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Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia

Significance Connectivity within the brain’s resting-state default mode network (DMN) has been shown to be compromised in multiple genetically complex/heritable neuropsychiatric disorders. Uncovering the source of such alterations will help in developing targeted treatments for these disorders. To our knowledge, this study is the first attempt to do so by using a multivariate data-driven fusion approach. We report five major DMN subnodes, all of which were found to be hypo-connected in probands with psychotic illnesses. Further, we found an overrepresentation of genes in major relevant pathways such as NMDA potentiation, PKA/immune response signalling, synaptogenesis, and axon guidance that influenced altered DMN connectivity in psychoses. The study thus identifies several putative genes and pathways related to an important biological marker known to be compromised in psychosis. The brain’s default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging–genetic relationships. ICA identified three DMNs. Hypo-connectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases.