An axis of genetic heterogeneity in autism is indexed by age at diagnosis and is associated with varying developmental and mental health profiles.

There is growing recognition that earliest signs of autism need not clearly manifest in the first three years of life. To what extent is this variation in developmental trajectories associated with age at autism diagnosis? Does the genetic profile of autism vary with age at autism diagnosis? Using longitudinal data from four birth cohorts, we demonstrate that two different trajectories of socio-emotional behaviours are associated with age at diagnosis. We further demonstrate that the age at autism diagnosis is partly heritable (h 2 SNP = 0.12, s.e.m = 0.01), and is associated with two moderately correlated (r g = 0.38, s.e.m = 0.07) autism polygenic factors. One of these factors is associated with earlier diagnosis of autism, lower social and communication abilities in early childhood. The second factor is associated with later autism diagnosis, increased socio-emotional difficulties in adolescence, and has moderate to high positive genetic correlations with Attention-Deficit/Hyperactivity Disorder, mental health conditions, and trauma. Overall, our research identifies an axis of heterogeneity in autism, indexed by age at diagnosis, which partly explains heterogeneity in autism and the profiles of co-occurring neurodevelopmental and mental health profiles. Our findings have important implications for how we conceptualise autism and provide one model to explain some of the diversity within autism.

Genome-wide fine-mapping improves identification of causal variants.

Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic segments without considering the global genetic architecture. Here, we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods in error control, mapping power and precision, replication rate, and trans-ancestry phenotype prediction. For 48 well-powered traits in the UK Biobank, we identify causal variants that collectively explain 17% of the SNP-based heritability, and predict that fine-mapping 50% of that would require 2 million samples on average. We pinpoint a known causal variant, as proof-of-principle, at FTO for body mass index, unveil a hidden secondary variant with evolutionary conservation, and identify new missense causal variants for schizophrenia and Crohn's disease. Overall, we analyse 600 complex traits with 13 million SNPs, highlighting the efficacy of GWFM with functional annotations.

Genome-wide meta-analyses of non-response to antidepressants identify novel loci and potential drugs.

Antidepressants exhibit a considerable variation in efficacy, and increasing evidence suggests that individual genetics contribute to antidepressant treatment response. Here, we combined data on antidepressant non-response measured using rating scales for depressive symptoms, questionnaires of treatment effect, and data from electronic health records, to increase statistical power to detect genomic loci associated with non-response to antidepressants in a total sample of 135,471 individuals prescribed antidepressants. We performed genome-wide association meta-analyses, leave-one-out polygenic prediction, and bioinformatics analyses for genetically informed drug prioritization. We identified two novel loci associated with non-response to antidepressants and showed significant polygenic prediction in independent samples. In addition, we investigated drugs that target proteins likely involved in mechanisms underlying antidepressant non-response, and shortlisted drugs that warrant further replication and validation of their potential to reduce depressive symptoms in individuals who do not respond to first-line antidepressant medications. These results suggest that meta-analyses of GWAS utilizing real-world measures of treatment outcomes can increase sample sizes to improve the discovery of variants associated with non-response to antidepressants.

Genome-wide fine-mapping improves identification of causal variants.

Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic segments without considering the global genetic architecture. Here, we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods in error control, mapping power and precision, replication rate, and trans-ancestry phenotype prediction. For 48 well-powered traits in the UK Biobank, we identify causal variants that collectively explain 17% of the SNP-based heritability, and predict that fine-mapping 50% of that would require 2 million samples on average. We pinpoint a known causal variant, as proof-of-principle, at FTO for body mass index, unveil a hidden secondary variant with evolutionary conservation, and identify new missense causal variants for schizophrenia and Crohn disease. Overall, we analyse 600 complex traits with 13 million SNPs, highlighting the efficacy of GWFM with functional annotations.

R2ROC: an efficient method of comparing two or more correlated AUC from out-of-sample prediction using polygenic scores.

