The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study

Lemvigh, Cecilie K; Brouwer, Rachel M.; Hilker, Rikke; Anhøj, Simon; Baandrup, Lone; Pantelis, Christos; Glenthøj, Birte; Fagerlund, Birgitte

doi:10.1017/s0033291721002749

Cited by 13 publications

(22 citation statements)

References 68 publications

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“… 26 No statistically significant evidence was found in a subpopulation of first-episode psychosis cases in the same sample 47 as all the CIs included zero. The 2 other studies 48 , 59 did not find evidence of an additive interaction but it is likely the studies were underpowered. It is possible that other studies ran interaction analyses but did not report negative results, resulting in publication bias.…”

Section: Discussionmentioning

confidence: 92%

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Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis

Woolway

Smart

Lynham

et al. 2022

Schizophrenia Bulletin

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Background and Hypothesis Schizophrenia has been robustly associated with multiple genetic and environmental risk factors. Childhood adversity is one of the most widely replicated environmental risk factors for schizophrenia, but it is unclear if schizophrenia genetic risk alleles contribute to this association. Study Design In this systematic review and meta-analysis, we assessed the evidence for gene-environment correlation (genes influence likelihood of environmental exposure) between schizophrenia polygenic risk score (PRS) and reported childhood adversity. We also assessed the evidence for a gene-environment interaction (genes influence sensitivity to environmental exposure) in relation to the outcome of schizophrenia and/or psychosis. This study was registered on PROSPERO (CRD42020182812). Following PRISMA guidelines, a search for relevant literature was conducted using Cochrane, MEDLINE, PsycINFO, Web of Science, and Scopus databases until February 2022. All studies that examined the association between schizophrenia PRS and childhood adversity were included. Study Results Seventeen of 650 identified studies met the inclusion criteria and were assessed against the Newcastle-Ottawa Scale for quality. The meta-analysis found evidence for gene-environment correlation between schizophrenia PRS and childhood adversity (r = .02; 95% CI = 0.01, 0.03; P = .001), but the effect was small and therefore likely to explain only a small proportion of the association between childhood adversity and psychosis. The 4 studies that investigated a gene-environment interaction between schizophrenia PRS and childhood adversity in increasing risk of psychosis reported inconsistent results. Conclusions These findings suggest that a gene-environment correlation could explain a small proportion of the relationship between reported childhood adversity and psychosis.

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Section: Discussionmentioning

confidence: 92%

“… 48 Lastly, a Danish twin study in 56 schizophrenia spectrum proband pairs, 49 healthy control pairs, and 6 individual probands found no evidence of an interaction between schizophrenia PRS and childhood adversity (OR = 1.00, 95% CI = 0.48, 2.07, P = .999). 59 …”

Section: Resultsmentioning

confidence: 99%

Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis

Woolway

Smart

Lynham

et al. 2022

Schizophrenia Bulletin

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“…Consistent with imaging data, molecular markers are also indicative of accelerated cortical aging in schizophrenia [10], possibly contributing to a markedly increased rate of dementia in late life for people with schizophrenia [11]. Accordingly, deciphering the mechanisms through which chronic stress [12,13], neuroinflammation [14][15][16][17][18], redox dysregulation [19,20], drug abuse [21][22][23] and antipsychotic treatment [24,25] could accelerate cortical tissue loss during late neurodevelopment becomes critical [8,9]. Iron, the most abundant transition metal in the brain, has been implicated in these potential insults [26][27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 73%

Perturbed iron biology in the prefrontal cortex of people with schizophrenia

et al. 2023

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Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

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“…Prospective epidemiological studies have consistently reported an association between cannabis use and an increased risk for subsequent psychotic experiences and psychotic disorders 1 – 3 . However, only a minority of individuals who use cannabis will eventually develop a psychotic disorder.…”

Section: Introductionmentioning

confidence: 99%

A network approach to relationships between cannabis use characteristics and psychopathology in the general population

Betz

Penzel

Kambeitz

2022

Sci Rep

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Cannabis use characteristics, such as earlier initiation and frequent use, have been associated with an increased risk for developing psychotic experiences and psychotic disorders. However, little is known how these characteristics relate to specific aspects of sub-clinical psychopathology in the general population. Here, we explore the relationships between cannabis use characteristics and psychopathology in a large general population sample (N = 2,544, mean age 29.2 years, 47% women) by employing a network approach. This allows for the identification of unique associations between two cannabis use characteristics (lifetime cumulative frequency of cannabis use, age of cannabis use initiation), and specific psychotic experiences and affective symptoms, while controlling for early risk factors (childhood trauma, urban upbringing). We found particularly pronounced unique positive associations between frequency of cannabis use and specific delusional experiences (persecutory delusions and thought broadcasting). Age of cannabis use initiation was negatively related to visual hallucinatory experiences and irritability, implying that these experiences become more likely the earlier use is initiated. Earlier initiation, but not lifetime frequency of cannabis use, was related to early risk factors. These findings suggest that cannabis use characteristics may contribute differentially to risk for specific psychotic experiences and affective symptoms in the general population.

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The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study

Cited by 13 publications

References 68 publications

Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis

Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis

Perturbed iron biology in the prefrontal cortex of people with schizophrenia

A network approach to relationships between cannabis use characteristics and psychopathology in the general population

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