ABOVE: Differences in brain protein expression based on sex could help improve diagnoses and identify better treatments for individuals. ©iStock, Radachynskyi

Many neurological and psychiatric conditions differ in their prevalence and risk based on biological sex. “There is a sort of dearth of understanding of how biologic sex influences traits,” said Thomas Wingo, a neurologist at Emory University. Wingo and his team investigated this problem and showed that sex influences gene and protein expression in the brain. The findings, published in Nature Medicine, are a first step toward mechanistically understanding why some neurological conditions have pronounced sex-biases, which could guide improved treatments.1

The team used donated post-mortem brain samples from individuals over the age of 60 with and without neurologic conditions. Using mass spectrometry, the researchers studied the proteome in six brain regions from more than 1,200 brains. After quality control analysis, the team evaluated just under 10,200 proteins for sex-based differences. More than 1,300 of these proteins exhibited different expression levels based on sex. “[The study] stands out because it has a very big sample [size],” noted Christina Dalla, a neuropsychopharmocologist at the National and Kapodistrian University of Athens, who was not involved in the study.

To investigate potential differences in genetic regulation based on sex, the team analyzed gene variants for their influence on protein expression levels, or protein quantitative trait loci (pQTL). They focused this analysis on the dorsolateral prefrontal cortex as it was highly represented in their sample and therefore provided robust proteomic and genetic data. They assessed protein expression between alleles with single nucleotide polymorphisms and looked for pQTL differences to determine if sex influenced this allele expression. “The natural hypothesis is, they’re probably pretty similar,” said Thomas Wingo. “Generally, that’s not what we saw.” The researchers found almost 1,200 loci that corresponded to about 150 proteins with sex-biased expression.

 “Looking at brain proteins and genetic regulation of brain proteins would be a great window into the mechanisms of these neuropsychiatric disorders,” said Aliza Wingo, a psychiatrist at Emory University and study coauthor.

Because several brain conditions exhibit sex biases, the researchers compared the identified sex-biased proteins and their genes to gene-protein pairs that they previously associated with causal roles in a set of psychiatric, neurologic, or morphologic traits.2  The team identified 35 proteins from this group with sex-biased expression. Dalla noted that a strength of the present study was that it did not focus on a single disorder. “It really makes it unique that it manages to investigate so many different causal genes and proteins,” she said.

Aliza Wingo explained that this is only the beginning for this work. “I believe that we can find more [sex-biased risk genes] when we have access to more sex-stratified genome wide association studies because, right now, those are limited,” she said, adding that more data could improve the design of therapeutic interventions.

The team anticipates that factors such as the environment can influence brain protein expression between sexes, but they are excited about their current findings. “The fact that we are able to detect things that are changing or different between the brain that are relevant to these outcomes may start to help us understand why there’s prevalence differences for these traits,” said Thomas Wingo. “That’s an interesting new avenue to explore.”