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PubMed2026

Exploring the shared genetic architecture of sarcopenia using genomic structural equation modeling.

Sarcopenia is a common age-associated condition characterized by the progressive loss of skeletal muscle mass, strength, and physical functionality. While large-scale genome-wide association studies (GWAS) have previously addressed isolated traits of sarcopenia, the multifactorial genetic architecture underlying this condition remains largely undefined. To characterize the common genetic basis of sarcopenia-related traits, genomic structural equation modeling (Genomic-SEM) was implemented. Multiple post-GWAS analytic approaches were integrated to pinpoint susceptibility loci. These analyses encompassed identifying enriched genetic pathways and relevant genomic elements, as well as cell-type-specific enrichment in skeletal muscle satellite stem cells, mesenchymal stem cells, and skeletal muscle satellite cells in limb muscle. Furthermore, based on the integrated GWAS data of sarcopenia-related traits, polygenic risk score (PRS) analysis was conducted to evaluate risk associations at the chromosomal level. A well-fitted Genomic-SEM successfully integrated the GWAS data, revealing the shared genetic architecture of sarcopenia-related traits. We identified 110 single nucleotide polymorphisms (SNPs) reaching genome-wide significance (p < 5 × 10-8), of which 9 represent novel discoveries. Subsequent fine-mapping procedures and gene-set analyses identified 15 causal variants alongside 77 candidate susceptibility genes. This study provides a comprehensive genetic characterization of sarcopenia via Genomic-SEM, offering new insights into the etiological pathways underlying sarcopenia.

Sarcopenia↗

PubMed2025

Genetic Differences in Reactivity to the Environment Impact Psychotic-Like and Affective Reactivity in Daily Life.

BACKGROUND AND HYPOTHESIS: Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. STUDY DESIGN: Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. STUDY RESULTS: PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. CONCLUSIONS: Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Humans↗

PubMed2025

The Role of Genomic-Informed Risk Assessments in Predicting Dementia Outcomes.

INTRODUCTION: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. METHODS: We constructed an additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score in NACC and ADNI, and assessed its association with progression to all-cause dementia. RESULTS: 81% of participants had at least one high-risk indicator for dementia, with each additional risk indicator linked to a 34% increase in the hazard of dementia onset. DISCUSSION: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

dementia risk scores↗

PubMed2025

DiscoDivas: Leveraging genetic ancestry continuum information to interpolate PRS for admixed populations.

The relatively low representation of admixed populations in both discovery and fine-tuning individual-level datasets limits polygenic risk score (PRS) development and equitable clinical translation for admixed populations. Under the assumption that the most informative PRS model for a genetically homogeneous sample varies linearly in an ancestry continuum space, we introduce a Genetic Distance-assisted PRS Combination Pipeline for Diverse Genetic Ancestries (DiscoDivas) to interpolate a harmonized PRS for diverse, especially admixed, genetic ancestries, leveraging multiple PRS models fine-tuned within existing samples, which are mostly of single ancestry, and genetic distance. DiscoDivas treats genetic ancestry as a continuous variable and does not require shifting between different models when calculating PRS for different ancestries. We generated PRS with DiscoDivas and the current conventional method, i.e. fine-tuning multiple GWAS PRS using the matched or similar genetic ancestry samples. DiscoDivas generated a harmonized PRS of the accuracy comparable to or higher than the conventional approach, with the greatest advantage exhibited in admixed individuals.

PRS harmonization↗

PubMed2026

Genome-Wide Association Analyses Identify Distinct Genetic Architectures for Extreme Early-Onset and Late-Onset T2D.

AIMS: Type 2 diabetes (T2D) is a heterogeneous disorder with substantial variation in age at onset (AAO). This study aimed to characterize the distinct genetic architectures and biological mechanisms underlying extreme AAO-defined T2D subtypes. MATERIALS AND METHODS: Using 74 795 European-ancestry participants from the UK Biobank, we performed genome-wide association studies (GWAS) of relatively early-onset T2D (eoT2D; AAO < 55 years) and late-onset T2D (loT2D; AAO ≥ 70 years). We investigated subtype-specific genetic loci, SNP-based heritability, genetic correlations, Mendelian randomization (MR)-based relationships, polygenic risk scores (PRS) and phenome-wide association studies (PheWAS). Single-cell transcriptomic data from human pancreatic tissues were further used to evaluate cell-type-specific expression patterns of candidate genes. RESULTS: SNP-based heritability was substantially higher for eoT2D than loT2D (11.2% vs. 6.4%), with eoT2D displaying distinct genetic loci related to β-cell function and insulin regulation, including SLC30A8 and IRS1. By contrast, loT2D showed a comparatively lipid-related genetic profile, featuring APOE-associated signals and expression patterns in immune-related cell populations. Linkage disequilibrium score regression (LDSC) and MR analyses further underscored this divergence: eoT2D exhibited broader genetic overlap with cardiometabolic traits, whereas loT2D showed stronger relationships with traditional metabolic risk factors. Finally, subtype-specific PRSs improved risk discrimination beyond conventional covariates, although their clinical utility warrants further evaluation. CONCLUSIONS: Extreme AAO-defined T2D subtypes exhibit partially distinct genetic architectures, highlighting AAO as an important dimension of T2D heterogeneity and providing a framework for future age-stratified genetic risk assessment.

