9 research outputs found
Genetic variants associated with longitudinal changes in brain structure across the lifespan
Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging
Cortical mediation of relationships between dopamine receptor D2 and cognition is absent in youth at risk of bipolar disorder
Bipolar disorder is associated with cognitive deficits and cortical changes for which the developmental dynamics are not well understood. The dopamine D2 receptor (DRD2) gene has been associated with both psychiatric disorders and cognitive variability. Here we examined the mediating role of brain structure in the relationship between DRD2 genomic variation and cognitive performance, with target cortical regions selected based on evidence of association with DRD2, bipolar disorder and/or cognition from prior literature. Participants (n = 143) were aged 12â30 years and comprised 62 first-degree relatives of bipolar patients (deemed âat-riskâ), 55 controls, and 26 patients with established bipolar disorder; all were unrelated Caucasian individuals with complete data across the three required modalities (structural magnetic resonance imaging, neuropsychological and genetic data). A DRD2 haplotype was derived from three functional polymorphisms (rs1800497, rs1076560, rs2283265) associated with alternative splicing (i.e., D2-short/-long isoforms). Moderated mediation analyses explored group differences in relationships between this DRD2 haplotype, three structural brain networks which subsume the identified cortical regions of interest (frontoparietal, dorsal-attention, and ventral-attention), and three cognitive indices (intelligence, attention, and immediate memory). Controls who were homozygous for the DRD2 major haplotype demonstrated greater cognitive performance as a result of dorsal-attention network mediation. However, this association was absent in the âat-riskâ group. This study provides the first evidence of a functional DRD2-brain-cognition pathway. The absence of typical brain-cognition relationships in young âat-riskâ individuals may reflect biological differences that precede illness onset. Further insight into early pathogenic processes may facilitate targeted early interventions
Predictors of developmental surveillance completion at six months of age in south western Sydney
Background: While developmental surveillance programs promote early identification of child developmental problems, evidence has indicated suboptimal uptake. This study aimed to identify predictors of developmental surveillance completion at 6 months postpartum. Methods: Questionnaires were administered to the parents of 510 infants who were born in south western Sydney, Australia over a 22-month period. Attendance for developmental screening and completion of the Parents' Evaluation of Developmental Status (PEDS) at 6 months postpartum were modelled separately using multivariable logistic regression. Results: Developmental surveillance attendance was predicted by higher levels of maternal education, annual income and being informed about checks. PEDS completion at 6 months of age was predicted by higher income and being informed, as well as being married, employed, speaking English at home, full-term birth and the professional status of the practitioner completing the check. Conclusions: Barriers to developmental surveillance included low socioeconomic status, linguistic diversity and possible gaps in parental knowledge and professional education. Developmental surveillance rates may be increased by the addition of targeted parental and professional support within current universal frameworks
THE RELATIONSHIP BETWEEN FUNCTIONAL DOPAMINE D2 RECEPTOR HAPLOTYPES AND COGNITIVE OUTCOMES, AS MEDIATED BY REGIONAL BRAIN STRUCTURE: A COMPARISON OF CONTROL, AT-RISK, AND BIPOLAR DISORDER SUBJECTS
Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder
AbstractAimsBipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRS) â a quantitative index of genomic risk â and variability in brain structures implicated in SA.MethodsParticipants (n=206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives (âhigh-riskâ), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRS were computed using genome-wide association data for SA in BD (SA-in-BD), SA in Major Depressive Disorder (SA-in-MDD) [Mullins et al., 2019], and risky behavior [Karlsson LinnĂ©r et al., 2019]. Structural MRI processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction.ResultsSA-in-MDD and SA-in-BD PRS negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRS inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the âhigh-riskâ group. SA-in-MDD and SA-in-BD PRS positively predicted cuneus structure, irrespective of group.ConclusionsThis study demonstrated associations between PRS for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRS, in conjunction with a range of biological, phenotypic, environmental and experiential data in high-risk populations, may inform predictive models for suicidal behaviors.</jats:sec
Knowledge mobilisation for chronic disease prevention: the case of the Australian Prevention Partnership Centre
Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group
Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18â75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted âbrain ageâ and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohenâs dâ=â0.14, 95% CI: 0.08â0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates
Intelligence, educational attainment, and brain structure in those at familial highârisk for schizophrenia or bipolar disorder
Firstâdegree relatives of patients diagnosed with schizophrenia (SZâFDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. Firstâdegree relatives of patients diagnosed with bipolar disorder (BDâFDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BDâFDRs are inconsistent. Here, we performed a metaâanalysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZâFDRs, 867 BDâFDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZâFDRs showed a pattern of widespread thinner cortex, while BDâFDRs had widespread larger cortical surface area. IQ was lower in SZâFDRs (d = â0.42, p = 3âĂâ10â5), with weak evidence of IQ reductions among BDâFDRs (d = â0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the groupâeffects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZâFDRs and more pronounced effects in BDâFDRs. To conclude, SZâFDRs and BDâFDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZâFDRs and BDâFDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment