Genetically defined ancestry alters NPS prevalence estimates in AD, suggesting that standard race categories obscure population-level disease burden and compromise risk stratification, screening, and trial design.
Abstract
Introduction. Neuropsychiatric symptoms (NPS), including aggression, psychosis, anxiety, apathy, and depression, affect up to 85% of individuals with Alzheimer's disease (AD) and are among its most disabling and costly manifestations, accelerating cognitive and functional decline, institutionalization, mortality, and healthcare costs. NPS prevalence has largely been characterized using self-reported race. Whether NPS differs across genetically defined ancestry groups and whether self-reported race obscures these differences remains unknown, limiting accurate risk stratification and treatment development. Methods. Using whole-genome sequencing data from 7,118 ADSP participants, we defined three NPS clusters from the NPI-Q: early psychosis (CDR 0.5-1), late psychosis (CDR 2-3), and affective symptoms. Genetic ancestry was inferred by principal component clustering, identifying six groups (EUR, AFR, EAS, SAS, AMR, ADMIXED), and compared with self-reported race/ethnicity. NPS prevalence was compared across genetic ancestry groups and genetic ancestry and self-reported race using Fisher's exact and regression models. Results. Genetic ancestry assignment differed markedly from self-reported race, affecting NPS prevalence estimates. NPS prevalence also differed across ancestry groups; affective symptoms were highest in EAS (90%) and SAS (77%) and lowest in AFR (66%), while psychosis was highest in EAS (74%) and SAS (70%) and lowest in AMR (55%) and EUR (56%), with similar patterns for early and late psychosis. Discussion. Genetically defined ancestry alters NPS prevalence estimates in AD, suggesting that standard race categories obscure population-level disease burden and compromise risk stratification, screening, and trial design. Ancestry-associated differences suggest partially distinct genetic and environmental drivers, underscoring the need to incorporate genetic ancestry into AD research and care.
Summary Alzheimer’s disease (AD) has a higher prevalence in women than men and is more frequently inherited from mothers than fathers. Yet, while neuroimaging and biomarker studies link maternal family history to stronger AD-related alterations, epidemiological studies suggest that paternal history confers comparable or even greater risk. Here, we leverage the deeply profiled PREVENT-AD cohort to derive three intermediate phenotypes of AD susceptibility. Drawing on nearly 1,000 individual study visits, we quantify how these intermediate phenotypes vary as a function of maternal versus paternal AD lineage. We show that lineage-specific differentiation, including both maternal and paternal biases, is reflected in the brain structure and phenome of adult children of AD patients. Cognitive and cardiovascular risk markers, together with associated genetic variants, show the strongest differentiation along the parental-lineage spectrum of disease susceptibility relative to other correlates of AD burden. Our cross-generational analysis ultimately delineates multidimensional parent-of-origin effects in AD genealogy.
Chloé Savignac, Frédéric St-Onge, S. Villeneuve et al.· Cell Reports Medicine· 0 citations
Objective: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson’s Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. Methods: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. Results: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) vs 2.72E-4 (1.47E-05), p < .001), but lower discoverability than PD (4.20E-05 (2.69E-06) vs 1.40E-04 (6.95E-06), p < .001). Global genetic correlation was significant (e.g., bivariate LDSC rg = 0.10, p = 0.0033). Novel analyses identified cross-disorder enrichment, and cross-disorder risk at chr3p21.31. Conclusions: Cross-disorder AN and PD research identified shared risk variants at chr3p21.31, genes and mechanisms (e.g., conditioning, fear, and reward) linked to a shared endophenotype.
A. Bergen, Carolina Makowski, Michael Garvin et al.· European eating disorders re...· 0 citations
Background: Neurodevelopmental copy number variants (ND-CNVs) are associated with diverse neuropsychiatric outcomes, but most evidence derives from clinically ascertained cohorts enriched for severe disease. Whether these associations generalize to large, heterogeneous population biobanks, and whether they reflect locus-specific or distributed genetic effects, remains unclear. Methods: We developed a scalable analytic pipeline within the All of Us Research Program to identify ND-CNV carriers from structural variant callsets and evaluate associations across neuropsychiatric phenotypes derived from electronic health records (EHRs). Logistic regression models estimated associations between carrier status and individual phenotypes, adjusting for age, healthcare utilization, observation time, and genetic ancestry principal components. Sensitivity analyses included exclusion of mosaic chromosomal alteration (mCA)-suspected events and leave-one-locus-out (LOLO) models. Phenotypes were further grouped into Research Domain Criteria (RDoC) domains to assess domain-level structure and cross-domain burden. Results: ND-CNV carrier status was associated with modest but consistent enrichment across neuropsychiatric phenotypes spanning affective, psychotic, neurodevelopmental, and trauma-related domains. Although no individual phenotype survived false discovery rate correction, global permutation analyses demonstrated directional enrichment exceeding expectations under randomized exposure assignment. Effects were distributed rather than driven by a single phenotype or locus, with deletion-overlapping carriers showing stronger associations than duplication-overlapping carriers. Associations remained stable after mCA exclusion and LOLO analyses. Domain-level analyses revealed correlated enrichment across RDoC systems, while cross-domain burden measures demonstrated strong interdependence but limited discriminative separation. Conclusions: ND-CNV carriers exhibit distributed, pleiotropic neuropsychiatric risk in a large biobank. These findings provide empirical support for a distributed model of ND-CNV-associated neuropsychiatric liability in which numerous modest, directionally concordant phenotype associations collectively contribute to pleiotropic risk across neuropsychiatric domains.
