Parental origin, DNA structure, and the schizophrenia spectrum.
Ontology highlight
ABSTRACT:
SUBMITTER: Bassett AS
PROVIDER: S-EPMC3276592 | biostudies-literature | 2011 Apr
REPOSITORIES: biostudies-literature
Publications
Parental origin, DNA structure, and the schizophrenia spectrum.
The American journal of psychiatry 20110401 4
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Project description:Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.
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Project description:BACKGROUND:Mounting evidence implicates early life and prenatal immune disturbances in the etiology of severe mental illnesses. Asthma is a common illness associated with chronic aberrant immune responses. We aimed to determine if asthma in childhood and parents is associated with bipolar and schizophrenia spectrum disorders. METHODS:A cohort study including all children born in Sweden 1973-1995 (N > 2 million) assessing associations between childhood hospitalization for asthma, parental asthma during and pre-pregnancy, and subsequent bipolar and schizophrenia spectrum disorders. RESULTS:Children with hospitalizations for asthma between 11 and 15 years had increased rates of bipolar (adjusted hazard ratio [aHR] = 1.73, 95% confidence interval [CI] = 1.21-2.47) and schizophrenia spectrum disorders (aHR = 1.62, 95% CI = 1.08-2.42). However, there was no association with asthma before aged 11. These results were supported by an analysis of siblings discordant for asthma. We found an association between both maternal and paternal asthma and bipolar disorder (aHR = 1.60, 95% CI = 1.27-2.02, and aHR = 1.44, 95% CI = 1.08-1.93, respectively), but not between parental asthma and schizophrenia spectrum disorders. CONCLUSIONS:As far as we are aware, this is the first study to find increased risk of bipolar disorder in children of individuals with asthma. Asthma admissions before aged 11 do not appear to be linked to bipolar or schizophrenia spectrum disorders. Taken together, our results do not suggest a straightforward link between asthma and severe mental illness via neurodevelopmental effects of inflammation, but potentially there is shared genetic vulnerability. This finding has implications for understanding the differential pathogenic mechanisms of bipolar and schizophrenia spectrum disorders.
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Project description:Eukaryotic origins of replication are licensed upon loading of the MCM helicase motor onto DNA. ATP hydrolysis by MCM is required for loading and the post-catalytic MCM is an inactive double hexamer that encircles duplex DNA. Origin firing depends on MCM engagement of Cdc45 and GINS to form the CMG holo-helicase. CMG assembly requires several steps including MCM phosphorylation by DDK. To understand origin activation, here we have determined the cryo-EM structures of DNA-bound MCM, either unmodified or phosphorylated, and visualize a phospho-dependent MCM element likely important for Cdc45 recruitment. MCM pore loops touch both the Watson and Crick strands, constraining duplex DNA in a bent configuration. By comparing our new MCM-DNA structure with the structure of CMG-DNA, we suggest how the conformational transition from the loaded, post-catalytic MCM to CMG might promote DNA untwisting and melting at the onset of replication.
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Project description:AimsChildhood maltreatment and a family history of a schizophrenia spectrum disorder (SSD) are each associated with social-emotional dysfunction in childhood. Both are also strong risk factors for adult SSDs, and social-emotional dysfunction in childhood may be an antecedent of these disorders. We used data from a large Australian population cohort to determine the independent and moderating effects of maltreatment and parental SSDs on early childhood social-emotional functioning.MethodsThe New South Wales Child Development Study combines intergenerational multi-agency data using record linkage methods. Multiple measures of social-emotional functioning (social competency, prosocial/helping behaviour, anxious/fearful behaviour; aggressive behaviour, and hyperactivity/inattention) on 69 116 kindergarten children (age ~5 years) were linked with government records of child maltreatment and parental presentations to health services for SSD. Multivariable analyses investigated the association between maltreatment and social-emotional functioning, adjusting for demographic variables and parental SSD history, in the population sample and in sub-cohorts exposed and not exposed to parental SSD history. We also examined the association of parental SSD history and social-emotional functioning, adjusting for demographic variables and maltreatment.ResultsMedium-sized associations were identified between maltreatment and poor social competency, aggressive behaviour and hyperactivity/inattention; small associations were revealed between maltreatment and poor prosocial/helping and anxious/fearful behaviours. These associations did not differ greatly when adjusted for parental SSD, and were greater in magnitude among children with no history of parental SSD. Small associations between parental SSD and poor social-emotional functioning remained after adjusting for demographic variables and maltreatment.ConclusionsChildhood maltreatment and history of parental SSD are associated independently with poor early childhood social-emotional functioning, with the impact of exposure to maltreatment on social-emotional functioning in early childhood of greater magnitude than that observed for parental SSDs. The impact of maltreatment was reduced in the context of parental SSDs. The influence of parental SSDs on later outcomes of maltreated children may become more apparent during adolescence and young adulthood when overt symptoms of SSD are likely to emerge. Early intervention to strengthen childhood social-emotional functioning might mitigate the impact of maltreatment, and potentially also avert future psychopathology.
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