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Summary: Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. Methods: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. Findings: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). Interpretation: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. Funding: Funding acknowledgements for each cohort can be found in the Supplementary Note.

Abstract Background Prior work suggests that higher fruit and vegetable consumption may protect against depression in older adults. Better understanding of the influence of genetic and environmental factors on fruit and vegetable intakes may lead to the design of more effective dietary strategies to increase intakes. In turn this may reduce the occurrence of depression in older adults. Objectives The primary aim of this study is to estimate the genetic and environmental influences on the consumption of fruit and vegetables in older adults. The secondary aim is an exploratory analysis into possible shared genetic influences on fruit and vegetable intakes and depression. Methods Analysis of observational data from 374 twins (67.1% female; 208 monozygotic (MZ); 166 dizygotic (DZ)) aged ≥ 65 years drawn from the Older Australian Twins Study. Dietary data were obtained using a validated food frequency questionnaire and depressive symptoms were measured using the 15-item short form Geriatric Depression Scale. The contribution of genetic and environmental influences on fruit and vegetable intake were estimated by comparing MZ and DZ twin intakes using structural equation modelling. A tri-variate twin model was used to estimate the genetic and environmental correlation between total fruit and vegetable intakes and depression. Results In this study, vegetable intake was moderately influenced by genetics (0.39 95%CI 0.22, 0.54). Heritability was highest for brassica vegetables (0.40 95%CI 0.24, 0.54). Overall fruit intake was not significantly heritable. No significant genetic correlations were detected between fruit and vegetable intake and depressive symptoms. Conclusions Vegetable consumption, particularly bitter tasting brassica vegetables, was significantly influenced by genetics, although environmental influences were also apparent. Consumption of fruit was only influenced by the environment, with no genetic influence detected, suggesting strategies targeting the food environment may be particularly effective for encouraging fruit consumption.

Background Prisoners with an intellectual disability are overrepresented in custody and more likely to reoffend and be reincarcerated compared with the general prison population. Although prisoners with intellectual disability have many of the same risk factors for recidivism as the general prison population, the high rates of mental illness experienced by this group are key drivers of recidivism. Aims We aimed to assess the impact of provision of post-release disability and community mental health support on rates of reincarceration in a cohort with identified intellectual disability and serious mental illness diagnosis. Method We conducted a historical cohort study using linked administrative data-sets, including data on hospital admissions, community mental health, disability support and corrections custody in New South Wales, Australia (n = 484). To assess the time to return to adult custody, we used survival analysis on multiple failure-time data. Results Over the median follow-up period of 7.4 years, 73.7% (357) received community mental health support, 19.8% (96) received disability support and 18.6% (85) received a combination of supports during a post-release period from prison. Lower hazards of reincarceration in a post-release period were associated with receipt of community mental health support (hazard ratio [HR] = 0.58, CI 0.49–0.69, P < 0.001), or a combination of community mental health and disability support (HR = 0.46, CI 0.34–0.61, P < 0.001). Conclusions High rates of reincarceration for prisoners with intellectual disability and history of serious mental illness may be modifiable by provision of appropriate mental health and disability supports.

Purpose: Clear understanding of mental health phenotypes and associated socioeconomic, physical health and well-being impacts in adult women with an FMR1 premutation (PM) is needed for counseling and primary healthcare. Methods: A questionnaire captured mental health conditions in women with a PM, using lifetime diagnosis and nested psychometric scales (Liebowitz Social Anxiety Scale; Depression and Anxiety Stress Scale). Socioeconomic, physical health and well-being data were entered into 2 multivariable logistic regression models (1 with depression status as the outcome variable and 1 with social anxiety as the outcome). Results: 137 participants were included. Depression was found in ∼30% and social anxiety in ∼38%. With depression status the outcome variable, strongest associations were for low education, diagnosis of migraine, diagnosis of irritable bowel syndrome, and self-reported hearing loss symptoms. With social anxiety status as the outcome, strongest associations were with education, migraine, irritable bowel syndrome, relationship status, and subjective memory complaints. Conclusion: Mental health impacts were found in more than 1 in 3 women. Poor mental health was significantly associated with socioeconomic and physical health factors. Findings may inform health care professionals about personalized treatment options for women with a PM.