Polygenic risk scores (PRSs) enable early prediction of disease risk. Evaluating PRS performance for binary traits commonly relies on the area under the receiver operating characteristic curve (AUC). However, the widely used DeLong's method for comparative significance tests suffer from limitations, including computational time and the lack of a one-to-one mapping between test statistics based on AUC and R 2 . To overcome these limitations, we propose a novel approach that leverages the Delta method to derive the variance and covariance of AUC values, enabling a comprehensive and efficient comparative significance test. Our approach offers notable advantages over DeLong's method, including reduced computation time (up to 150-fold), making it suitable for large-scale analyses and ideal for integration into machine learning frameworks. Furthermore, our method allows for a direct one-to-one mapping between AUC and R 2 values for comparative significance tests, providing enhanced insights into the relationship between these measures and facilitating their interpretation. We validated our proposed approach through simulations and applied it to real data comparing PRSs for diabetes and coronary artery disease (CAD) prediction in a cohort of 28,880 European individuals. The PRSs were derived using genome-wide association study summary statistics from two distinct sources. Our approach enabled a comprehensive and informative comparison of the PRSs, shedding light on their respective predictive abilities for diabetes and CAD. This advancement contributes to the assessment of genetic risk factors and personalized disease prediction, supporting better healthcare decision-making.

Exercise rejuvenates microglia and reverses T cell accumulation in the aged female mouse brain.

Slowing and/or reversing brain ageing may alleviate cognitive impairments. Previous studies have found that exercise may mitigate cognitive decline, but the mechanisms underlying this remain largely unclear. Here we provide unbiased analyses of single-cell RNA sequencing data, showing the impacts of exercise and ageing on specific cell types in the mouse hippocampus. We demonstrate that exercise has a profound and selective effect on aged microglia, reverting their gene expression signature to that of young microglia. Pharmacologic depletion of microglia further demonstrated that these cells are required for the stimulatory effects of exercise on hippocampal neurogenesis but not cognition. Strikingly, allowing 18-month-old mice access to a running wheel did by and large also prevent and/or revert T cell presence in the ageing hippocampus. Taken together, our data highlight the profound impact of exercise in rejuvenating aged microglia, associated pro-neurogenic effects and on peripheral immune cell presence in the ageing female mouse brain.

Genetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank.

The causes of temporal fluctuations in adult traits are poorly understood. Here, we investigate the genetic determinants of within-person trait variability of 8 repeatedly measured anthropometric traits in 50,117 individuals from the UK Biobank. We found that within-person (non-directional) variability had a SNP-based heritability of 2-5% for height, sitting height, body mass index (BMI) and weight (P ≤ 2.4 × 10-3). We also analysed longitudinal trait change and show a loss of both average height and weight beyond about 70 years of age. A variant tracking the Alzheimer's risk APOE- E 4 allele (rs429358) was significantly associated with weight loss ( ß = -0.047 kg per yr, s.e. 0.007, P = 2.2 × 10-11), and using 2-sample Mendelian Randomisation we detected a relationship consistent with causality between decreased lumbar spine bone mineral density and height loss (bxy = 0.011, s.e. 0.003, P = 3.5 × 10-4). Finally, population-level variance quantitative trait loci (vQTL) were consistent with within-person variability for several traits, indicating an overlap between trait variability assessed at the population or individual level. Our findings help elucidate the genetic influence on trait-change within an individual and highlight disease risks associated with these changes.

Phenomewide Association Study of Health Outcomes Associated With the Genetic Correlates of 25 Hydroxyvitamin D Concentration and Vitamin D Binding Protein Concentration.

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding protein (DBP, encoded by the GC gene) with a comprehensive range of health disorders and laboratory tests in a large academic medical center. We used summary statistics for 25OHD and DBP to generate polygenic scores (PGS) for 66,482 participants with primarily European ancestry and 13,285 participants with primarily African ancestry from the Vanderbilt University Medical Center Biobank (BioVU). We examined the predictive properties of PGS25OHD, and two scores related to DBP concentration with respect to 1322 health-related phenotypes and 315 laboratory-measured phenotypes from electronic health records. In those with European ancestry: (a) the PGS25OHD and PGSDBP scores, and individual SNPs rs4588 and rs7041 were associated with both 25OHD concentration and 1,25 dihydroxyvitamin D concentrations; (b) higher PGS25OHD was associated with decreased concentrations of triglycerides and cholesterol, and reduced risks of vitamin D deficiency, disorders of lipid metabolism, and diabetes. In general, the findings for the African ancestry group were consistent with findings from the European ancestry analyses. Our study confirms the utility of PGS and two key variants within the GC gene (rs4588 and rs7041) to predict the risk of vitamin D deficiency in clinical settings and highlights the shared biology between vitamin D-related genetic pathways a range of health outcomes.

Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries.

We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP density and annotation information, suggesting whole-genome sequence variants with annotations may further improve prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from nonsynonymous SNPs.

Patterns of stressful life events and polygenic scores for five mental disorders and neuroticism among adults with depression.

The dominant ('general') version of the diathesis-stress theory of depression views stressors and genetic vulnerability as independent risks. In the Australian Genetics of Depression Study (N = 14,146; 75% female), we tested whether polygenic scores (PGS) for major depression, bipolar disorder, schizophrenia, anxiety, ADHD, and neuroticism were associated with reported exposure to 32 childhood, past-year, lifetime, and accumulated stressful life events (SLEs). In false discovery rate-corrected models, the clearest PGS-SLE relationships were for the ADHD- and depression-PGSs, and to a lesser extent, the anxiety- and schizophrenia-PGSs. We describe the associations for childhood and accumulated SLEs, and the 2-3 strongest past-year/lifetime SLE associations. Higher ADHD-PGS was associated with all childhood SLEs (emotional abuse, emotional neglect, physical neglect; ORs = 1.09-1.14; p's < 1.3 × 10-5), more accumulated SLEs, and reported exposure to sudden violent death (OR = 1.23; p = 3.6 × 10-5), legal troubles (OR = 1.15; p = 0.003), and sudden accidental death (OR = 1.14; p = 0.006). Higher depression-PGS was associated with all childhood SLEs (ORs = 1.07-1.12; p's < 0.013), more accumulated SLEs, and severe human suffering (OR = 1.17; p = 0.003), assault with a weapon (OR = 1.12; p = 0.003), and living in unpleasant surroundings (OR = 1.11; p = 0.001). Higher anxiety-PGS was associated with childhood emotional abuse (OR = 1.08; p = 1.6 × 10-4), more accumulated SLEs, and serious accident (OR = 1.23; p = 0.004), physical assault (OR = 1.08; p = 2.2 × 10-4), and transportation accident (OR = 1.07; p = 0.001). Higher schizophrenia-PGS was associated with all childhood SLEs (ORs = 1.12-1.19; p's < 9.3-8), more accumulated SLEs, and severe human suffering (OR = 1.16; p = 0.003). Higher neuroticism-PGS was associated with living in unpleasant surroundings (OR = 1.09; p = 0.007) and major financial troubles (OR = 1.06; p = 0.014). A reversed pattern was seen for the bipolar-PGS, with lower odds of reported physical assault (OR = 0.95; p = 0.014), major financial troubles (OR = 0.93; p = 0.004), and living in unpleasant surroundings (OR = 0.92; p = 0.007). Genetic risk for several mental disorders influences reported exposure to SLEs among adults with moderately severe, recurrent depression. Our findings emphasise that stressors and diatheses are inter-dependent and challenge diagnosis and subtyping (e.g., reactive/endogenous) based on life events.

Comprehensive Sex-Stratified Genetic Analysis of 28 Blood Biomarkers and Depression Reveals a Significant Association between Depression and Low Levels of Total Protein in Females.

Introduction: Major depression (MD) is more common amongst women than men, and MD episodes have been associated with fluctuations in reproductive hormones amongst women. To investigate biological underpinnings of heterogeneity in MD, the associations between depression, stratified by sex and including perinatal depression (PND), and blood biomarkers, using UK Biobank (UKB) data, were evaluated, and extended to include the association of depression with biomarker polygenic scores (PGS), generated as proxy for each biomarker. Method: Using female (N = 39,761) and male (N = 38,821) UKB participants, lifetime MD and PND were tested for association with 28 blood biomarkers. A GWAS was conducted for each biomarker and genetic correlations with depression subgroups were estimated. Using independent data from the Australian Genetics of Depression Study, PGS were constructed for each biomarker, and tested for association with depression status (n [female cases/controls] = 9,006/6,442; n [male cases/controls] = 3,106/6,222). Regions of significant local genetic correlation between depression subgroups and biomarkers highlighted by the PGS analysis were identified. Results: Depression in females was significantly associated with levels of twelve biomarkers, including total protein (OR = 0.90, CI = [0.86, 0.94], p = 3.9 × 10-6) and vitamin D (OR = 0.94, CI = [0.90, 0.97], p = 2.6 × 10-4), and PND with five biomarker levels, also including total protein (OR = 0.88, CI = [0.81, 0.96], p = 4.7 × 10-3). Depression in males was significantly associated with levels of eleven biomarkers. In the independent Australian Genetics of Depression Study, PGS analysis found significant associations for female depression and PND with total protein (female depression: OR = 0.93, CI = [0.88, 0.98], p = 3.6 × 10-3; PND: OR = 0.91, CI = [0.86, 0.96], p = 1.1 × 10-3), as well as with vitamin D (female depression: OR = 0.93, CI = [0.89, 0.97], p = 2.0 × 10-3; PND: OR = 0.92, CI = [0.87, 0.97], p = 1.4 × 10-3). The male depression sample did not report any significant results, and the point estimate of total protein (OR = 0.98, CI = [0.92-1.04], p = 4.7 × 10-1) did not indicate any association. Local genetic correlation analysis highlighted significant genetic correlation between PND and total protein, located in 5q13.3 (rG = 0.68, CI = [0.33, 1.0], p = 3.6 × 10-4). Discussion and Conclusion: Multiple lines of evidence from genetic analysis highlight an association between total serum protein levels and depression in females. Further research involving prospective measurement of total protein and depressive symptoms is warranted.

