A transcriptome-wide association study to dissect ADHD subtypes by age at first diagnosis offers a bridge between statistical genetic associations and biologically interpretable pathways relevant to clinical heterogeneity and provides a functional explanation for previously reported genetic and comorbidity differences by age at diagnosis.
Abstract
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.
It is found that schizophrenia and ADHD show distinct genetic patterns: schizophrenia shares more genetic factors with brain structure and diabetes, while ADHD is more strongly linked to metabolic pathways.
J. Kopal, A. Shadrin, Dennis van der Meer et al.· Communications Medicine· 0 citations
Autism is a neurodevelopmental disorder with a significant male prevalence bias. While recent evidence suggests that genetic heterogeneity is indexed by age at diagnosis, males are also typically diagnosed earlier, such that the extent to which these age-specific findings are confounded by shared genetic signal with sex-specific genetic architecture remains unclear. To test this, we leveraged sex- and age of diagnosis-stratified GWAS summary statistics for autism and applied a multiple regression framework within Genomic Structural Equation Modeling (Genomic SEM). This approach allowed us to disentangle the overlapping genetic variance between sex, diagnostic timing, and 68 clinically relevant phenotypes reflecting a host of different psychiatric, cognitive, health, and social outcomes. Consistent with prior findings, we identified significantly divergent genetic associations with external traits between early- and late-diagnosed autism subtypes. We also identified few findings for sex-specific associations, along with high genetic correlations across these two traits, which questions the biological basis for disproportionate prevalence rates in males. Multiple regression models confirmed that early-specific associations were not confounded by biological sex. Conversely, the correlations between late-diagnosed autism and the sex-stratified autism GWAS were near 1, indicating that late-specific associations may be confounded. Follow-up analyses using an internalizing factor provided support for sex differences in clinical presentation and age at diagnosis, with female-diagnosed and late-diagnosed autism estimated to have stronger genetic correlations with internalizing traits compared to male and early-diagnosed counterparts. This study underscores the importance of subtyping in genetic analyses and provides a framework to disentangle confounded genetic pathways.
S. Breunig, Lukas Schaffer, Jeremy M Lawrence et al.· Behavior Genetics· 0 citations
Copy number variations (CNVs) are a major contributor to the etiology and phenotypic variability in schizophrenia. CNVs are also independently associated with certain neurological, cognitive, and behavioral conditions, yet their role in early neurodevelopment in the context of treatment-resistant schizophrenia remain largely unexplored. This study aimed to investigate the contribution of neurodevelopmental CNVs to early development among individuals with treatment-resistant schizophrenia (TRS). We conducted a structured, systematic, retrospective record review within a case-control analytic framework. Our cases were the group of neurodevelopmental disorder (NDD) CNV carriers (N = 25) identified in the Pennsylvania State Hospital (PASH) cohort of individuals with treatment resistant psychotic symptoms; non-CNV controls were demographically matched individuals with treatment resistant psychotic symptoms (N = 24) from the PASH cohort. We examined the differences in early NDD phenotypes between cases and controls. CNV carriers had a higher total NDD burden score compared to non-CNV controls (z = 2.20, unadjusted p = 0.03, adjusted p = 0.08). Learning disabilities were significantly more prevalent among CNV carriers compared to non-CNV controls (χ2 = 13.437, df = 1, unadjusted p = 0.0002, adjusted p = 0.0015), with 88% of CNV carriers having a history of learning disabilities relative to 38% of non-CNV controls. CNVs carriers with TRS had a higher prevalence of early NDDs compared to non-CNV controls, particularly in learning disabilities. Prospective studies are needed to elucidate the mechanisms linking CNVs, neurodevelopmental phenotypes, and disease progression in treatment resistant schizophrenia.
Wenxin Bian, R. M. Xavier, T. Dietterich et al.· Biological Research for Nurs...· 0 citations
Autism spectrum disorder (ASD) is genetically heterogeneous, involving rare and common variants that disrupt neurodevelopmental pathways. To explore this complexity, we performed whole-exome sequencing in children with ASD. Clinical phenotypes were systematically recorded, and severity was classified according to DSM-5 criteria. Variants were interpreted using ACMG guidelines, with recurrence analysis to identify genes shared across individuals and cohort enrichment testing against gnomAD. To examine genotype-phenotype relationships, we applied SKAT/SKAT-O across 16 phenotypes after covariate adjustment. Among 25 included individuals, pathogenic or likely pathogenic variants were found in 9, yielding a diagnostic yield of 36%. These involved genes linked to neurodevelopmental, epileptic, metabolic, and syndromic disorders. Recurrence analysis identified 586 genes present in at least two individuals, with PABPC1, GTF2I, PCLO, PKD1, and EP400 being the most frequent. SKAT/SKAT-O revealed the strongest burden associations for motor delay, aggressive behavior, mutism, anxiety, unresponsiveness to spoken voice, digestive disorder, and sleep disturbances, with limited overlap across phenotypes. Several recurrent genes also showed phenotype-specific associations. Overall, this integrative WES study provides clinically actionable diagnoses, highlights recurrent genes, and uncovers phenotype-specific signals, supporting convergent pathways with gene-level heterogeneity.
Zainab Gaouzi, Giulia Spoto, F. Polito et al.· International Journal of Mol...· 0 citations
Schizophrenia and bipolar disorder are diagnostically distinct categories that overlap substantially in clinical features and genetic aetiology. Understanding genetic variants that contribute liability specifically to each disorder can offer insights into biological processes that differentiate them. Here we used Case-Case GWAS (CC-GWAS) to identify common genetic variants differentially associated with schizophrenia and bipolar disorder, analysing 67,390 schizophrenia cases and 41,917 bipolar disorder cases. We identified 19 genome-wide significant loci, of which 16 (84%) demonstrated divergent genetic effects with risk alleles showing opposite directions of association between disorders. The CC-GWAS summary statistics had detectable disorder-differentiating heritability (10.27%, SE=0.01) and showed genetic correlations indicating that SCZ-differentiating alleles were associated with lower educational attainment, lower cognitive performance, and increased risk of ADHD, anorexia, autism, BD1 (though not BD2), cannabis use disorder, and OCD. Four loci showed divergent effects despite not reaching genome-wide significance in either individual disorder GWAS, demonstrating enhanced power to detect opposite-direction effects. Functional annotation identified 102 mapped genes significantly enriched for expression across all 13 tested brain regions, with no significant enrichment in peripheral tissues, and gene set enrichment analysis implicated neuronal projection and synaptic compartments as the strongest biological themes differentiating the two disorders. Polygenic risk scores derived from these disorder-differentiating variants were associated with earlier age at onset and more severe negative symptoms in schizophrenia, consistent with these variants marking neurodevelopmental dimensions of illness. Our findings provide targets for understanding pathogenic differences between schizophrenia and bipolar disorder and demonstrate that genuine divergent genetic effects exist beyond the substantial shared liability.
I. Willcocks, A. Richards, S. Legge et al.· medRxiv· 0 citations
Abstract Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity, beyond subtypes.
Tracey van der Veen· Research Square· 0 citations
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