Sinan Gülöksüz - Genomic and exposomic drivers of mental health trajectories and resilience.

 

Biography:
Sinan Guloksuz, MD, PhD is an Associate Professor of Psychiatry at the Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, and the Department of Psychiatry, Specialized Treatment Early in Psychosis (STEP) Program, Yale University School of Medicine.

With a background in clinical psychiatry and epidemiology, Dr. Guloksuz’s main research focus has been on understanding the mechanisms underlying mental health outcomes and investigating the contribution of exposome and genome to multidimensional behavioral and cognitive phenotypes in the general population cohorts and large case-control samples (EUGEI, EFPTS, EDSP, GROUP, TWINSCAN, NEMESIS-I/II, UK Biobank). The second body of his work has been in the areas of clinical trials and service research for psychosis spectrum disorder, in particular Early Detection and Prevention. To investigate Gene-Environment theories, Dr. Guloksuz’s research team has applied novel methods such as digital phenotyping, network models, and machine learning to make multiple contributions in areas including gene-environment interactions, psychosis, and transdiagnostic phenotypes.

To bridge the gap between genetics and environment in psychiatric research and acknowledge the multiplicity of interconnected environmental factors, Dr. Guloksuz has been the first investigator proposing the exposome paradigm for psychiatry and constructing a cumulative environmental score (environmental equivalent of polygenic risk score): the exposome score for schizophrenia. His team has successfully applied the exposome score for schizophrenia in several independent population and clinical datasets to improve risk prediction and test gene-environment theories.

His work has resulted in over 140 peer-reviewed publications, 12 book chapters, and awarded with international prizes from the European Psychiatry Association, World Psychiatry Association, European Accreditation Committee in CNS, and the Society of Biological Psychiatry. He currently serves as the Work-Package Leader (Gene-Environment Interaction) in the ongoing ZonMw-funded project: Outcome of Psychosis: Heterogeneity Explained by Long-lasting Individual Attributes (OPHELIA) with a total budget of € 1.5 million, and the Vice Coordinator and the Work-Package Leader (Data Inference) in the recently funded EU Horizon 2021 project: Gene Environment interactions in Mental health trajectorieS of Youth (Youth-GEMs) with a total budget of € 10 million. Dr. Guloksuz’s team aims to integrate exposomic, genomic, and epigenomic data to execute the next phase of gene-environment research to provide clues for potentially modifiable factors and mechanistic understanding to transform the prevention and treatment of mental disorders.   

Dr. Guloksuz’s contribution to the international scientific community also includes ongoing active roles in professional organizations, such as the Schizophrenia International Research Society, as well as editorial roles, such as the Associate Editor of the Nature Mental Health Research and the Editorial Board Member of the British Journal of Psychiatry, Frontiers in Psychiatry, and the PLOS One.

NCBI Bibliography: https://www.ncbi.nlm.nih.gov/myncbi/1-Iq8dtFcLQA9/bibliography/public/

 

Abstract:
There is active interest in understanding the relationship between neuropsychiatric disorders and modifiable and potentially preventable environmental exposures. However,
mental disorders have complex pathoetiology involving genetic and environmental risk factors, as well as their interactions. For instance, our recent series of work using polygenic risk score for schizophrenia has provided molecular evidence for gene-environment interaction in psychosis. We showed that genetic liability to psychosis moderated the influence of several environmental factors, such as cannabis use and childhood adversities, to increase psychosis risk.  Moving from candidate genes to genome-wide approaches has increased the replicability of genetics research. However, the complexity of the environment, involving many causal and noncausal pathways, continues to make research challenging.   

To tackle these challenges, we have recently proposed the use of the exposome paradigm. The exposome represents the totality of exposures in a lifetime from conception onward. The framework offers a solution to handle the complexity of all “non-genetic” factors. We recently adopted the exposome approach to construct an exposome score for schizophrenia (ES-SCZ). Our findings demonstrate that ES-SCZ can be used for risk stratification, adjusting for cumulative environmental load in statistical testing, and collecting risk enriched cohorts. Increasing data availability will help improve ES-SCZ that can be used in staging models to enhance clinical characterization and outcome forecasting.

Although ES-SCZ already provides several practical benefits for research practice, the exposome paradigm offers much more. Agnostic exposome-wide analyses might be the first step to mapping the exposome of mental health phenotypes. In the UK Biobank, we showed that an exposome-wide study followed by Mendelian Randomization analyses might help distinguish genuine signals from selective reporting and uncover novel risk and resilience factors.  The exposome approach will also increase our understanding of the differential impact of the environment on mental health across geographical settings and ethnic communities. We are in the early phases of exposome research in psychiatry; however, if successfully applied, the exposome framework is poised to embrace complexity and enable advanced analytical solutions to harness ever-growing data to gain insight into the complex dynamic network of exposures.

As the logical continuation of our research line, our research team aims to integrate exposomic, genomic, and epigenomic data to execute the next phase of gene-environment research to provide clues for potentially modifiable factors, increase mechanistic understanding of trans-syndromal risk and resilience trajectories over the lifetime, and translate these findings into clinical practice to transform the prevention and treatment of mental disorders.