approach, starting with diagnosis to identify brain phenotypes and genetic factors.
• This diagnostic-first strategy has yielded insights but struggles to explain overlapping genetic and neuroimaging findings across different psychiatric conditions.

Purpose of the Study:

• To review neuroimaging genomic findings in autism and schizophrenia.
• To compare 'top-down' (diagnostic-first) and 'bottom-up' (molecular-first) research strategies.
• To propose a more effective approach for understanding the underlying mechanisms of these complex conditions.

Main Methods:

• Review of existing literature on neuroimaging genetics in autism and schizophrenia.
• Analysis of findings from both 'top-down' and 'bottom-up' study designs.
• Discussion of the implications of pleiotropic mechanisms and polygenic architecture.

Main Results:

• Top-down studies reveal small effect sizes for neuroimaging alterations and polygenic architecture in autism and schizophrenia.
• Genomic variants and neuroimaging patterns are shared across diagnostic categories, suggesting pleiotropic effects.
• Bottom-up studies demonstrate larger effect sizes for high-risk mutations on neuroimaging and behavioral traits, but with low specificity.

Conclusions:

• Top-down approaches alone are insufficient to fully elucidate the mechanisms of autism and schizophrenia.
• A bottom-up strategy is crucial for dissecting heterogeneity and understanding biological risk.
• Future research should integrate gene expression data and focus on individuals with high-risk variants and diverse psychiatric symptoms for improved predictive modeling.