Molecular Psychiatry

Robinson, Natassia; Ploner, Alexander; Ohlsson, Henrik; Lichtenstein, Paul; Kendler, Kenneth S.; Bergen, Sarah E.

doi: 10.1038/s41380-026-03715-zpmid: N/A

Both genetic and environmental risk factors contribute to the development of schizophrenia (SCZ) and bipolar disorder (BD), but simultaneous investigation of how these factors influence risk has not yet been comprehensively examined in a large population. Therefore, we aimed to investigate and quantify how a multi-generational index of aggregated genetic risk (family genetic risk scores, FGRS) and environmental exposures jointly contribute to risk for SCZ and BD, and whether these relationships differ between the disorders. We conducted a Swedish register-based matched nested case-control study with 3057 SCZ and 15,029 BD cases diagnosed 1988–2013. We used conditional logistic regression to determine individual and joint effects of established environmental risk factors including adverse childhood experiences (ACEs), substance use, adverse perinatal factors, childhood infections, urban birth and longest residence, and FGRS (quintiles) for SCZ and BD and risk of SCZ/BD. We also estimated population attributable fractions (PAFs) for environmental exposures. FGRS were associated with incremental increases in SCZ and BD, with highest risk observed for the highest quintile (SCZ IRR 9.63, 95% CI 7.17–12.94; BD IRR 6.30, 95% CI 5.80–6.84). FGRS and most environmental exposures were independently associated with risk of SCZ and BD. The greatest PAFs were observed for substance use (SCZ 18.3%; BD 13.2%) and ACEs (SCZ 14.1%; BD 19.8%). FGRS are associated with increased risk for SCZ and BD and were largely independent from environmental risk factors. Potentially modifiable factors, ACEs and substance use, accounted for a moderate proportion of all cases and were particularly impactful for BD (PAF 19.8, 95% CI 18.4, 21.2) and SCZ (PAF 18.3, 95% CI 17.6–19.0), respectively.

Chen, Yu; Cheng, Lei; Wang, Qi; Liu, Qing; Li, Wenqiang; Wang, Chuansheng; Lv, Luxian; Yue, Weihua

doi: 10.1038/s41380-026-03735-9pmid: N/A

Epidemiological and clinical observations linking schizophrenia (SCZ) to increased dementia risk, together with the occurrence of psychosis in Alzheimer’s disease and related dementias (ADRD), suggest that shared genetic liabilities may contribute to their co-occurrence. Leveraging large-scale genome-wide association study summary statistics for SCZ (53,386 cases and 77,258 controls) and ADRD (111,326 cases and 677,663 controls), we systematically investigated their shared genetic architecture and potential biological mechanisms. We identified three significant local genetic correlations (P < 2.0 × 10⁻⁵) and cross-trait polygenic enrichment between SCZ and ADRD, with 39 genomic loci jointly associated at conjunctional false discovery rate (conjFDR) < 0.05. Fifteen high-confidence genes (CNIH4, CD302, PCGF3, TFR2, EPHX2, SNX32, EFEMP2, CTSW, ASPHD1, TAOK2, INO80E, DOC2A, MAPK3, KANSL1, and XPNPEP3) were consistently prioritized across positional, expression quantitative trait locus, and chromatin-interaction mapping. Tissue- and cell-type enrichment analyses highlighted cerebellar tissues and ependymal-cell-related signals, while pathway analyses implicated synaptic signaling, axonal growth, and presynaptic structural organization. At the locus level, colocalization and transcriptome-wide association analyses converged on 16p11.2, prioritizing INO80E, YPEL3, SLX1B, and TMEM219. Developmental trajectory modeling further revealed region- and stage-specific expression divergence of prioritized 16p11.2 genes, with prominent differences spanning childhood and adulthood. Brain-wide association analysis linked the 16p11.2 lead variant rs9932702 to cortical gray-white contrast (β = −0.062, P = 7.5 × 10⁻¹⁵), a neuroimaging phenotype related to gray-white boundary microstructure and myelination. Finally, bidirectional Mendelian randomization supported a modest directional association between genetic liability to SCZ and increased ADRD risk, but not the reverse direction. Collectively, these findings provide convergent genetic, regulatory, transcriptomic, developmental, and imaging evidence for partial shared liability between SCZ and ADRD, highlighting 16p11.2 and biological processes related to neurodevelopment, synaptic and axonal organization, myelination-related microstructure, and later-life brain vulnerability.

