CigDay was associated with variants in neurturin (NRTN), a type of glial cell line-derived neurotrophic factor involved in the development and survival of dopamine neurons18. This gene has been studied in relation to Parkinson disease for its potential to restore dopamine neurocircuitry19. Likewise, PAK6 was another novel gene strongly associated with CigDay in TWAS results and was fine-mapped to just three variants in the 90% credible interval. PAK6 encodes a p21-activated kinase that is highly expressed in the striatum and hippocampus, has been implicated in the migration of GABAergic interneurons20 as well as the modulation of dopaminergic neurotransmission21, and is involved in locomotor activity and cognitive function22. PAK6 has been robustly associated with schizophrenia23 and neurodegenerative diseases24,25, such as Parkinson disease and Alzheimer disease, further highlighting its role in synaptic changes. Finally, we found a novel association between ECE2 and DrnkWk. ECE2 is involved in cortical development26 as well as the processing of several neuroendocrine peptides, including neurotensin and substance P27, and may also have a role in amyloid-β processing28. ECE2 also generates peptides such as BAM 12 (which shows κ-opioid receptor selectivity) and BAM 22 (which shows μ-opioid receptor selectivity), suggesting a link with pain transmission27.
