Differences in White Matter Structural Networks in Family Risk of Major Depressive Disorder and Suicidality: A Connectome Analysis

Background Depression and suicide are leading global causes of disability and death and are highly familial. Family and individual history of depression are associated with neurobiological differences including decreased white matter connectivity; however, this has only been shown for individual regions. We use graph theory models to account for the network structure of the brain with high levels of specialization and integration and examine whether they differ by family history of depression or of suicidality within a three-generation longitudinal family study with well-characterized clinical histories. Methods Clinician interviews across three generations were used to classify family risk of depression and suicidality. Then, we created weighted network models using 108 cortical and subcortical regions of interest for 96 individuals using diffusion tensor imaging derived fiber tracts. Global and local summary measures (clustering coefficient, characteristic path length, and global and local efficiencies) and network-based statistics were utilized for group comparison of family history of depression and, separately, of suicidality, adjusted for personal psychopathology. Results Clustering coefficient (connectivity between neighboring regions) was lower in individuals at high family risk of depression and was associated with concurrent clinical symptoms. Network-based statistics showed hypoconnected subnetworks in individuals with high family risk of depression and of suicidality, after controlling for personal psychopathology. These subnetworks highlighted cortical-subcortical connections including between the superior frontal cortex, thalamus, precuneus, and putamen. Conclusions Family history of depression and of suicidality are associated with hypoconnectivity between subcortical and cortical regions, suggesting brain-wide impaired information processing, even in those personally unaffected. ### Competing Interest Statement In the last three years, Dr. Weissman has reported receiving royalties from Oxford University Press, Perseus Books Group, American Psychiatric Association Publishing, and Multi-Health Systems. JP has received funding from Takeda (formerly Shire) and Aevi Genomics and was on an advisory board for Innovation Sciences. None of these present any conflict with the present work. The other authors have nothing to disclose. ### Funding Statement This project was supported by the National Institute of Mental Health R01MH036197 (MMW, JP) and K99MH129611 (MvD), an American Foundation for Suicide Prevention Awards YIG-R-001-19 (MvD) and SRG-0-130-16 (AT), and a Depression Center Pilot Award from the Columbia Department of Psychiatry (AT). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, of American Foundation for Suicide Prevention or of any other sponsor. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of the New York State Psychiatric Institute gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data analyzed in this study are from a subsample of the longitudinal Three Generations at High and Low Risk for Depression Study. In the last wave participants were approached to give consent for their data to be included in the NDA repository. Data are being uploaded to the NDA for participants who provided consent, and will be made available to qualified investigators with the necessary approval.