Boosting Schizophrenia Genetics by Utilizing Genetic Overlap With Brain Morphology

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Schizophrenia is a complex polygenic disorder with subtle brain abnormalities.
• Shared genetic architecture between schizophrenia and brain measures is suggested, despite low genetic correlations.
• Analytical methods can leverage this overlap to understand schizophrenia mechanisms and improve polygenic risk prediction.

Purpose of the Study:

• To investigate the genetic overlap between schizophrenia and brain morphology.
• To identify novel genetic loci associated with schizophrenia risk and brain morphology.
• To develop an enriched polygenic score for improved schizophrenia risk prediction.

Main Methods:

• Multivariate genome-wide analysis of 175 brain morphology measures in 33,735 UK Biobank participants.
• Conditional false discovery rate analysis integrating brain morphology data with schizophrenia genome-wide association study statistics.
• Development and validation of a pleiotropy-enriched polygenic score in an independent sample.

Main Results:

• Significant genetic overlap found: 20% of loci and 50% of genes associated with schizophrenia also linked to brain morphology.
• Identified 428 loci associated with brain-linked schizophrenia risk, including 267 novel loci.
• The pleiotropy-enriched polygenic score explained more variance in liability compared to conventional polygenic scores.

Conclusions:

• Strong genetic overlap exists between schizophrenia and brain morphology, with mixed directions of effect.
• Exploiting polygenic overlap can enhance the discovery of brain tissue-specific genetic variants.
• This approach holds potential for improving polygenic risk prediction frameworks for mental disorders.