Abstract Background People with intellectual disability (ID) have multiple and complex health needs, more frequent healthcare episodes, and experience poorer health outcomes. Research conducted two decades ago showed that medical professionals were lacking in the knowledge and skills required to address the complex needs of this patient group. The aim of the current study was to determine whether Australian undergraduate medical schools that offer ID health education content had changed the amount and nature of such teaching over this period. Methods Identical or equivalent questionnaire items were compared across eight Australian medical schools that participated in curricula audits conducted in 1995 (referred to as T1) and 2013/14 (T2). The audits were of the nature of the ID content, methods used to teach it, and who taught it. Results There was no significant difference in the number of hours of compulsory ID content offered to medical students at T2 (total = 158.3 h; median = 2.8 h per ID unit) compared with T1 (total = 171 h; median = 2.5 h). At T2 compared with T1, units with ID content taught in the area of general practice had increased (2 units; 3.6% to 7 units; 16.3%), while decreases were seen in paediatrics (22 units; 40.0% to 10 units; 23.3%) and psychiatry (10 units; 18.2% to 4 units; 9.3%). The number of schools using problem- and/or enquiry-based learning rose to six at T2 from one at T1. Inclusive teaching practices (people with ID develop or deliver content) in compulsory/elective units had increased at T2 (10 units; 23.3%) compared with T1 (6 units; 10.9%), but direct clinical contact with people with ID had decreased (29 units; 52.7% to 11 units; 25.6%). Conclusions Overall, little progress has been made to address the gaps in ID education for medical students identified from an audit conducted in 1995. Renewal of ID content in medical curricula is indicated as a key element in efforts to improve workforce capacity in this area and reduce barriers to care, with the aim of reversing the poor health outcomes currently seen for this group.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.

Background Psychotropic medications are sometimes used off-label and inappropriately. This may cause harm to adolescents with intellectual disability. However, few studies have analysed off-label or inappropriate prescribing to this group. Aims To examine the appropriateness of psychotropic prescribing to adolescents with intellectual disability living in the community in south-east Queensland, Australia. Method Off-label medication use was determined based on whether the recorded medical condition treated was approved by the Australian Therapeutic Goods Administration. Clinical appropriateness of medication use was determined based on published guidelines and clinical opinion of two authors who specialise in developmental disability medicine (J.N.T. and D.H.). Results We followed 429 adolescents for a median of 4.2 years. A total of 107 participants (24.9%) were prescribed psychotropic medications on at least one occasion. Of these, 88 (82.2%) were prescribed their medication off-label or inappropriately at least once. Off-label or inappropriate use were most commonly associated with challenging behaviours. Conclusions Off-label or inappropriate use of psychotropic medications was common, especially for the management of challenging behaviours. Clinical decision-making accounts for individual patient factors and is made based on clinical experience as well as scientific evidence, whereas label indications are developed for regulatory purposes and, although appropriate at a population level, cannot encompass the foregoing considerations. Education for clinicians and other staff caring for people with intellectual disability, and a patient-centred approach to prescribing with involvement of families should encourage appropriate prescribing. The effect of the National Disability Insurance Scheme on the appropriateness of psychotropic medication prescribing should be investigated.

Individual differences in the Big Five personality traits have emerged as predictors of health and longevity. Although there are robust protective effects for higher levels of conscientiousness, results are mixed for other personality traits. In particular, higher levels of neuroticism have significantly predicted an increased risk of mortality, no-risk at all, and even a reduced risk of dying. The current study hypothesizes that one potential reason for the discrepancy in these findings for neuroticism is that interactions among neuroticism and other key personality traits have largely been ignored. Thus, in the current study we focus on testing whether the personality traits neuroticism and conscientiousness interact to predict mortality. Specifically, we borrow from recent evidence of “healthy neuroticism” to explore whether higher levels of neuroticism are only a risk factor for increased mortality risk when conscientiousness levels are low. We conducted a pre-registered integrative data analysis using 12 different cohort studies (total N = 44,702). Although a consistent pattern emerged of higher levels of conscientiousness predicting a reduced hazard of dying, neuroticism did not show a consistent pattern of prediction. Moreover, no study provided statistical evidence of a neuroticism by conscientiousness interaction. The current findings do not support the idea that the combination of high conscientiousness and high neuroticism can be protective for longevity. Future work is needed to explore different protective factors that may buffer the negative effects of higher levels of neuroticism on health, as well as other behaviors and outcomes that may support the construct of healthy neuroticism.

BackgroundChildren and adolescents with autism spectrum disorder (ASD) are a highly medicated group. Few studies have examined the neuropsychiatric profile and patterns of psychotropic medication use among adults with ASD.AimsTo describe and compare the neuropsychiatric profile and psychotropic medication use in a cohort of adults with ASD and non-autistic controls.MethodBaseline data from a survey-based, longitudinal study of adults with ASD in Australia. Participants were 188 adults with ASD and 115 controls aged 25–80 years.ResultsASD was associated with increased odds of psychotropic medication use even when controlling for the presence of any neurological or psychiatric disorder. There were no corresponding indications for 14.4% of psychotropic medications prescribed to adults with ASD.ConclusionsThis study found substantial psychotropic prescribing for adults with ASD. Patterns of psychotropic medication use may reflect prescribing for behavioural indications despite limited evidence to support this practice.Declaration of interestNone.

