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Brain Proteins May Mediate Effects of Genetic Variants on Some Neurological Phenotypes

NEW YORK – Researchers in the UK conducted an analysis of human proteome data derived from brain tissue to evaluate whether targeted proteins putatively mediated the effects of genetic variants on neurological phenotypes such as Alzheimer disease, amyotrophic lateral sclerosis, depression, insomnia, intelligence, neuroticism, and schizophrenia.

In a study published on Thursday in the American Journal of Human Genetics, the researchers said they applied a Mendelian randomization (MR) analysis systematically across the genome, and observed 43 effects between genetically predicted proteins derived from the dorsolateral prefrontal cortex and those seven neurological phenotypes. Further, they added, they found that the same causal variant at 12 of these loci was responsible for variation in both protein and neurological phenotypes because of genetic co-localization. This included genes such as DCC, which encodes the netrin-1 receptor and has an important role in the development of the nervous system, as well as SARM1, which has been implicated in axonal degeneration.

The researchers also conducted a phenome-wide MR study for each of these 12 genes to assess potential pleiotropic effects on 700 complex traits and diseases, and found that genes such as SNX32, which was initially associated with increased risk of Alzheimer disease, may potentially influence other complex traits in the opposite direction, such as lower levels of HDL cholesterol and high body fat percentage. Further evaluations of this target would be necessary to discern whether increased genetic liability toward Alzheimer disease risk is responsible for these additional predicted effects, the researchers said. Alternatively, genetic variation at this locus may influence these outcomes separately via horizontal pleiotropy, which could make SNX32 less attractive as a therapeutic target.

However, they also found that genes such as CTSH (which was also associated with Alzheimer disease) and SARM1 may make worthwhile therapeutic targets because they did not have genetically predicted effects on any of the other phenotypes. SARM1 had an effect on ALS risk in the initial analysis, but didn't show evidence of an effect with any of the 700 outcomes assessed based on multiple testing corrections, the researchers said. They further explored evidence of potential side effects for SARM1 and found a potential secondary effect on coronary artery disease, but this effect was not supported by evidence of co-localization.

"The influx of high-dimensional datasets concerning intermediate phenotypes provides an exceptional opportunity to unravel the biological mechanisms responsible for GWAS signals," the authors concluded. "The tissue type used to capture these molecular signatures has been shown to play an important role in such endeavors. … Future endeavors which continue to uncover the genetic architecture of the human proteome in disease-relevant tissue types will improve our capability to reliably instrument them under the principle of MR. This will also improve the robustness of evidence from genetic co-localization analyses."

They also noted that their findings may help elucidate the causal pathway for genetic variants associated with neurological phenotypes and prioritize candidate targets for therapeutic intervention, adding that follow-up studies will be able to leverage increasingly large-scale molecular datasets derived from disease-relevant tissues in order to develop insights into the mechanisms linking genetic variation to complex traits and disease.

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