A. M. Wells, F. Zhao, S. Seshadri et al.· medRxiv· 0 citations
Abstract Background Major psychiatric illnesses are highly heritable, yet the search for replicable genetic and neurobiological mechanisms has proven highly challenging. One of the major reasons for this non-replicability is the focus on discrete clinical disease constructs, as categorized in current classificatory systems. Studying large numbers of multiplex families with affected members having several psychiatric illnesses, and unaffected relatives, would provide the most statistically robust method for the identification of neurocognitive endophenotypes that cut across traditional diagnostic boundaries. Aims & Objectives The Centre for Brain and Mind (CBM) is such an attempt to develop a family-based longitudinal cohort and biobank of major psychiatric illnesses in India. Method CBM has longitudinal family cohorts of schizophrenia, bipolar disorder, obsessive-compulsive disorder, addiction and Alzheimer’s dementia, along with their unaffected first-degree relatives (FDR) and population healthy controls. All individuals undergo detailed clinical assessments, and a blood sample is drawn to isolate DNA and peripheral blood mononuclear cells. Genetic studies are conducted in parallel with deep endophenotype assessments (cognition, brain imaging, psychophysics and electroencephalogram) and induced pluripotent stem cell (IPSC) generation to develop a comprehensive understanding of the biology of these disorders. Results So far, we have screened ca. 5000 families and recruited 900 families (3500 individuals) with multiple affected members, and 500 population healthy controls. Deep endophenotype assessments have been performed in 700 families (2500 individuals) and 300 population healthy controls. Whole exome sequencing (N=500) and IPSC generation (N=120) have been performed for a subset of individuals. We identified general factor of cognition as a transdiagnostic endophenotype. Minor physical anomalies and gaze fixation abnormalities were found to be specific for psychotic disorders (schizophrenia and psychotic mood disorders). Adverse childhood events were found to worsen the cognitive deficits in FDRs. Whole exome sequencing identified rare damaging variants in several genes related to neurodevelopment, and subsequent studies in IPSC derived neural precursors and cortical organoids showed cell migration deficits. Specific cell signatures of lithium treatment response (mitochondrial bioenergetics) in bipolar disorder and clozapine response (actin cytoskeleton) in schizophrenia were identified. Discussion & Conclusions Overall, we find various interesting leads about the biology of major psychiatric illnesses using the CBM study sample in India. Correlating deep clinical assessments, genomic variations, and phenotypes at various levels (cell, tissue, organ and system) may help us understand the biological links related to disease mechanisms in psychiatry.
B. Viswanath, P. Jayasankar, S. Nayok et al.· International Journal of Neu...· 0 citations
Abstract Background Alcohol use disorder (AUD) and alcohol consumption (AC) are highly heritable, globally burdensome, and frequently comorbid with severe psychiatric disorders like schizophrenia (SCZ) and bipolar disorder (BD). While these comorbidities are often linked to greater illness severity, it remains unclear whether they arise solely as complications of substance use or from a shared underlying genetic architecture. Aims & Objectives The overall aim was to leverage massive, diverse datasets and novel statistical frameworks to: i) Identify novel genetic loci associated with a narrow AUD phenotype across multiple ancestries. ii) Characterize the shared genomic loci and polygenic overlap between alcohol traits (AUD/AC) and psychiatric phenotypes (SCZ/BD). iii) Map identified variants to biological pathways and brain regions to uncover potential drug targets. Method A multi-ancestry GWAS was conducted on 1,041,450 individuals (including European, African, Hispanic, and Asian ancestries) using novel statistical tools and cross-ancestry functional analyses. We also used European-ancestry summary statistics (AUD: 34,658 cases; AC: n=200,680; SCZ: 31,013 cases; BD: 20,352 cases), and applied conjunctional False Discovery Rate (conjFDR) analysis to increase the power to detect shared genomic loci. The identified loci were mapped to gene expression data in the brain and examined for enrichment in specific neuronal pathways (GABAergic, dopaminergic, serotonergic) and immune-related gene sets. Results The multi-ancestry analysis identified 37 genome-wide significant loci, including seven novel for AUD. The conjFDR analysis further identified 28 loci shared between SCZ and AUD, and 2 loci shared between BD and AUD, many of which were previously unknown for these phenotypes. Loci were mapped to genes with altered expression in the striatum, hypothalamus, and prefrontal cortex. While European and African samples showed distinct immune-related patterns, shared loci between AUD and psychiatric disorders exhibited a complex mixture of both same and opposite effect directions. Extensive positive genetic correlations and polygenic overlap were found between AUD and both mental and general medical phenotypes, confirming that AUD shares a significant genetic liability with these conditions. Discussion & Conclusions These findings underscore the value of multi-ancestry and cross-disorder genetic studies in SUD. By identifying shared and novel genomic loci, we demonstrates that the relationship between alcohol use and psychiatric disorders is driven by a complex, shared genetic architecture rather than environmental complications alone. This advances our understanding of AUD risk and highlights potential neuronal and immune pathways for future clinical intervention.
O. Andreassen, R. Icick, E. Wistrom et al.· International Journal of Neu...· 0 citations
Genetic evidence supporting a causal role for depression in the etiology of late-onset AD is provided, a link not observed for other major psychiatric disorders tested and highlighted the specific importance of managing depression as a potential strategy for mitigating AD risk.
Yan-Lin Chen, Xiaohua Chen· Medicine· 0 citations
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