Abstract Background Individuals with intellectual disability experience higher rates of physical and mental health conditions compared with the general population, yet have inequitable access to health care services. Improving the workplace capacity of medical professionals to meet the needs of this population is one way to reduce barriers to care and improve health outcomes. Using diverse pedagogy appropriate to learning outcomes to teach medical students about intellectual disability is a necessary step in improving future workplace capacity. However, there is a lack of research into how, and by whom, medical students are taught about intellectual disability. The aim of this study was to investigate this through an audit of Australian medical school curricula. Methods The Deans of Australian universities that provide accredited medical degrees (n = 20) were invited by email to participate in a two-phase audit of intellectual disability content in the curricula. Phase 1 (n = 14 schools) involved the Dean’s delegate completing a telephone interview or questionnaire regarding medical course structure. If intellectual disability content was identified, a unit coordinator was invited to complete a survey regarding how this content was taught and by whom (Phase 2; n = 12 schools). Results There was considerable variability across Australian medical schools regarding methods used to teach content about intellectual disability. Didactic teaching methods were most frequently used (62% of units included some form of lecture), but workshops and tutorials were reasonably well represented (34% of units contained one or both). Thirty-six percent of units included two or more teaching methods. Almost all schools (83%) used some problem- and/or enquiry-based learning. Educator backgrounds included medicine, nursing, and allied health. A majority of schools (n = 9, 75%) involved people with intellectual disability designing and teaching content, but the extent to which this occurred was inconsistent. Conclusions Renewing curricula around intellectual disability across all medical schools by introducing varied teaching methods and the inclusion of people with intellectual disability would assist students to develop knowledge, skills, attitudes, and confidence in intellectual disability health. Such renewal offers the potential to reduce barriers to service this population regularly face, thereby improving their health outcomes.

Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Adequate cerebral blood flow (CBF) is necessary to maintain brain metabolism and function. Arterial spin labeling (ASL) is an emerging MRI technique offering a non-invasive and reliable quantification of CBF. The genetic basis of CBF has not been well documented, and one approach to investigate this is to examine its heritability. The current study aimed to examine the heritability of CBF using ASL data from a cohort of community-dwelling older twins (41 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs; age range, 65–93 years; 56.4% female). The results showed that the cortex had higher CBF than subcortical gray matter (GM) regions, and CBF in the GM regions of the anterior cerebral artery (ACA) territory was lower than that of the middle (MCA) and posterior (PCA) cerebral arteries. After accounting for the effects of age, sex and scanner, moderate heritability was identified for global CBF (h2 = 0.611; 95% CI = 0.380–0.761), as well as for cortical and subcortical GM and the GM in the major arterial territories (h2 = 0.500–0.612). Strong genetic correlations (GCs) were found between CBF in subcortical and cortical GM regions, as well as among the three arterial territories (ACA, MCA, PCA), suggesting a largely convergent genetic control for the CBF in brain GM. The moderate heritability of CBF warrants future investigations to uncover the genetic variants and genes that regulate CBF.

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the“COPI-mediated anterograde transport” gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

Background: Late-life depression has been associated with white matter changes in studies using the regions of interest approach., Aims: To investigate the cross-sectional and longitudinal relationship between white matter integrity and depression in community-dwelling individuals using diffusion tensor imaging with tract-based spatial statistics., Method: The sample comprised 381 participants aged between 72 and 92 years who were assessed twice within 2 years. Depressive symptoms were measured with the Geriatric Depression Scale. Tract-based spatial statistics were applied to investigate white matter integrity in currently depressed v. non-depressed elderly people and in those with a history of depression v. no history of depression. The relationship between white matter integrity and development of depressive symptoms after 2 years were analysed with logistic regression., Results: Individuals with current depression had widespread white matter integrity reduction compared with non-depressed elderly people. Significant fractional anisotropy reductions were found in 45 brain areas with the most notable findings in the frontal lobe, association and projection fibres. A history of depression was not associated with reduced fractional anisotropy. White matter changes in the superior frontal gyrus, posterior thalamic radiation, superior longitudinal fasciculus and in the body of corpus callosum predicted depression at follow-up., Conclusions: Reduced white matter integrity is associated with late-life depression and predicts future depressive symptoms whereas a history of depression is not related to white matter changes. Disruption to white matter integrity may be a biomarker to predict late-life depression., (Royal College of Psychiatrists.)