FLOURISH · IdentiFication of brain deveLopmental gene co-expression netwOrks to Understand RIsk for SchizopHrenia

IdentiFication of brain deveLopmental gene co-expression netwOrks to Understand RIsk for SchizopHrenia

The symptoms of schizophrenia severely compromise the quality of life of patients and of their families. Although schizophrenia is a heritable disorder, identifying the specific genes involved and the biological mechanisms they affect has only recently met with some success. Studies by the Psychiatric Genomic Consortium have revealed hundreds of genetic variants bearing minimal effects on risk for schizophrenia. Still, the biology of these genetic variants remains mostly unknown. Genetic variation between individuals is associated with the function of many genes; the genes affected by variants associated with schizophrenia are generally called “risk genes”. The current understanding of the genetics of schizophrenia suggests that gene networks are key to understanding how genes function in the context of brain cells. However, prior work did not account for lifespan changes in gene networks, mostly involving adult subjects only. Therefore, the function of schizophrenia risk genes in neurotypical development and lifespan changes remains undetermined. This information is vital in fighting schizophrenia because it is thought that the disease’s cause lies in brain developmental changes occurring before the onset. FLOURISH aimed to fill this gap by studying how gene networks in multiple brain regions change from fetal life to older adulthood and how they impact neuroimaging measures that can be acquired in subjects at risk. A methodological objective of FLOURISH was to develop rigorous models of gene networks derived from postmortem brain materials of neurotypical individuals. A further methodological challenge was obtaining gene networks comparable across time points in the lifespan and across brain regions, despite the biological differences existing between early and advanced ages and between brain regions. Then, FLOURISH aimed to identify schizophrenia risk gene networks and assess their changes from fetal life along the lifespan to translate early and later risk into brain function. To understand how gene networks translate into brain changes across the lifespan, FLOURISH collected genetic and neuroimaging data in a young cohort of individuals between 15 and 25 years old and in a cohort of adult participants (aged 30 to 50 years). FLOURISH successfully generated well-matched networks carefully controlled for confounding variables which revealed a preeminent role of the perinatal and juvenile dorsolateral prefrontal cortex in aggregating risk for schizophrenia dispersed across many genes. Genes co-expressed with schizophrenia risk genes, not detected in previous genetic studies, were identified and could be used as novel targets for drug development. Within functional magnetic resonance imaging data collected in Bari, Italy, FLOURISH identified connectivity patterns characteristic of young ages that appear overly mature in individuals at risk to develop schizophrenia. These results have been communicated in several scientific meetings and in a workshop targeted at families of patients with schizophrenia and other psychotic disorders.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз