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

Periodic Reporting for period 1 - FLOURISH (IdentiFication of brain deveLopmental gene co-expression netwOrks to Understand RIsk for SchizopHrenia)

Reporting period: 2018-11-08 to 2020-11-07

The symptoms of schizophrenia severely compromise the quality of life of patients and of their families. Currently available drug treatments only in part mitigate this burden. A major hindrance to the development of effective early detection and treatment of schizophrenia is the lack of consensus on the causes of the disease. 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 multiple risk genes work together rather than in isolation. Therefore, gene networks can be used to understand how genes function in the context of brain cells. FLOURISH investigates how gene networks involved in risk for schizophrenia change during the lifespan, to understand how genetic risk for schizophrenia affects neurodevelopment and brain function.

The current understanding of how gene networks affect schizophrenia is limited because prior work did not account for their lifespan changes, mostly involving adult subjects only. Investigating differences between patients and controls may also be not enough: in fact, gene networks identified in clinical samples may be biased by the effects of drug treatment and disease chronicity. 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. Yet, we currently do not have a model of the normal function of schizophrenia risk gene networks in the maturation of different brain regions and in lifespan changes. We do not know which genes exert their effects on risk during early or later stages, hindering drug target identification directed at molecules active in the period preceding schizophrenia onset. FLOURISH aims to fill this gap by studying how gene networks in multiple brain regions change from fetal life to older adulthood and how they impact upon neuroimaging measures that can be acquired in subjects at risk.

A methodological objective of FLOURISH is to develop rigorous models of gene networks derived from postmortem brain materials of neurotypical individuals. A further methodological challenge is 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 aims 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 collects 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).
Addressing the methodological challenge of developing rigorous models of gene networks, Dr. Pergola published an article associating a reproducible schizophrenia risk gene network with treatment response to olanzapine in patients with schizophrenia (Pergola, Di Carlo, et al., 2019 Biological Psychiatry 86(1):45-55). He also investigated behavioral developmental trajectories associated with genetic risk for schizophrenia in children and adolescents (Pergola et al., 2019 World Psychiatry 18(3):366-367).

To assess gene network changes along the lifespan, Dr. Pergola analyzed the LIBD repository of postmortem brain mRNA sequencing data from the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus of 562 individuals deceased between fetal and older adult age with a novel pipeline ensuring age-specific networks comparable with each other. Results revealed the centrality of early prefrontal cortical schizophrenia risk gene networks and have been submitted for a presentation at the Society of Biological Psychiatry meeting in 2021.

To generate neuroimaging and genetic data, FLOURISH recruited 132 participants in Bari, Italy (30 adult neurotypical, 77 young neurotypical, and 33 young individuals at risk for schizophrenia). Dr. Pergola tested the hypothesis that risk for schizophrenia is related with anticipated maturation trajectories by assessing differences in brain connectivity between the young and adult neurotypical groups; brain connectivity patterns showing an effect of age were tested for differences between young neurotypical and young at-risk participants. Results supporting the hypothesis have been submitted for a presentation at the Society of Biological Psychiatry meeting in 2021. Part of the neuroimaging work has been used for a study of structural brain developmental trajectories (Wierenga et al, 2020 Human Brain Mapping doi: 10.1002/hbm.25204).
For the first time, FLOURISH has developed a model of risk gene network changes during the lifespan. Findings revealed that schizophrenia risk genes converge into networks especially in prefrontal cortex between fetal life and 25 years of age, while the prefrontal cortex is still completing its maturation. The evidence supports an early prefrontal and later hippocampal/caudate involvement in the biology underlying schizophrenia. Notably, effects are seen and vary across regions and across time points, thus providing a fuller understanding of the regional and temporal dynamics of schizophrenia risk in brain.

Compounding these results, the neuroimaging study revealed that the functional connectivity of the prefrontal cortex with the same regions examined in the postmortem study differed between neurotypical age groups; participants at risk for schizophrenia presented connectivity patterns characteristic of adult life and not of young adulthood, thus suggesting altered functional connectivity lifespan trajectories.

In the Incoming phase of the project, Dr. Pergola will connect the postmortem networks identified with the neuroimaging evidence using genetic information. Participants in the neuroimaging study will be profiled for their genetic background to test the hypothesis that early prefrontal schizophrenia risk gene networks are associated with functional connectivity trajectories decades later in life. This work will impact genetic risk profiling and novel treatment development by separating early genes (e.g. perinatal) that are key for early genetic risk calculation aimed at improving prevention from genes active later in life which may be better suited to develop drug targets.
FLOURISH concept