Contributions of Genetic Risk and Fetal Hypoxia to Hippocampal Volume in Patients With Schizophrenia or Schizoaffective Disorder, Their Unaffected Siblings, and Healthy Unrelated Volunteers

Erp, Theo G.M. van; Saleh, Peter A.; Rosso, Isabelle M.; Huttunen, Matti; Lönnqvist, Jouko; Pirkola, Tiia; Salonen, Oili; Valanne, Leena; Poutanen, Veli-Pekka; Standertskjöld-Nordenstam, Carl-Gustav; Cannon, Tyrone D.

doi:10.1176/appi.ajp.159.9.1514

Cited by 206 publications

(133 citation statements)

References 36 publications

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“…Adult diseases such as schizophrenia have also been linked to infection, fetal malnutrition, or hypoxia in early life (Dalman et al, 1999;Van Erp et al, 2002;Boksa and El-Khodor, 2003). A study by Bilbo et al (2005) showed that perinatal exposure to an infectious agent affected how the nervous system responded to an immune challenge and memory consolidation later in adulthood.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

Wu¹,

Basha²,

Brock³

et al. 2008

J. Neurosci.

443

271

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The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic ␤-amyloid (A␤) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (␤-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of A␤ staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

Wu¹,

Basha²,

Brock³

et al. 2008

J. Neurosci.

443

271

View full text Add to dashboard Cite

show abstract

“…Familial risk may determine hippocampal volume loss, 19 which may be both heritable and linked to the specific genetic risk for schizophrenia. 7,20 However, Stefanis and colleagues 21 found no evidence of familial effects once patients with a history of obstetric complications were removed from their analysis, 21 whereas Van Erp and colleagues 22 suggested a gene × environment interaction involving perinatal hypoxic insult to the hippocampus.…”

Section: Introductionmentioning

confidence: 99%

Familial and environmental influences on brain volumes in twins with schizophrenia

Picchioni

Rijsdijk²,

Toulopoulou

et al. 2017

JPN

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“…1,5,[7][8][9][10] A recent review by Schmidt-Kastner and colleagues 11 suggested that susceptibility genes for schizophrenia were more likely than randomly selected genes to be regulated by hypoxia/ischemia and/or expressed in the cerebrovasculature. In fact, a substantial fraction of the genes reported to be significantly associated with schizophrenia in at least two published studies fit this description, even though only 1-2% of known genes are involved in hypoxia-induced regulation.…”

Section: Introductionmentioning

confidence: 99%

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

et al. 2008

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The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-a) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.

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Contributions of Genetic Risk and Fetal Hypoxia to Hippocampal Volume in Patients With Schizophrenia or Schizoaffective Disorder, Their Unaffected Siblings, and Healthy Unrelated Volunteers

Cited by 206 publications

References 36 publications

Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

Familial and environmental influences on brain volumes in twins with schizophrenia

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

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