Moisan, F. | bioRxiv Science

bioRxiv2024

Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease

Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH), and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and here we investigated the association between inbreeding, GBC, gallstone disease (GSD) and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROH above 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions between FROH and sex, age, and genetic risk of GSD on GBC risk. Specifically, the increase in GBC risk per 1% FROH was 19% in men (P-value = 0.002), 30% in those under 60 years of age (P-value = 0.001), and 12% in those with a genetic risk of GSD above the median (P-value = 0.01). The present study highlights the complex interplay between inbreeding, genetic ancestry and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscore the importance of considering the population-specific genetic architecture, along with sex- and age specific-effects, when investigating the genetic basis of complex traits in Latin Americans.

genetics↗

bioRxiv2023

Causal Role of the Medial Prefrontal Cortex in Learning Social Hierarchy

Social hierarchy is a fundamental principle of social organization and an important attribute of community stability and development. Yet, little is known about the causal role of specific brain regions in learning hierarchies. Here, using transcranial direct current stimulation (tDCS), we investigated the causal role of the medial prefrontal cortex (mPFC) in learning social and non-social hierarchies. In the Training phase, participants(N=128) acquired knowledge of social and non-social hierarchy in parallel, by trial and error. During the Test phase, they were presented with two items from hierarchies that were never encountered together and required to make transitive inferences. Anodal stimulation over mPFC impaired social hierarchy learning compared with non-social learning and this modulation was influenced by the relative social rank of the members (i.e. higher or lower status). Anodal stimulation also impaired transitive inference making, but only during early blocks before learning was established. Together, our results provide causal evidence of mPFC engagement in learning social ranks by observation.

neuroscience↗