Shapira, Guy; Blatt, Jason; Guz, Liri S.; Shomron, Noam; Gozes, Illana

doi: 10.1038/s41380-026-03709-xpmid: N/A

Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women’s significant improvements in total raw score, letter–number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.

Jen, Yawen; Yu, Sung-Liang; Hsiao, Po-Chang; Kuo, Po-Hsiu; Liu, Chih-Min; Liu, Chen-Chung; Hwang, Tzung-Jeng; Hsieh, Ming H.; Chien, Yi-Ling; Lin, Yi-Ting; Huang, Hailiang; Feng, Yen-Chen Anne; Hsiao, Chuhsing K.; Lin, Yen-Feng; Faraone, Stephen V.; Neale, Benjamin; Glatt, Stephen J.; Tsuang, Ming T.; Hwu, Hai-Gwo;

Feng, Yu; Guo, Xiaonan; Huang, Peng; Jia, Ningning; Hu, Shaohua; Yang, Sheng

doi: 10.1038/s41380-026-03730-0pmid: N/A

Depression arises from dynamic interactions among genetic predisposition, brain alterations, and environmental stressors. Despite genome-wide association studies (GWAS) identifying risk loci, the mechanisms translating genetic variation into brain changes remain elusive. Imaging-derived phenotypes (IDPs) were the intermediate traits linking genetic architecture to neural circuit dysfunction. Here, we collected large-scale GWAS summary statistics of depression and IDPs across European (EUR; N = 1,293,933 and 33,224, respectively) and East Asian (EAS; N = 82,874 and 7058, respectively). In the multiple-trait analysis between depression and IDPs, we clarified their genetic correlation through MTAG, identified the pleiotropic single nucleotide variants (SNVs) and genes with functional insight, and established the causal relationship through Mendelian randomization via TwoSampleMR in EUR and EAS ancestry, respectively. To discern the heterogeneous genetic drivers, we selected independent SNVs from the multiple-trait analyses to perform unsupervised clustering. Six clusters delineated distinct biological pathways for metabolic regulation, neurotransmitter dynamics, and neuroimmune interactions, with tissue/cell type specificity through MAGMA. Finally, we dissected relationships between depression and polygenic risk score, IDPs, and modifiable lifestyle factors, and introduced a machine learning framework to refine risk stratification (N = 16,166). Our study advanced the understanding of the multiscale etiology of depression while providing dynamic depression risk stratification for precision prevention.

Du, Jun Ni; Tio, Earvin S.; Bennett, David A.; Schneider, Julie A.; Sevim Bayrak, Cigdem; Alexander-Bloch, Aaron; Zhang, Bin; Felsky, Daniel

doi: 10.1038/s41380-026-03725-xpmid: N/A

Late-onset Alzheimer’s disease (LOAD) is the most common cause of dementia in older adults, with specific genomic copy number variants (CNVs) implicated in its pathology. However, the aggregate burden of genome-wide CNVs in dementia and age-related neuropathologies is uncharacterized. This study investigated the association between genome-wide CNV scores (CNV-S) and dementia, as well as LOAD-related neuropathologies, in 1011 elderly participants (mean age 88.06) from two ongoing US-based longitudinal clinical-pathological cohort studies who were initially dementia-free and consented to brain donation upon death. Participants exhibited varying cognitive statuses at death (429 dementia, 258 mild cognitive impairment, 324 cognitively normal). We evaluated effects of (1) eight individual-level CNV-S based on gene loss intolerance and dosage sensitivity; (2) a single nucleotide polymorphism (SNP)-based LOAD polygenic score (PGS-LOAD) calculated using Bayesian continuous shrinkage; and (3) covariates (age, sex, and education). Outcomes included cognitive scores across 19 tests, clinical diagnoses of Alzheimer’s disease or mild cognitive impairment, and four LOAD-related neuropathologies assessed postmortem. Analyses identified 4867 CNVs (3918 deletions, 949 duplications) mapped to 3211 genes. Higher deletion CNV-S were significantly associated with increased cerebrovascular pathologies (pLI: β = 0.14, 95% CI [0.08, 0.21]; LOEUF: β = 0.14, 95% CI [0.08, 0.20]; pHI: β = 0.15, 95% CI [0.08, 0.21]; binarized pHI: β = 0.14, 95% CI [0.08, 0.21]). Models predicting cerebral atherosclerosis that included deletion CNV-S significantly outperformed models based on only PGS-LOAD (R2 increase: 0.02). These findings suggest that genome-wide CNV burden, particularly deletions in dosage-sensitive genes, contributes to cerebrovascular pathology in aging. CNV-S may augment existing LOAD genetic risk models by capturing vascular pathways distinct from traditional SNP-based risk.