Type 2 diabetes↗

PubMed2025

The role of candidate genetic polymorphisms in covid-19 susceptibility and outcomes.

BACKGROUND: This study aims to investigate the association between candidate host genetic polymorphisms and COVID-19 susceptibility, severity, hospitalization, hypoxia, and their combined effect, measured by the polygenic risk score (PRS). METHODS: Three hundred and seventy-six Lebanese participants, comprising 151 controls and 225 cases, were included. Clinical data were obtained from questionnaires and medical records. DNA isolated from peripheral blood was genotyped for ACE1 rs1799752, ACE2 rs2074192, TMPRSS2 rs75603675 and OAS1 rs107746771 using TaqMan assays, and for TMPRSS2 rs35074065 using Sanger Sequencing. Candidate genetic variants were analyzed in association with COVID-19 susceptibility, severity, hospitalization and hypoxia, using univariate and multivariate models. PRS constructed from the weighted sum of variants was evaluated in association with COVID-19 outcomes. RESULTS: In this study, there were no statistically significant differences in the frequencies of candidate variant alleles between cases, controls and within disease outcomes subgroups, after adjustment for confounders. PRS was not associated with COVID-19 susceptibility and hospitalization, it however significantly predicted COVID-19 severity (P = 0.01). CONCLUSION: This study highlights the importance of genetic testing for key host genes involved in COVID-19 life cycle and eventually measuring the PRS which proves to be an important tool for prognosis assessment in vulnerable individuals, potentially enhancing patient care.

Polymorphism, Genetic↗

PubMed2026

Impacts of host genetics on gut microbiome composition in Alzheimer's disease.

BACKGROUND: Host-microbiome interactions play essential roles in the development of Alzheimer's disease (AD), yet the host genetic impacts on gut microbial alterations in AD remain poorly understood. RESULTS: Here, we simultaneously profiled host genotype and gut microbiome in 252 Chinese individuals with varying degrees of cognitive disability. Using the latent Dirichlet allocation topic model, we identified the Anaerostipes-enriched enterosignature (ES-Ana) at the microbial subgroup level as significantly negatively associated with cognitive disability, which could be recapitulated in external cohorts. With the whole-genome sequencing data, we performed microbiome genome-wide association studies for the ES-Ana relative abundance. We prioritized 41 lead genetic variants and confirmed that the high ES-Ana relative abundance showed a negative correlation with the polygenic risk score of AD, indicating its protective effect against AD. Furthermore, we identified 174 ES-Ana-associated genes, which are enriched in AD-related biological functions and phenotypes, and exhibite pervasive underexpression in glial cells during brain aging. CONCLUSIONS: In summary, our study reveals the complex genetic effects on the gut microbiota in AD, and provides novel evidence for the roles of the gut-brain axis in AD. Video Abstract.

Alzheimer Disease↗

PubMed2026

Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.

Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.

common variants↗

PubMed2026

Cross-ancestry proteome-wide Mendelian randomization prioritizes 12 plasma protein candidates for breast cancer risk.

The plasma proteome provides a molecular bridge between genetic variation and disease risk, yet its contribution to breast cancer susceptibility across ancestries remains unclear. We conducted a proteome-wide Mendelian randomization (MR) study of 2,923 plasma proteins using cis-protein quantitative trait loci from 34,557 European participants in the UK Biobank Pharma Proteomics Project, integrated with genome-wide association studies of 156,901 breast cancer cases and 204,634 controls of European, East Asian, and African ancestries. Cross-ancestry meta-analysis identified 12 candidate proteins associated with breast cancer risk (P < 2.5×10-5), including six previously reported and six newly implicated in MR studies. DNPH1 showed cross-ancestry heterogeneity, with a risk-increasing association in European populations and a nominally inverse association in East Asian populations. CASP8, RALB, and USP28 displayed subtype-differentiated associations. Orthogonal validation provided variable support: six demonstrated strong evidence of statistical colocalization; four replicated in an independent European proteomic dataset (deCODE, n = 35,559); two replicated in an independent East Asian proteomic dataset (JCTF, n = 1,384); and four were supported by polygenic-score analyses in the ancestrally diverse All of Us cohort (9,250 cases, 214,857 controls). These findings prioritize a high-confidence subset of plasma proteins, including LRRC25, PARK7, and LRRC37A2, for future mechanistic and translational investigation.

Mendelian randomization↗

PubMed2004

Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls.

Ischemic stroke is thought to have a polygenic basis, but identification of stroke susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. We performed a meta-analysis of all candidate gene association studies in ischemic stroke. Electronic databases were searched up until January 2003 for all case-control and nested case-control studies in English-language journals relating to the investigation of any candidate gene for ischemic stroke in humans. Cases were required to have neuroimaging evidence of the diagnosis. To maintain genetic homogeneity, only studies in white adults were included. Studies that evaluated quantitative traits or intermediate phenotypes were excluded. Data from 120 case-control studies were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random- and fixed-effects models were calculated. Of 32 genes studied, 15 polymorphisms were identified for which at least 3 studies had been conducted. Statistically significant associations with ischemic stroke were identified for factor V Leiden Arg506Gln (OR, 1.33; 95% CI, 1.12-1.58), methylenetetrahydrofolate reductase C677T (OR, 1.24; 95% CI, 1.08-1.42), prothrombin G20210A (OR, 1.44; 95% CI, 1.11-1.86), and angiotensin-converting enzyme insertion/deletion (OR, 1.21; 95% CI, 1.08-1.35). These were also the most investigated candidate genes, including 4588, 3387, 3028, and 2990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes (factor XIII, apolipoprotein E, and human platelet antigen type 1). There is a genetic component to common stroke. No single gene with major effect was identified; rather, common variants in several genes, each exerting a modest effect, contribute to the risk of stroke. These findings have important implications for the design of future genetic studies and for predictive genetic testing for stroke and other multifactorial diseases.

Brain Ischemia↗

PubMed1981

Genetic influences in the epilepsies. Review of the literature with practical implications.

We review hereditary influences in the epilepsies from the perspective of medical genetics. The recurrence risk for epilepsy in close relatives may vary from 2% to 5% up to 50% depending on the etiology of the seizure disorder in the proband. We emphasize the identification of specific disorders with single-gene inheritance that will lead to useful conclusions regarding treatment, prognosis, and family counseling. Also discussed are chromosomal aberrations, polygenic inheritance, gene-environment interactions, animal models of epilepsy, and the pharmacogenetics of anticonvulsants.

Animals↗

PubMed1983

Linear growth patterns in patients with cleft lip or palate or both.

Sequential height determinations were made in patients with isolated cleft palate (ICP) and in patients with cleft lip with or without cleft palate (CLP) during an 11-year period. In 31 patients with ICP height percentiles tended to decrease with age. Beyond 8 years of age, none exceeded the 50th percentile, and measurements in eight (26%) of the patients with ICP were consistently below the fifth percentile. In 34 patients with CLP, after 4 years of age height percentiles were bimodular and clearly separable into a short group (65% below the 50th percentile) and a tall group (35% at or above the 70th percentile). The average height of the parents was normal and suggests alteration of the polygenic inheritance of stature in patients with ICP. While the heights of short and tall patients with CLP reflect the mean height of their parents, the distinct bimodular distribution of the heights of patients with CLP was not anticipated.

Adolescent↗

PubMed1977

Early- and late-onset bipolar affective disorder. A genetic study.

A group of 46 bipolar probands was divided equally into those with early (before age 30) and later onset. The only significant difference found was a higher morbidity risk for the relatives of the early-onset group. Slater's model for a polygenic transmission was found compatible with this group, but insufficient data prevented its application in the older-onset group. In all other respects, however, no significant differences were found. Age of onset of illness may be unhelpful in elucidating the genetic basis of affective disorder. Further progress will depend on the development of more sensitive mathematical models and the finding of specific genetic markers.

Adult↗

PubMed1981

Early- and late-onset bipolar illness.

