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PubMed2025

Protective Effects of Genetic Proxies of Cognitive Reserve in Parkinson's Disease: A Longitudinal Multi-Cohort Study.

BACKGROUND: Resilience factors are crucial in the progression of neurodegenerative diseases. However, it remains unclear whether a genetic predisposition to cognitive reserve influences clinical heterogeneity in the prognosis of Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the utility of polygenic scores (PGSs) for cognitive reserve proxies, including intelligence (INT), educational attainment (EA), and occupational attainment (OA), in predicting the clinical progression of PD. METHODS: Genetic and clinical data for progression of PD (progression to Hoehn and Yahr stage ≥3, progression to a Montreal Cognitive Assessment score ≤24, and occurrence of psychosis) were obtained from the Accelerating Medicine Partnership Parkinson's Disease database. We conducted multivariate Cox regression analysis, adjusting for relevant covariates, including years of education, variants in APOE, GBA1, LRRK2, and other cognitive reserve-related PGSs. RESULTS: All cognitive reserve-related PGSs significantly reduced the risk of cognitive decline, and EA-PGS (hazard ratio [HR], 0.550; 95% confidence interval [CI], 0.447-0.676; P < 0.001) remained significant after controlling for INT-PGS and OA-PGS. EA-PGS (HR, 0.805; 95% CI, 0.672-0.964; P = 0.019) was significantly associated with better motor prognosis after controlling for other PGSs. OA-PGS was linked to a decreased risk of developing psychosis in PD and remained significant after adjusting for others (HR, 0.784; 95% CI, 0.631-0.975; P = 0.029). CONCLUSIONS: Genetic proxies of cognitive reserve are associated with a reduced risk of cognitive decline, motor progression, and development of psychosis in PD. These findings may enhance our understanding of individual differences in resilience in progression of PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Humans↗

PubMed2026

Improving the reliability of polygenic risk score-based prediction for cardiovascular and renal complications across ancestries in type 2 diabetes using Mondrian Cross-Conformal Prediction.

Polygenic risk scores (PRS) developed in European populations often show reduced predictive performance in non-European populations, limiting their clinical utility. This lack of transferability across ancestries remains a major challenge in genomic medicine and raises concerns about health equity. We aimed to evaluate whether uncertainty-aware prediction, implemented through Mondrian Cross-Conformal Prediction, improves the performance and reliability of polygenic risk score-based predictions across ancestries for nephropathy, stroke, and myocardial infarction in individuals with type 2 diabetes in a multi-ethnic cohort. We leveraged Mondrian Cross-Conformal Prediction (MCCP), an uncertainty quantification framework, combined with logistic regression applied to a multi-polygenic risk score (multiPRS) to predict the risk of nephropathy, stroke, and myocardial infarction in individuals with type 2 diabetes. Two training frameworks were evaluated: one using 4,098 individuals with type 2 diabetes of European ancestry from the ADVANCE trial for training and 17,574 White British, 1,145 South Asian, and 749 African UK Biobank participants for testing; and another using the 17,574 White British UK Biobank participants for training and the South Asian and African participants for testing. Logistic regression provided robust baseline performance across populations. On top of this baseline, MCCP did not improve performance but added capabilities absent from probability-based stratification: for each individual, it issued a prediction together with an explicit confidence and credibility level; it allowed a tolerated error level to be set in advance and delivered prediction sets respecting it in the majority of settings; and it flagged individuals for whom no reliable prediction could be made. Applying MCCP to PRS-based prediction thus enables uncertainty-aware risk stratification and improves the reliability of risk prediction across ancestries, providing a more equitable framework for clinical use.

Female↗

PubMed2026

Unravelling sex differences in the genetic architecture of anxiety.

BACKGROUND: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. METHODS: Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications. RESULTS: In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI. CONCLUSIONS: While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.

Female↗

PubMed2026

Polygenic Risk Identifies Older Adults Who May Benefit From Aspirin for the Primary Prevention of Ischemic Stroke.

BACKGROUND: Low-dose aspirin is no longer recommended for routine primary prevention in older adults due to bleeding risks outweighing vascular benefits. We hypothesized that an integrative polygenic score (iPGS) could identify a subgroup of older individuals who derive net benefit from aspirin for the primary prevention of ischemic stroke. METHODS: We performed post hoc analysis of the ASPREE randomized, placebo-controlled trial (Aspirin in Reducing Events in the Elderly) of daily 100-mg aspirin, in 12 031 genotyped participants of European ancestry aged >70 years without prior cardiovascular disease. The iPGS was derived from >1.2 million variants and evaluated both continuously and by quintiles. Cox models assessed associations between polygenic risk, ischemic stroke, and major bleeding events, and tested the interaction between the iPGS and treatment allocation, with adjustment for baseline lifestyle and clinical covariates. RESULTS: The mean age of participants was 75.1 years, and 54.9% were women. Over a median of 4.6 years, 187 ischemic strokes and 373 major bleeds occurred, including 101 intracranial bleeds (46 hemorrhagic strokes). Each 1-SD increase in the iPGS was associated with higher incident ischemic stroke risk (hazard ratio, 1.39 [95% CI, 1.20-1.62]). An interaction between the continuous iPGS and aspirin allocation was observed for ischemic stroke (P=0.04) but not major bleeding. In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (hazard ratio, 0.49 [95% CI, 0.28-0.85]) without significantly increasing major bleeding (hazard ratio, 1.15 [95% CI, 0.71-1.88]). No benefit was observed in the overall cohort or in lower-risk quintiles. CONCLUSIONS: Among older adults, high polygenic risk identifies individuals who may experience substantial stroke reduction with aspirin, with no excess bleeding. These findings raise the possibility that genomic risk stratification may enable targeted aspirin use for the primary prevention of ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Humans↗

PubMed2024

Polygenic burden and its association with baseline cognitive function and postoperative cognitive outcome in temporal lobe epilepsy.

OBJECTIVE: Demographic and disease factors are associated with cognitive deficits and postoperative cognitive declines in adults with pharmacoresistant temporal lobe epilepsy (TLE), but the role of genetic factors in cognition in TLE is not well understood. Polygenic scores (PGS) for neurological and neuropsychiatric disorders and IQ have been associated with cognition in patient and healthy populations. In this exploratory study, we examined the relationship between PGS for Alzheimer's disease (AD), depression, and IQ and cognitive outcomes in adults with TLE. METHODS: 202 adults with pharmacoresistant TLE had genotyping and completed neuropsychological evaluations as part of a presurgical work-up. A subset (n = 116) underwent temporal lobe resection and returned for postoperative cognitive testing. Logistic regression was used to determine if PGS for AD, depression, and IQ predicted baseline domain-specific cognitive function and cognitive phenotypes as well as postoperative language and memory decline. RESULTS: No significant findings survived correction for multiple comparisons. Prior to correction, higher PGS for AD and depression (i.e., increased genetic risk for the disorder), but lower PGS for IQ (i.e., decreased genetic likelihood of high IQ) appeared possibly associated with baseline cognitive impairment in TLE. In comparison, higher PGS for AD and IQ appeared as possible risk factors for cognitive decline following temporal lobectomy, while the possible relationship between PGS for depression and post-operative cognitive outcome was mixed. SIGNIFICANCE: We did not observe any relationships of large effect between PGS and cognitive function or postsurgical outcome; however, results highlight several promising trends in the data that warrant future investigation in larger samples better powered to detect small genetic effects.

Adult↗

PubMed2024

Multi-ancestry polygenic mechanisms of type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (BMI) of 30 kg m-2 in the European subpopulation and 24.2 (22.9-25.5) kg m-2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg m-2 in the East Asian group. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.

Humans↗

PubMed2026

Effects of quetiapine on cognitive functioning in schizophrenia: evidence for the remyelination hypothesis?

Postmortem findings, neuroimaging data, and in-vitro models suggest a decrease in number and density of oligodendrocytes is driving cognitive deficits in schizophrenia (SCZ). Second-generation antipsychotics are discussed to improve oligodendrocyte dysfunction with most conclusive evidence available for quetiapine (QET). We postulate that sustained QET treatment leads to cognitive improvement in SCZ, particularly, in tests with high demands for working memory function. We further hypothesize that these effects are moderated by polygenic factors associated with hippocampus-related brain volumes, general white matter integrity, and/or oligodendroglia-related SCZ risk. Using data of the prospective PsyCourse study, we identified 166 patients with SCZ spectrum disorder receiving QET at one or two consecutive visits plus 166 matched patients without QET. Polygenic scores were calculated for subcortical brain volumes, measures of white matter integrity, and for cell type-specific genetic SCZ risks. QET treatment was consistently associated with improved cognitive function independent of time, specifically, in tests with high, but not with low to medium working memory load. Polygenic analyses did not reveal significant moderation effects. In contrary, low genetic SCZ risk specific for genes related to human oligodendrocyte function was associated with higher cognitive performance independent from QET. While we observed improved cognitive performance under QET in high working memory tests, we did not find evidence that polygenic factors associated with hippocampus-related brain volumes, white matter integrity, or oligodendroglia-related SCZ risk moderate this association. Thus, our tentative findings do not provide evidence for the hypothesis that polygenic estimates of hippocampal remyelination capacities influence the association between QET and cognitive performance in SCZ.