Wang, Yu; Li, Ji-Tao; Zhu, Lin-Lin; Wu, Yan-Kun; Su, Yun-Ai; Si, Tian-Mei

doi: 10.1038/s41380-026-03732-ypmid: N/A

Despite its high prevalence, the precise mechanisms underlying major depressive disorder (MDD) remain incompletely understood. Growing evidence identifies mitochondrial dysfunction, including abnormalities in mitochondrial DNA, impaired bioenergetics, disrupted quality control, and redox imbalance, as a central pathological feature of MDD. Beyond deficits in energy production, mitochondria function as upstream regulators of neuroinflammation. Mitochondria derived damage associated molecular patterns and excessive reactive oxygen species activate innate immune signaling, while inflammatory challenges in turn compromise mitochondrial integrity. This bidirectional and self-reinforcing interaction between mitochondrial dysfunction and inflammation may contribute to disease onset, progression, and clinical heterogeneity. Preclinical and clinical studies indicate that conventional antidepressants gradually restore mitochondrial function while suppressing oxidative and inflammatory stress, whereas rapid-acting agents such as ketamine induce acute metabolic reprogramming and mitophagy, enabling swift functional recovery. Mechanistically distinct interventions, including mitochondria targeted antioxidants, metabolic modulators, and psychedelic compounds, further highlight the therapeutic potential of targeting mitochondrial pathways. By integrating current evidence, this review delineates mitochondrial-inflammation crosstalk in MDD and supports mitochondrial regulation as a promising target for novel antidepressant strategies.

Michelini, Giorgia; Liao, Wangjingyi; Lu, Shiqi D.; Caserini, Chiara; Eley, Thalia C.; Ronald, Angelica; Wilson, Sylia; Malanchini, Margherita; Rimfeld, Kaili

doi: 10.1038/s41380-026-03714-0pmid: N/A

Neurodevelopmental conditions are highly heritable, heterogeneous, and frequently co-occur. Transdiagnostic dimensional approaches have advanced understanding and classification of psychiatric disorders, but have largely omitted neurodevelopmental conditions. Using longitudinal data for >10,000 children from the Twins Early Development Study, we investigated the structure of a transdiagnostic “neurodevelopmental spectrum” across development, its etiology, its ability to predict functional outcomes, and the specificity of these associations. Hierarchical exploratory factor modeling of a broad set of traits/symptoms delineated a neurodevelopmental spectrum encompassing neurodevelopmental traits at ages 7, 12, and 16. This spectrum emerged as a distinct dimension alongside separable dimensions of internalizing, externalizing, and psychosis symptoms. The neurodevelopmental spectrum was highly heritable across development in twin analyses (h2 = 0.60–0.82) and predicted by polygenic scores (PGS) for neurodevelopmental, cognitive, and educational phenotypes (R2 up to 2.30% in single-PGS analyses, 3.36% in multi-PGS analyses). Perinatal and early developmental factors (e.g., low birth weight, language delays) were also associated with this spectrum (R2 up to 8.65%). Individual differences in the neurodevelopmental spectrum predicted cognitive and educational outcomes both concurrently and longitudinally (R2 up to 20.61%), largely due to overlapping genetic effects. Associations with predictors and outcomes remained largely unchanged after adjusting for internalizing, externalizing, and psychosis dimensions, indicating they were specific to the neurodevelopmental spectrum and not attributable to shared variance with other co-occurring symptoms. Our novel results on the phenotypic architecture, etiological validity, predictive utility, and specificity of the neurodevelopmental spectrum across development support its integration into transdiagnostic frameworks, with important implications for advancing research, psychiatric classification, and clinical care.