Little is known about health-related quality of life (HRQoL) in familial intellectual disability. Economic evaluations of interventions for familial intellectual disability require HRQoL measured through utility data.

We aimed to estimate HRQoL in individuals with familial intellectual disability and their carers and spouses, and identify factors associated with HRQoL.

Families with at least one member with familial intellectual disability were recruited and completed a tailored questionnaire. HRQoL was measured with the Assessment of Quality-of-Life 8D for carers and spouses, and the Health Utilities Index 2 (HUI2) and 3 (HUI3) for individuals with intellectual disability.

A total of 108 carers and 35 spouses, caring for 171 individuals with intellectual disability, completed the survey. Health utility values for carers (0.58) and spouses (0.63) were significantly lower than age- and gender-adjusted population norms (0.8) (p < 0.05). Utility values for individuals with intellectual disability were 0.51 (HUI2) and 0.31 (HUI3), also significantly below age-adjusted norms (p < 0.05). In carers, approximately half reported a mental health condition, and multivariate regression showed that having a mental health disorder, financial stress and caring for someone with aggressive behaviour were associated with lower HRQoL. In individuals with intellectual disability, greater disability severity and need for full-time supervision were associated with lower HRQoL, whereas living with their carer was associated with higher HRQoL.

Familial intellectual disability is associated with significantly lower quality of life of individuals with intellectual disability, their carers and their spouses. HRQoL across the family may help guide planning of health and social support, and demonstrate to policy makers the additional support needs for these families.

Major psychiatric disorders (MPDs) and premenstrual disorders (PMDs) are often comorbid, with indications of shared genetic architecture. However, the specific genetic variants underlying this comorbidity remain elusive. The aim of this study was to identify genomic loci shared between MPDs and PMDs, and to assess the functional characteristics of genes mapped to these loci.

We used genome-wide association data for symptoms of PMDs (S-PMD, n = 67 068) from the Norwegian Mother, Father and Child Cohort Study (MoBa), and for MPDs (schizophrenia, n = 130 644; bipolar disorder, n = 827 335; major depression, n = 1 918 432) from the Psychiatric Genomic Consortium. Shared genetic loci were identified with the conjunctional false discovery rate (conjFDR). Genes mapped to the identified loci were included in functional and pharmacological gene-set enrichment analyses (GSEAs).

We identified 20 loci shared between S-PMD and the MPDs, including 19 novel loci for S-PMD (conjFDR<0.05). GSEA revealed genes involved in calcium signaling and neuronal projection pathways. The drug enrichment analysis identified 36 drugs, including riluzole and mianserin, significantly associated with the identified molecular pathways.

We identified 20 genetic loci shared between the S-PMD and MPDs, implicating calcium transmission in the pathogenesis of PMDs. Together with the drug enrichment results, this provides a biological basis for repurposing existing drugs in the treatment of PMD.

The psychosis continuum conceptualises psychotic phenomena as existing on a spectrum from subclinical experiences to psychotic disorders. Despite epidemiological and clinical evidence in support of this model, few studies have examined polygenic liability across the severity continuum: from subclinical experiences to first-episode psychosis (FEP).

To map polygenic liability for schizophrenia (SCZ), bipolar disorder and major depressive disorder (MDD) across the psychosis continuum. We hypothesised that schizophrenia polygenic scores (SCZ-PGS) would track phenotypic severity most closely across this continuum.

We harmonised data from 5 south-east London cohorts (N = 1315; 860 European, 455 African ancestries) across 4 ordered groups indicative of different levels of phenotypic severity: controls (n = 647), individuals with self-reported psychotic experiences (n = 89), individuals at clinical high risk (CHR) that did not convert to psychosis (n = 124) and individuals with FEP (n = 455). We computed ancestry-specific PGS for SCZ, bipolar disorder and MDD and compared these across groups using ordinal logistic regression.

In European ancestry participants, elevated SCZ-PGS (odds ratio 1.72, p = 4.57 × 10−15), bipolar disorder-PGS (odds ratio 1.56, p = 1.03 × 10−10) and MDD-PGS (odds ratio 1.44, p = 4.86 × 10−8) were individually associated with increasing phenotypic severity. SCZ-PGS explained the largest variance (R2 = 0.084) across the psychosis continuum and showed pairwise differences between CHR and controls (β = 0.32, p = 0.027), and between FEP and CHR (β = 0.38, p = 0.017). Multivariable models, combining three PGS, outperformed univariable models (R2 = 0.105). Similar trends in SCZ-PGS across the psychosis continuum phenotype were seen in African ancestry participants, but only controls and FEP groups differed significantly (β = 0.27, p = 0.037).

Our findings provide biological evidence supporting the psychosis continuum framework. In European ancestry, SCZ-PGS differences suggest that CHR who do not transition to psychosis have intermediate genetic vulnerability. Multivariable models, utilising all three PGS, explained additional variance compared with univariable ones, supporting transdiagnostic genetic liability. Improving PGS predictive power in African ancestry remains a priority.

Eating disorder treatment is most successful when delivered at first onset, underscoring the importance of early intervention. Genetic factors may contribute to earlier onset, but molecular genetic research into symptom onset and severity remains limited.

We investigated: (a) age at onset of behavioural symptoms and low weight, including sex and gender differences; and (b) the single-nucleotide polymorphism (SNP)-based heritability and cross-trait polygenic associations of symptoms, onset, and severity.

