Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human...

Area of Science:

• Neurogenetics
• Molecular Psychiatry
• Systems Biology

Background:

• Understanding the genetic basis of complex neurological traits is challenging.
• High-dimensional molecular data, such as proteomic information, offers a powerful resource for mechanistic insights.
• Genetic variants influencing complex traits may act through intermediate protein levels.

Purpose of the Study:

• To investigate whether proteins in the human brain mediate the effects of genetic variants on neurological phenotypes.
• To identify specific genes and proteins that causally influence conditions including Alzheimer disease, schizophrenia, and neuroticism.

Main Methods:

• Mendelian randomization (MR) was applied genome-wide using human brain proteome data (dorsolateral prefrontal cortex).
• Genetic colocalization analysis was performed to confirm shared causal variants for protein and phenotype associations.
• Phenome-wide MR was conducted for identified genes to assess pleiotropic effects across 700 complex traits.

Main Results:

• 43 significant effects were found between genetically predicted proteins and seven neurological phenotypes.
• 12 loci showed evidence of genetic colocalization, implicating specific genes like DCC (neuroticism) and SARM1 (amyotrophic lateral sclerosis).
• Phenome-wide analysis revealed potential pleiotropic effects for some genes, while others like CTSH and SARM1 emerged as promising therapeutic targets due to specific associations.

Conclusions:

• Proteins in the brain play a significant role in mediating genetic influences on neurological and psychiatric disorders.
• Specific genes, including DCC, SARM1, and CTSH, are highlighted as key players in neurological disease etiology.
• The study identifies potential therapeutic targets and underscores the utility of integrating proteomic and genetic data for understanding complex traits.