Characterizing the causal pathway for genetic variants associated with neurological phenotypes using human brain-derived proteome data

Leveraging high-dimensional molecular datasets can help develop mechanistic insight into associations between genetic variants and complex traits. In this study, we integrated human proteome data derived from brain-tissue to evaluate whether targeted proteins putatively mediate the effects of genetic variants on 7 neurological phenotypes (Alzheimer’s disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism and schizophrenia). Applying the principles of Mendelian randomization (MR) systematically across the genome highlighted 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and these outcomes. Furthermore, genetic colocalization provided evidence that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotype. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system (P=4.29x10-11 with neuroticism), as well as SARM1 which has been previously implicated in axonal degeneration (P=1.76x10-08 with amyotrophic lateral sclerosis). We additionally conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases. Findings suggested that genes such as SNX32, initially associated with increased risk of Alzheimer’s disease, may potentially influence other complex traits in the opposite direction. In contrast, genes such as CTSH (also associated with Alzheimer’s disease) and SARM1 may make worthwhile therapeutic targets as they did not have genetically predicted effects on any of the other phenotypes after correcting for multiple testing.