The neurodevelopmental origins of schizophrenia in the penumbra of genomic medicine

Weinberger, Daniel R.

doi:10.1002/wps.20474

Cited by 37 publications

(26 citation statements)

References 7 publications

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“…The current results showing a difference between the degree of genetic moderation of two stressors (CA and daily-life stressors) underscores the importance of the type, timing, and extent of stressor in mental health impact. This is consistent with the neurodevelopmental hypothesis (69,70) (22), while, in another study, Met/Met genotype was associated with increased PA in response to experiencing positive events (72). Momentary stress interacted with genetic variation in the brain-derived neurotrophic factor gene, Met carriers reporting higher paranoia scores than Val carriers (22).…”

Section: Genetic Vulnerability For Schizophrenia Moderates Sensitivitsupporting

confidence: 79%

Interaction between polygenic liability for schizophrenia and childhood adversity influences daily-life emotional dysregulation and psychosis proneness

Pries

Klingenberg

Menne-Lothmann

et al. 2019

Preprint

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AbstractBackgroundThe earliest stages of the pluripotent psychopathology on the pathway to psychotic disorders is represented by emotional dysregulation and subtle psychosis expression, which can be measured using the Ecological Momentary Assessment (EMA). However, it is not clear to what degree common genetic and environmental risk factors for psychosis contribute to variation in these early expressions of psychopathology.MethodsIn this largest ever EMA study of a general population twin cohort including 593 adolescents and young adults between the ages of 15 and 35 years, we tested whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity (the Childhood Trauma Questionnaire score) and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures.ResultsBoth childhood adversity and daily-life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS-S was only associated with increased positive affect. No gene–environment correlation was detected. We have provided novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, 95% CI 0.01 to 0.13, P = 0.013), positive affect (b = −0.05, 95% CI −0.10 to −0.00, P = 0.043), and subtle psychosis expression (b = 0.11, 95% CI 0.03 to 0.19, P = 0.007)] and stress-sensitivity measures.ConclusionExposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotional dysregulation and psychosis proneness.

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Section: Genetic Vulnerability For Schizophrenia Moderates Sensitivitsupporting

confidence: 79%

Interaction between polygenic liability for schizophrenia and childhood adversity influences daily-life emotional dysregulation and psychosis proneness

Pries

Klingenberg

Menne-Lothmann

et al. 2019

Preprint

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“…A connection between genes, schizophrenia, neurodevelopment and neurodegeneration is also reported in other studies (Allan and Rothwell, 2001;Nawa et al, 2000). According to Weinberger (2017b), new evidence from Ursini et al (2017) supports a neurodevelopmental origin of schizophrenia in which a sizable fraction of genes in the schizophrenia GWAS, directly influence placental biology and placental health and can cause complicated pregnancies. With respect to our findings, shorter gestational lengths may affect those vulnerable to psychosis, but the opposite may also be true, that a specific genetic vulnerability in the fetus affects the length of gestation.…”

Section: The Relationship Between Gestational Length and Cognitionmentioning

confidence: 71%

“…The theory implied neurodegenerative processes in psychoses. Kraepelin said that behavior peculiarities in children who later manifest dementia praecox are an expression of the "morbid pathology" at the time of life, thereby suggesting that schizophrenia has its origin long before the emergence of psychotic symptoms (Weinberger, 2017b). In 1911, Bleuler was the first to use the word schizophrenia.…”

Section: The Etiology Of Schizophrenia In a Neurodevelopmental Perspementioning

confidence: 99%

“…Even though the idea of a relationship between OC and the later development of schizophrenia in outcome has become well established (Brown and Patterson, 2011;Weinberger, 2017b), the pathophysiological link between OC and schizophrenia remains obscure. An early dichotomy hypothesis suggested that patients with sporadic schizophrenia more likely had experienced environmental insults like OC, while patients with family schizophrenia had a genetic disposition for the illness .…”

Section: Obstetric Complications As Risk-factors For Schizophreniamentioning

confidence: 99%

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Gestational length affects neurocognition in early-onset schizophrenia

Teigset

Mohn

Rund

2016

Psychiatry Research

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Obstetric complications (OC) have been linked to an increased risk for schizophrenia in offspring, especially in early-onset schizophrenia (EOS). Extensive cognitive deficits occur in EOS, although no study has yet to investigate the relationship between OC and cognition in EOS. This study aims to examine the frequency of OC in EOS compared to controls, and also investigates the relationship between OC and neurocognitive dysfunction in the two groups. Nineteen EOS patients and 53 healthy controls were tested with the MATRICS Consensus Cognitive Battery (MCCB), and the cognitive measures were combined with OC data from the Norwegian Birth Registry. The results indicated no group differences in OC in EOS and healthy controls, but a shorter gestational length in the EOS group led to significant decreases in the overall neurocognitive composite score, and in processing speed. This suggests that the poorer neuropsychological performances commonly found in EOS may be partly attributable to the length of gestation. The worsened neurocognitive functioning did not appear among controls, so gestational length had a different impact on the two groups. Our findings indicated that a shorter gestational length did not increase the risk for developing EOS, but did significantly affect the cognitive difficulties in this group.

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“…It is now obvious that metabolic dysregulation in patients with schizophrenia already exists before antipsychotic treatment ( 66 , 67 ). The fact that schizophrenia risk is driven by genes that not have direct relevance to disease, suggests that schizophrenia could rather be considered as developmental physiological defect ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

IL-33/ST2 Pathway and Galectin-3 as a New Analytes in Pathogenesis and Cardiometabolic Risk Evaluation in Psychosis

et al. 2018

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Schizophrenia and treatment of this disorder are often accompanied with metabolic syndrome and cardiovascular issues. Alterations in the serum level of innate immune mediators, such as interleukin-33 (IL-33) and its receptor IL-33R (ST2) and Galectin-3 (Gal-3) were observed in these conditions. Moreover, these parameters are potential prognostic and therapeutic markers. There is also accumulating evidence that these molecules play a role in neuroinflammation. Therefore, in this study we have investigated the serum level of Gal-3, IL-33 and soluble ST2 (sST2) in different stages of schizophrenia. Gal-3 levels were elevated in remission and lower in schizophrenia exacerbation in comparison with controls. Levels of IL-33 and sST2 are higher in schizophrenia exacerbation in comparison with controls and patients in remission. This initial analysis of new markers of neuroinflammation suggested their involvement in schizophrenia pathophysiology and/or cardiometabolic comorbidity.

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The neurodevelopmental origins of schizophrenia in the penumbra of genomic medicine

Cited by 37 publications

References 7 publications

Interaction between polygenic liability for schizophrenia and childhood adversity influences daily-life emotional dysregulation and psychosis proneness

Interaction between polygenic liability for schizophrenia and childhood adversity influences daily-life emotional dysregulation and psychosis proneness

Gestational length affects neurocognition in early-onset schizophrenia

IL-33/ST2 Pathway and Galectin-3 as a New Analytes in Pathogenesis and Cardiometabolic Risk Evaluation in Psychosis

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