We categorized a sample of 134 bipolar probands into early- and late-onset groups; age 30 years was the cutting point. Early-onset probands had three times the morbidity risk /MR) for affective disorder in first-degree relatives as late-onset probands and a greater proportion of relatives with the more severe, bipolar form. Early-onset patients also exhibited more neuropsychological dysfunction, less frequently had a unipolar manic course, and had a greater MR for alcoholism in first-degree relatives. The two groups did not differ in other clinical or historical characteristics or in the proportion of EEG abnormalities. Age at illness onset is useful in clarifying the genetic basis of affective disorder. The data are consistent with a polygenic or multifactorial model of illness in which the more severe genotype is expressed earlier in life and through the course of illness.

Adult↗

PubMed1983

A family study of panic disorder.

In a family study of panic disorder, we collected data on 278 first-degree relatives of 41 probands with panic disorder and 262 relatives of 41 control probands. The morbidity risk for panic disorder was 17.3% in the first group, and an additional 7.4% were categorized as having probable panic disorder. Both rates were significantly higher than the respective rates in the control relatives, 1.8% and 0.4%. The risk of panic disorder in female subjects was twice that in male subjects. The rate of generalized anxiety disorder was the same in both groups of families. No other psychiatric disorders were increased in the families of patients with panic disorder. In a preliminary genetic analysis, we tested the single major locus and the multifactorial polygenic transmission models. Neither model was excluded by the data. We conclude that panic disorder is a familial disease that affects women twice as frequently as men and is not associated with an increased familial risk of other psychiatric conditions. Its method of transmission remains uncertain.

Adult↗

PubMed1987

Early onset (under age 30 years) and panic disorder as markers for etiologic homogeneity in major depression.

Early onset of major depression (age, less than 30 years) in probands confers high risk to relatives, whereas late-onset depression (age, greater than 40 years) involves no elevation of risk over population rates. Analyses of data from families of probands with early onset from the Yale Family Study (47 three generation and 17 two generation) favored a major gene effect over polygenic inheritance. However, no genetic model was supported unambiguously. The increase in prevalence of depression over the past several decades complicates the genetic interpretation of results. Restriction of analyses to older (age, greater than 18 years) age cohorts appeared to simplify the pattern of transmission, but a consequent reduction of sample size provided only limited power for tests of competing genetic hypotheses. In a subgroup of 28 families in which the proband had both depression and panic disorder, a major gene mode of inheritance was not supported.

Adolescent↗

PubMed1989

Schizotaxia revisited.

A conjectured neural integrative defect (schizotaxia), due to a dominant schizogene completely penetrant for a parametric aberration in synaptic signal selectivity (hypokrisia), gives rise under ordinary social learning regimens to schizotypy, a personality showing ambivalence, aversive drift, dereism, autism, and cognitive slippage. Given unfavorable polygenic potentiators (eg, introversion, hypohedonia, and anxiety) and adverse life experiences (eg, childhood trauma or adult misfortune), around 10% develop schizophrenia. That schizophrenia is basically a neurologic disorder does not contradict whatever is known about its psychodynamics, nor preclude efficacy for psychotherapy or other psychosocial interventions. Research should concentrate on soft neurology and psychophysiology as indicators, being closer in the causal chain to the schizogene than psychometric, social, or high-level cognitive processes. Taxometric statistics are appropriate to testing a major locus model not simplistically formulated.

Central Nervous System↗

PubMed2001

Prospects for neurology and psychiatry.

Neurological and psychiatric illnesses are among the most common and most serious health problems in developed societies. The most promising advances in neurological and psychiatric diseases will require advances in neuroscience for their elucidation, prevention, and treatment. Technical advances have improved methods for identifying brain regions involved during various types of cognitive activity, for tracing connections between parts of the brain, for visualizing individual neurons in living brain preparations, for recording the activities of neurons, and for studying the activity of single-ion channels and the receptors for various neurotransmitters. The most significant advances in the past 20 years have come from the application to the nervous system of molecular genetics and molecular cell biology. Discovery of the monogenic disorder responsible for Huntington disease and understanding its pathogenesis can serve as a paradigm for unraveling the much more complex, polygenic disorders responsible for such psychiatric diseases as schizophrenia, manic depressive illness, and borderline personality disorder. Thus, a new degree of cooperation between neurology and psychiatry is likely to result, especially for the treatment of patients with illnesses such as autism, mental retardation, cognitive disorders associated with Alzheimer and Parkinson disease that overlap between the 2 disciplines.

Animals↗