Mapping genetic convergence across brain structure, mental health, and cardiometabolic disease

Genetically informed dissection of multimodal brain aging and ten major psychiatric disorders.

Shared genetic architecture between schizophrenia and subcortical brain susceptibility phenotypes.

Schizophrenia (SCZ) is a highly heritable and complex neuropsychiatric disorder. Emerging evidence implicates dysregulated brain iron, particularly in subcortical regions, in SCZ pathophysiology. Here, we systematically dissected the shared genetic architecture between SCZ and subcortical brain susceptibility phenotypes by integrating large-scale genome-wide association study (GWAS) data with quantitative susceptibility mapping (QSM) phenotypes across 16 subcortical regions. Using the MiXeR framework, we quantified the extent and pattern of shared genetic overlap between SCZ and each QSM phenotype, revealing the strongest overlap in the left and right nucleus accumbens. Conditional and conjunction false discovery rate analyses identified 666 unique shared SNPs. Functional annotation highlighted enrichment in pathways related to synaptic function and neuronal development, with pronounced expression in neurons. Additionally, we characterized their spatio-temporal expression patterns of shared genes and identified 89 significant expression-trait associations linked to SCZ-related phenotypes. Furthermore, the virtual drug screen identified 691 potential protein-drug pairs that may contribute to both iron regulation and SCZ. Our findings provide new insights into the complex interaction between subcortical brain susceptibility phenotypes and SCZ, highlighting pathways that may offer novel therapeutic strategies for SCZ and related brain susceptibility-associated conditions.

The genetic relationship between ADHD and shortened telomeres points to neurodevelopmental mechanisms.

Attention-Deficit/Hyperactivity Disorder (ADHD) is often accompanied by other psychiatric and somatic conditions. Telomere shortening as an accelerated biological aging marker may underlie this aggregate burden. Telomere length (TL) has previously been associated with childhood inattention and hyperactivity, as well as other neuropsychiatric conditions. We hypothesize that TL and ADHD may share overlapping genetic influences, suggesting that some of the same genes could affect both cellular aging and ADHD traits. We investigated the pleiotropic and causal associations between these traits. Using the latest and largest publicly available genome-wide association study (GWAS) summary data for ADHD (38,691 cases and 186,843 controls) and TL (472,174 subjects), we tested causality, global and local genetic correlations, and joint genomic effects. Polygenic scores (PGS) were evaluated in an independent clinical sample of 665 ADHD cases and 995 controls, and TL was quantified via qPCR in a subsample of 370 subjects. The pleiotropy analysis showed global and local (a chromosome 17 locus) negative correlations. Shared genomic analysis showed loci enriched across several chromosomes, notably including the same chromosome 17 locus. This locus contains a diverse set of genes involved in many biological pathways impacting core cellular functions, tissue development, cell cycle, and apoptosis. Mendelian randomization indicated a unidirectional causal effect of ADHD on shorter TL across four methods. In our independent clinical sample, TL was shorter in individuals with ADHD. Lastly, higher PGS for longer TL was associated with reduced ADHD symptomatology. Our findings suggest that ADHD may contribute to TL, and genetic predisposition to shorter TL is associated with greater ADHD severity.

Transcriptomic signatures of early- versus late-diagnosed ADHD and implications for treatment heterogeneity.

Attention-deficit/hyperactivity disorder (ADHD) is heterogeneous in the age at which symptoms first lead to clinical diagnosis. Recent genomic analyses of a large Danish population-based cohort showed that individuals diagnosed in childhood differ from those diagnosed in adulthood in polygenic risk scores, rare-variant burden, and patterns of genetic correlation with other psychiatric traits [1]. Childhood cases exhibited stronger overlap with autism and higher rates of rare protein-truncating variants in constrained genes, whereas late-diagnosed cases showed greater genetic overlap with depression. The functional transcriptomic mechanisms underlying these differences have remained unclear.We performed a transcriptome-wide association study (TWAS) using S-PrediXcan and GTEx v8 MASHR models from six adult brain tissues: amygdala, anterior cingulate cortex, caudate, frontal cortex, hippocampus, and nucleus accumbens. Analyses were based on GWAS summary statistics from the iPSYCH study for childhood ADHD (N = 14,878) and late-diagnosed ADHD (N = 6,961). Thirteen curated gene sets were examined, spanning synaptic plasticity, immune function, glial markers, and housekeeping controls.The transcriptomic profiles of the two subgroups showed substantial overall similarity (Spearman ρ = 0.77 across 13,580 genes), with near-perfect directional concordance among nominally significant associations; because the two GWAS contrasted different case groups against the same 38,303 population controls, these similarity estimates should be interpreted as upper bounds rather than unbiased estimates of aetiological overlap. Despite this shared architecture, gene-set analyses suggested biologically interpretable divergences: late-diagnosed ADHD displayed stronger enrichment in long-term potentiation (enrichment ratio = 1.34, Mann-Whitney p = 1.42 × 10⁻⁸) and complement cascade pathways (1.22, p = 5.14 × 10⁻⁵), whereas childhood ADHD showed only nominally greater signals in microglia marker and MHC genes. Eighty-two genes differed in association strength between groups after FDR correction, although this delta-Z comparison should be read cautiously because the shared-control design violates the independence assumption of the test.These findings provide a functional explanation for previously reported genetic and comorbidity differences by age at diagnosis and identify an 82-gene differential list for follow-up. The enrichment patterns generate cautious, hypothesis-level questions regarding potential variation in stimulant response and tolerability, but no direct treatment, adherence, or pharmacogenomic data were analysed. This represents the first TWAS to dissect ADHD subtypes by age at first diagnosis and offers a bridge between statistical genetic associations and biologically interpretable pathways relevant to clinical heterogeneity.

A Genetic Atlas of Direct and Inverse Neuropsychiatric-Cancer Comorbidity

Direct and inverse comorbidities between neuropsychiatric disorders and cancer are increasingly recognised as important features of the nervous system–cancer relationship, yet the inherited genetic architecture underlying these patterns remains poorly understood. Here, we analysed pairwise genetic correlations across 35 diseases represented by 115 GWAS datasets, including 9 psychiatric disorders, 10 neurological diseases and 16 cancers, using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL), complemented by meta-analysis, subtype-resolved analyses, local covariance mapping and multi-omic benchmarking. Genetic correlations were predominantly positive and strongest within disease categories, whereas cancer–neurological pairs showed the weakest overall genetic affinity. Meta-analysis and subtype resolution uncovered associations obscured in aggregate analyses, including opposing correlations between familial and late-onset Alzheimer’s disease and lung cancer, revealing subtype-dependent neuro-oncological biology. Local analyses identified recurrent genomic loci where direct comorbidities are consistent with shared inflammatory, interferon, survival and tissue-remodelling programs, whereas inverse comorbidities suggest competing demands on apoptotic regulation, immune tone and stress-response calibration between neuronal and tumour-cell states. Together, these findings provide a genome-scale genetic framework for neuropsychiatric–cancer comorbidity and identify shared inherited biological programs as candidates for mechanistic investigation and therapeutic translation.

Rare variation illuminates the distinct and pleiotropic genetic architecture of autism across neuropsychiatric traits

This study finds that rare variants across hundreds of genes contribute to autism with variable phenotypic outcomes, and clusters them based on association evidence from large-scale studies of developmental disorders, schizophrenia, bipolar disorder, and epilepsy.