Neuronal Cell-Specific sc-eQTL and Integrative eQTL-pQTL Mendelian Randomization Prioritize CKAP2 as a Candidate Gene...

Area of Science:

• Neurogenetics
• Psychiatric Disorders
• Systems Biology

Background:

• Major depressive disorder (MDD) presents a significant global health challenge.
• Understanding the genetic underpinnings and cell-specific mechanisms of MDD is crucial but incomplete.

Purpose of the Study:

• To identify genes associated with MDD using an integrated transcriptomic and proteomic Mendelian randomization (MR) approach.
• To investigate cell-type-specific effects of candidate genes in brain cells.
• To explore potential imaging-derived phenotypes as mediators in the MDD pathway.

Main Methods:

• Utilized Mendelian randomization (MR) incorporating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) data.
• Performed neuron-specific single-cell eQTL analyses across various brain cell types.
• Employed two-step MR mediation analysis with brain imaging phenotypes.

Main Results:

• Identified 20 genes associated with MDD at both transcriptomic and proteomic levels.
• CKAP2 exhibited discordant associations: inverse association with MDD risk via CNS expression, but a different direction via plasma protein levels.
• Single-cell eQTL analysis suggested a protective role for CKAP2 expression in excitatory neurons, inhibitory neurons, and oligodendrocyte precursor cells.
• Mediation analysis indicated right thalamic ventral anterior nucleus volume as a potential exploratory mediator (17.0% of total effect).

Conclusions:

• CKAP2 is prioritized as a candidate gene for MDD, with convergent but not fully confirmatory genetic evidence.
• The discordant genetic signals for CKAP2 highlight potential tissue- or layer-specific effects.
• Further experimental validation is warranted to confirm CKAP2's role in MDD pathogenesis.