Exploring the Causal Effects of Immune Responses to Cognitive and Mental Health - Integrating Large-scale Genomics with Longitudinal Studies

Healthy communications between the brain and immune systems are the key to maintain brain and cognitive health. Perturbations from both genetic and environmental factors may undermine such proper functioning of the brain across lifespan thereby leading to mental disorders. Using stored dried blood spots collected at birth, we showed that common genetic variations can account for a sizeable proportion of variations in circulation cytokine levels, signalling proteins that play important roles in the immune response. Furthermore, our identified genetic variants overlapped with those discovered using adult sample. We found that, through working together with our new collaborator from China, dysbiosis in the gut microbiota can modulated levels of cytokines, and was associated with risk of schizophrenia. Lastly, as a proof of concept, we demonstrated that advanced machine learning models could outperform standard genetic risk predictions to complex disease, including mental disorder. Our next step is to improve such models by incorporating multimodality data, including microbiome, protein levels and brain scans, to elucidate the causal roles of immune mediators in brain health.

The immune system and the brain are arguably the two major adaptive systems in the body, and, they communicate with each other extensively to cope with physiological and external changes. Abnormalities in such communications underlie many neuropsychiatric and neurodegenerative diseases, such as schizophrenia, autism spectral disorders, depression, Alzheimer's and Parkinson's diseases. Hence, properly controlled immune responses to inflammation and antigens are important for brain, cognitive and mental health. Cytokines are key components in the immune system, and function as signaling molecules for communications among cells, tissues and organs. In this project, we will study the effects of circulating levels of several cytokines on brain, cognitive and mental health. We will go beyond statistical correlations by estimating the causal effects of cytokine levels on brain structural changes and cognitive performance. To achieve our goal, we will integrate the unprecedented statistical power of large-scale genomic data with fine-grained longitudinal samples. In addition, we will investigate whether the effects of cytokine on brain, cognitive and mental health varies with age, sex and environmental factors. Leveraging on the state-of-the-art methodologies and big data, this project will contribute to our knowledge on the relations between immune responses and brain, cognitive and mental health.