Genetic control of DNA methylation is largely shared across European and East Asian populations.

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Connecting genomic results for psychiatric disorders to human brain cell types and regions reveals convergence with functional connectivity.

Understanding the temporal and spatial brain locations etiological for psychiatric disorders is essential for targeted neurobiological research. Integration of genomic insights from genome-wide association studies with single-cell transcriptomics is a powerful approach although past efforts have necessarily relied on mouse atlases. Leveraging a comprehensive atlas of the adult human brain, we prioritized cell types via the enrichment of SNP-heritabilities for brain diseases, disorders, and traits, progressing from individual cell types to brain regions. Our findings highlight specific neuronal clusters significantly enriched for the SNP-heritabilities for schizophrenia, bipolar disorder, and major depressive disorder along with intelligence, education, and neuroticism. Extrapolation of cell-type results to brain regions reveals important patterns for schizophrenia with distinct subregions in the hippocampus and amygdala exhibiting the highest significance. Cerebral cortical regions display similar enrichments despite the known prefrontal dysfunction in those with schizophrenia highlighting the importance of subcortical connectivity. Using functional MRI connectivity from cases with schizophrenia and neurotypical controls, we identified brain networks that distinguished cases from controls that also confirmed involvement of the central and lateral amygdala, hippocampal body, and prefrontal cortex. Our findings underscore the value of single-cell transcriptomics in decoding the polygenicity of psychiatric disorders and offer a promising convergence of genomic, transcriptomic, and brain imaging modalities toward common biological targets.

Impact of genetic, sociodemographic, and clinical features on antidepressant treatment trajectories in the perinatal period.

Pregnant women on antidepressants must balance potential fetal harm with the relapse risk. While various clinical and sociodemographic factors are known to influence treatment decisions, the impact of genetic factors remains unexplored. We conducted a cohort study among 2,316 women with diagnosed affective disorders who had redeemed antidepressant prescriptions six months before pregnancy, identified from the Danish Integrated Psychiatric Research study. We calculated polygenic risk scores (PGSs) for major depression (MDD), bipolar disorder (BD), and schizophrenia (SCZ) using individual-level genetic data and summary statistics from genome-wide association studies. We retrieved data on sociodemographic and clinical features from national registers. Applying group-based trajectory modeling, we identified four treatment trajectories across pregnancy and postpartum: Continuers (38.2 %), early discontinuers (22.7 %), late discontinuers (23.8 %), and interrupters (15.3 %). All three PGSs were not associated with treatment trajectories; for instance, the relative risk ratio for continuers versus early discontinuers was 0.93 (95 % CI: 0.81-1.06), 0.98 (0.84-1.13), 1.09 (0.95-1.27) for per 1-SD increase in PGS for MDD, BD, and SCZ, respectively. Sociodemographic factors were generally not associated with treatment trajectories, except for the association between primiparity and continuing antidepressant use. Women who received ≥2 classes or a higher dose of antidepressants had a higher probability of being late discontinuers, interrupters, and continuers. The likelihood of continuing antidepressants or restarting antidepressants postpartum increased with the previous antidepressant treatment duration. Our findings indicate that continued antidepressant use during pregnancy is influenced by the severity of the disease rather than genetic predisposition as measured by PGSs.

