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

Abstract

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. Hypoconnectivity 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.genetics | BSNIP | architecture | molecular S chizophrenia (SZ) and psychotic bipolar disorder (PBP) are common, serious, heritable, genetically complex illnesses, sharing multiple characteristics, including risk genes and abnormalities in cognition, neural function, and brain structure (1-4). However, despite recent advances, their underlying biological mechanisms are largely undetermined and may be shared across the two diagnostic groups. Recent large-scale analyses have used various statistical informatics strategies to dissect these biological underpinnings better (5, 6). A recent study using a pathwayenrichment strategy showed that genes involved in neuronal cell adhesion, synaptic formation, and cell signaling are overrepresented in SZ and bipolar disorder (BP) (6). Another study using an informatics-based approach identified several cohesive genetic networks related to axon guidance, neuronal cell mobility, and synaptic functioning as key players in schizophrenia (5).Although risk for psychotic illnesses is driven in small part by highly penetrant, often private mutations such as copy number variants, substantial...

Hemispheric lateralization abnormalities of the white matter microstructure in patients with schizophrenia and bipolar disorder

“…[13][14][15][16][17][18] Clinically, the boundaries between schizophrenia and BD can be blurred early in the illness and even over time. 19,20 Given the overlap of psychotic symptomatology and risk gene loci, 21,22 direct comparisons of hemispheric lateralization in patients with schizophrenia and BD can yield insight into common and different pathophysiology underlying the shared and unique clinical features of these disorders. More specifically, if we build on the assumption that hemispheric abnormalities reflect neurodevelopmental aberrancy in indi viduals with psychosis, 2 then shared lateralization abnormal ities in neural substrates across schizophrenia and BD could represent a trait rather than a state feature of psychosis.…”

Contrasting variability patterns in the default mode and sensorimotor networks balance in bipolar depression and mania

“…Although showing strong intranetwork functional connectivity, the DMN is also related to other networks, including the sensorimotor (SMN) (10), salience (SN) (11,12), and central executive (CEN) (12,13) networks with the relationships between networks being either positive (i.e., correlating) or negative (i.e., anticorrelating). The DMN is involved in affective regulation and internal thoughts (14)(15)(16), showing major changes in psychiatric illnesses, such as BD (17)(18)(19)(20)(21), and major depressive disorder (22)(23)(24). At the same time, the DMN may be related to psychomotor behavior through its relationship with the sensorimotor network (10).…”

Schizophrenia: neuroinflammation, neurodegeneration or neurodevelopment? A genetic overview

“…Maintaining the analysis of large-scale studies, another three papers were identified. The first tried to correlate sets of SNPs with connectivity within brain default mode, which may indicate the resting neuronal activity 35 . This approach differed from GWAS as they used multivariate analysis instead of univariate analysis.…”