Participants (n = 24 973) of genetically derived European ancestry were from the National Institute for Health and Care Research BioResource, including the Genetic Links to Anxiety and Depression Study, the Eating Disorders Genetics Initiative UK and the COVID-19 Psychiatry and Neurological Genetics study. Symptoms were assessed with the ED100K questionnaire. We described sex-stratified onset of binge eating, low weight, self-induced vomiting, laxatives, diuretics, excessive exercise, and fasting. SNP-based heritability was estimated with genome-wide complex trait analysis using genomic-relatedness-based restricted maximum-likelihood. We tested associations with 26 polygenic scores (PGS), which were calculated using SBayesRC.

Symptom median onset ranged from 16 to 20 years: vomiting (16 years), fasting and excessive exercise (17 years), binge eating (18 years), laxatives (19 years), diuretics (20 years) and low weight (20 years). Males were disproportionately likely to report adult onset. In females, behavioural symptoms and low weight showed substantial heritability (SNP-based h2 = 0.31–0.78), but age at onset and cognitive symptoms were less heritable. PGS analyses identified distinct pathways: in females, higher childhood obesity PGS was linked to earlier binge eating onset (approximately 7 months), and higher educational attainment PGS to earlier low weight onset (approximately 6 months).

Eating disorder symptoms begin in adulthood as frequently as adolescence, challenging stereotypes and underscoring investment needed in adult services, particularly for males. Although behavioural symptoms and low weight were strongly heritable, age at onset and cognitive symptoms showed limited genetic contribution. Symptom-level PGS analyses highlight distinct biological and developmental pathways. Larger sample sizes and more accurate phenotyping are needed.

To identify resilience to trauma using longitudinal psychological assessments and uncover its genetic components.

This prospective cohort study included 12,946 surgical patients from the China Surgery and Anesthesia Cohort (CSAC) with assessments of depressive symptoms from pre-surgery through 1, 6, and 12 months post-surgery, using the 9-item Patient Health Questionnaire (PHQ-9). Linear mixed-effects models predicted post-surgery PHQ-9 scores; individuals with much lower observed PHQ-9 score than expected (i.e. lowest 25th percentile of residuals) were defined as resilient. We performed genome-wide association study (GWAS) analysis to identify variants associated with psychological resilience. We examined the identified variant in 2,285 patients from the China Severe Trauma Cohort (CSTC) using genotype stratification and additive models.

CSAC participants had a mean age of 52.2 years and 58.5% were female. Overall, 2,328 (18.0%) were identified as resilient and exhibited a lower prevalence of psychological symptoms. GWAS identified a lead single-nucleotide polymorphism (rs11766511, P = 3.082 × 10−8) mapped to the gene sidekick cell adhesion molecule 1 (SDK1), as a candidate locus implicating neural signaling pathways in stress response and resilience. In CSTC, genotype stratification suggested a lower symptom burden among GG genotype of rs11766511 compared with AA carriers (e.g. Beta = −0.94 [−1.76 to −0.12] for PHQ-9 score). The additive genetic model showed a directionally consistent but non-significant protective pattern of the G allele across psychological symptoms.

Longitudinal assessments of depressive symptoms offer a reliable method for measuring psychological resilience. The rs11766511 locus mapped to SDK1 may represent a candidate genetic signal for psychological resilience and warrants confirmation.

Compared with heterosexual persons, non-heterosexual persons have worse mental health. Sexual Minority Stress Theory (SMST) explains the disparity as resulting from stigma and discrimination. To the extent that heterosexual genetic relatives reared with non-heterosexual persons also have worse mental health, SMST is falsified. We conducted a systematic meta-analysis of studies containing family-genetic comparison data to interrogate the empirical support for SMST.

We systematically identified 17 empirical studies in which twins or non-twin siblings reported on both their sexual orientation and their mental health. Subsequently, we conducted a multilevel meta-analysis, focusing on the degree to which any sexual orientation disparity in mental health diminished with genetic relatedness.

Most of the mental health disparities between non-heterosexual and heterosexual persons were eliminated after controlling for family-genetic factors.

The mental health disparity between non-heterosexual and heterosexual persons is reduced by up to two-thirds once familial background factors are accounted for by comparing monozygotic twins discordant for sexual orientation. This suggests that shared familial causes, and not minority stress, are the most important causes of mental health disparities in non-heterosexual persons.

Advances in the use of genomic technologies in newborn bloodspot screening (NBS) raise ethical challenges that should be systematically and critically considered. We examine how ethical analyses have been incorporated into health technology assessments (HTA) relevant to genomic NBS to inform how ethics might be incorporated in Australian HTAs of genomic NBS.

We conducted an inductive content analysis of publicly available HTA reports and summaries relevant to genomic NBS published between January 2013 and June 2023 across 18 countries. Eligible reports related to genetic or genomic testing or population screening. These reports were screened for inclusion of ethical considerations and coded with NVivo for their presence, structure, and reported influence on decision making. Twelve reports with substantial ethical discussion were examined in-depth through qualitative thematic analysis.

One hundred and ninety reports met our inclusion criteria, with Spain, Australia, and the United Kingdom heavily represented. Ethics was mentioned in 39 percent of reports, and ethical analysis appeared to influence recommendations in 13 percent. When present, ethical considerations focused on equity, harm, and autonomy. Consideration of ethical issues was mostly unstructured, descriptive, and lacked normative conclusions.

Although a range of ethical considerations were raised in the HTA reports relevant to genomic NBS, ethical analyses were generally inconsistently applied or reported, and the way in which ethics has influenced HTA recommendations was not always clear. Further work is needed to understand how the role of ethics in Australian HTAs of genomic NBS could be strengthened to ensure ethically defensible decisions.

Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored.

First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes.

Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05–1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08–1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases.

Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.

Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced.

Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications.

In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI.

While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.