Genes, Behavior and Psychosis Risk in Kenya

Mamah, Daniel

Abstract

Psychotic disorders, including schizophrenia, are among the most disabling illnesses worldwide, but have not been extensively studied in Africa. Early treatment of schizophrenia is linked to better outcomes, and accurately identifying individuals before disorder onset holds promise for prevention. However, using existing clinical risk criteria to predict the development of psychotic disorders is inadequate, as only about a third of identified individuals progress to full-blown disorder. Over the years, major research efforts for ascertaining prodromal individuals have been established in North America, Europe and Australia. Through our previous R21 work, we pioneered prodromal longitudinal assessments in Kenya, and remain the only group in Africa actively investigating this risk population. Behavioral data from the large multi-site North American Prodromal Longitudinal Study (NAPLS) was used to derive a psychosis prediction algorithm with high predictive power, which remains to be explored in Africa over a substantial time frame. Genetic studies are also rare in Africa, despite the need for characterizing allelic differences across ethnic groups, and such studies may be valuable in psychosis risk prediction. Recently, the largest meta-analysis of genome wide association study (GWAS) data for schizophrenia identified 108 independent genetic loci that met genome-wide significance. Polygenic risk scores (PRS) constructed from these alleles have been shown to predict schizophrenia-control status but have not been previously used in risk prediction studies. Through our elaborate 4-year longitudinal study design, our proposal aims to identify behavioral and genetic predictors of psychosis transition in an independent Kenyan adolescent sample. We will investigate the capacity of the NAPLS behavioral prediction algorithm and schizophrenia genetic risk profiling using PRS to index liability to developing psychotic disorders in Kenyan adolescents. Finally, we will develop a repository of 12,000 DNA samples and behavioral data for genotyping in the future. At no cost to this study, the Stanley Center at the Broad Institute has already committed to conducting a GWAS of 1,800 of these subjects, underscoring the importance of our unique cohort. Our proposal incorporates expansive capacity building strategies, which includes developing a neuropsychiatric genomic laboratory associated with our primary collaborating organization in Kenya. We will further strengthen local research through substantial genetics training and mentoring, and advance the prodromal research and clinical infrastructure in the country. These effects would have long-term impact in advancing independent and collaborative behavioral research and mental health care in Africa.

Public Health Relevance

Results from our studies would have a significant impact on the early identification and prevention of those at risk for developing psychotic disorders, such as schizophrenia. Longitudinal assessments of high-risk youth will facilitate the precise characterization of genetic and behavioral traits to improve psychosis prediction, allowing for appropriate monitoring and intervention. A DNA repository will be created to facilitate future genome-wide association studies of African adolescents.