Evening Chronotypes With Depression Report Poorer Outcomes of Selective Serotonin Reuptake Inhibitors: A Survey-Based Study of Self-Ratings.

BACKGROUND: Preliminary evidence suggests that evening chronotype is related to poorer efficacy of selective serotonin reuptake inhibitors. It is unknown whether this is specific to particular medications, self-rated chronotype, or efficacy. METHODS: In the Australian Genetics of Depression Study (n = 15,108; 75% women; 18-90 years; 68% with ≥1 other lifetime diagnosis), a survey recorded experiences with 10 antidepressants, and the reduced Morningness-Eveningness Questionnaire was used to estimate chronotype. A chronotype polygenic score was calculated. Age- and sex-adjusted regression models (Bonferroni-corrected) estimated associations among antidepressant variables (how well the antidepressant worked [efficacy], duration of symptom improvement, side effects, discontinuation due to side effects) and self-rated and genetic chronotypes. RESULTS: The chronotype polygenic score explained 4% of the variance in self-rated chronotype (r = 0.21). Higher self-rated eveningness was associated with poorer efficacy of escitalopram (odds ratio [OR] = 1.04; 95% CI, 1.02 to 1.06; p = .000035), citalopram (OR = 1.03; 95% CI, 1.01 to 1.05; p = .004), fluoxetine (OR = 1.03; 95% CI, 1.01 to 1.05; p = .001), sertraline (OR = 1.02; 95% CI, 1.01 to 1.04; p = .0008), and desvenlafaxine (OR = 1.03; 95% CI, 1.01 to 1.05; p = .004), and a profile of increased side effects (80% of those recorded; ORs = 0.93-0.98), with difficulty getting to sleep the most common. Self-rated chronotype was unrelated to duration of improvement or discontinuation. The chronotype polygenic score was only associated with suicidal thoughts and attempted suicide (self-reported). While our measures are imperfect, and not of circadian phase under controlled conditions, the model coefficients suggest that dysregulation of the phenotypic chronotype relative to its genetic proxy drove relationships with antidepressant outcomes. CONCLUSIONS: The idea that variation in circadian factors influences response to antidepressants was supported and encourages exploration of circadian mechanisms of depressive disorders and antidepressant treatments.

Linking Polygenic Risk of Schizophrenia to Variation in Magnetic Resonance Imaging Brain Measures: A Comprehensive Systematic Review.

BACKGROUND AND HYPOTHESIS: Schizophrenia is highly heritable, with a polygenic effect of many genes conferring risk. Evidence on whether cumulative risk also predicts alterations in brain morphology and function is inconsistent. This systematic review examined evidence for schizophrenia polygenic risk score (sczPRS) associations with commonly used magnetic resonance imaging (MRI) measures. We expected consistent evidence to emerge for significant sczPRS associations with variation in structure and function, specifically in frontal, temporal, and insula cortices that are commonly implicated in schizophrenia pathophysiology. STUDY DESIGN: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE, Embase, and PsycINFO for peer-reviewed studies published between January 2013 and March 2022. Studies were screened against predetermined criteria and National Institutes of Health (NIH) quality assessment tools. STUDY RESULTS: In total, 57 studies of T1-weighted structural, diffusion, and functional MRI were included (age range = 9-80 years, Nrange = 64-76 644). We observed moderate, albeit preliminary, evidence for higher sczPRS predicting global reductions in cortical thickness and widespread variation in functional connectivity, and to a lesser extent, region-specific reductions in frontal and temporal volume and thickness. Conversely, sczPRS does not predict whole-brain surface area or gray/white matter volume. Limited evidence emerged for sczPRS associations with diffusion tensor measures of white matter microstructure in a large community sample and smaller cohorts of children and young adults. These findings were broadly consistent across community and clinical populations. CONCLUSIONS: Our review supports the hypothesis that schizophrenia is a disorder of disrupted within and between-region brain connectivity, and points to specific whole-brain and regional MRI metrics that may provide useful intermediate phenotypes.

The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders.

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.

Naomi Wray.

Naomi Wray works at the interface of genetics, statistics and psychiatric disorders. With early training in quantitative genetics applied to livestock she brought to the field a perspective on the polygenic nature of common, complex disease. She advocates for experimental paradigms that exploit polygenicity to advance translational outcomes in psychiatry.