Project Details
Projekt
ENIGMA goes functional – exploring the neurogenetic architecture of brain (dys)function
Subject Area
Biological Psychiatry
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 411081216
Over the past decades, the field of biological psychiatry has witnessed many new techniques emerging, including genetics and neuroimaging. However, the search for biomarkers of mental disorders has been rather disappointing so far. This has motivated the initiation of so called Research Domain Criteria (RDoC), in which psychopathology is viewed as varying degrees of dysregulation in distinct neurocognitive domains. In the meantime, the field of imaging genetics has advanced considerably, identifying patterns of brain structure or function that are determined by genetic variability and, with respect to psychiatry, are associated with disease vulnerability or indicative thereof (i.e. intermediate phenotypes). Recent advances in high-throughput genetics and the collection of large samples resulted in the discovery of genetic variants associated with mental disorders, of which many are tested against altered brain function in various RDoC domains. However, given the expected increase in genetic associations and subsequent secondary imaging genetics studies, it would be appropriate to use neuroimaging data directly to screen the genome to discover genetic associations with brain measures. This would require a magnitude of statistical power that is difficult to achieve with typical sample sizes in imaging genetics. It is thus necessary to aggregate data from as many sites worldwide as possible, which has been the aim of the ENIGMA consortium using meta-analysis, but so far only for structural MRI data. We here propose to extend the ENIGMA framework to task-based functional MRI to reach a sufficiently large sample of functional imaging data to allow genome-wide association analysis with intermediate phenotypes. We focus on three task types that fall within the RDoC domains and are reliably associated with psychiatric disease. Existing ENIGMA pipelines will be extended and complemented with analysis tools tailored to the analysis of task-based fMRI. We will follow two complementary brain analysis strategies: (i) data reduction, using ROIs in which activation is heritable, and (ii) performing a voxelwise analysis that allows for richer data exploration. Although three domain-specific tasks are used within the current project at first, this approach can easily be translated to any domain relevant to the RDoC framework and extended to any of the existing ENIGMA disease workgroups. Importantly, we will generate methods and algorithms for large-scale analyses of imaging data, which will be made available on the ENIGMA website for download, also by third-party users. Ultimately, our endeavor will contribute to provide answers to the replicability crisis by better discerning true from false positives. Elucidating the genetic influences on functional brain circuits will greatly improve the understanding of mental function and dysfunction and advances the long-term goal of finding heritable measures of disease burden.
DFG Programme
Research Grants