Humans↗

PubMed2026

Genetics of major depressive disorder in a homogeneous population with uniform phenotyping.

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. Liability-scale SNP-based heritability was 12.0% (SE = 1.4%) as estimated by LDSC (assuming a lifetime prevalence of 15%) and 26.6% (SE = 1.1%) when estimated by LDAK-REML on individual-level genotype data, indicating substantial common-variant signal in this clinically harmonized sample. The genetic correlation with the latest major depression GWAS from the Psychiatric Genomics Consortium (PGC-MD) was high (rG = 0.89, SE = 0.048). Polygenic scores (PGSs) based on BIONIC predicted depression in UK Biobank, and PGSs derived from PGC-MD predicted MDD in BIONIC, supporting transferability of depression polygenic signal across cohorts and phenotype definitions. Within-family PGS analyses in twins suggested that the observed prediction was not primarily driven by detectable family-level confounding, and twin concordance for MDD increased with polygenic burden. We identified one genome-wide significant locus, indexed by rs3818852 in PALMD, but this finding currently lacks independent replication and should be interpreted cautiously. Finally, genetic correlation and latent causal variable analyses identified multiple traits showing shared or directionally consistent genetic associations with MDD. Together, these findings underscore the value of clinically harmonized phenotyping in regional biobank collaborations for studying the genetic architecture of MDD.

Humans↗

PubMed2026

Diabetes related genetics and outcomes after total pancreatectomy with islet autotransplantation.

CONTEXT: Approximately 20% of patients with chronic pancreatitis achieve insulin independence one year after total pancreatectomy with islet autotransplantation (TPIAT), an outcome associated with younger age and lower pre-transplant HbA1c. The contribution of diabetes-related genetics to TPIAT outcomes is unknown. Genetic risk scores (GRS) are associated with C-peptide levels in type 1 (T1D) and type 2 (T2D) diabetes. OBJECTIVE: To evaluate whether T1D and T2D GRS and partitioned metabolic polygenic scores (PGS) are associated with diabetes before TPIAT and metabolic outcomes one year after transplant. METHODS: We genotyped 318 patients with chronic pancreatitis undergoing TPIAT in the multicenter "Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT" using a global screening array. Regression models assessed associations of T1D- and T2D-GRS and metabolic PGS with diabetes outcomes one year after TPIAT. RESULTS: Participants were 29±17 years old, 61% female, 84% non-Hispanic White, and 13% had diabetes prior to transplant. T2D-GRS was higher among those with pre-TPIAT diabetes (-0.6±0.3 versus -0.8±0.2, p=0.003) and was associated with higher pre-transplant HbA1c (β=0.19 % per 1-SD [95% CI:0.04, 0.33], p = 0.011). Adjusted for genotype-derived ancestry and islet equivalents/kg, the beta-cell PGS was associated with higher insulin dose (β=0.05 units/kg/day per 1-SD, [95%CI:0.01, 0.09], p=0.016) and higher insulin dose adjusted A1c (IDAA1c) (β=0.34[95%CI:0.03, 0.67], p=0.029) 1-year post-transplant. The lipodystrophy PGS was associated with higher IDAA1c (β=0.38 [95%CI:0.06, 0.69], p=0.019) and lower fasting C-peptide (β=-0.09 [95%CI:-0.18, 0], p=0.041) at 1 year. CONCLUSIONS: T2D genetic risk is associated with diabetes prior to TPIAT, and beta cell and lipodystrophy PGS are associated with post-TPIAT diabetes outcomes. Diabetes-related genetics may influence transplantation outcomes and inform metabolic heterogeneity.

C-peptide↗

PubMed2026

Multivariate, Multi-Omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

INTRODUCTION: Somatoform traits (e.g., health anxiety, somatic preoccupation, and bodily distress symptoms) are prevalent and pose challenges to clinical practice. Understanding their genetic basis could improve diagnostic and therapeutic approaches. METHODS: Using available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits - fatigue, irritable bowel syndrome, pain intensity, and health satisfaction - in 799,429 individuals genetically similar to European reference panels. RESULTS: The GWAS identified 134 loci associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Novel loci were mechanistically informative, mapping to the DNM1 gene and the protocadherin gene cluster (PCDHA1-4), which are involved in nociceptor sensitization and synaptogenesis, respectively. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched expression in 11 brain tissues and the pituitary. Across two brain transcriptomic datasets, we identified 16 high-confidence genes whose expression in enriched tissues was associated with somatoform traits. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated with obesity, type 2 diabetes, and tobacco use disorder in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors, while Mendelian randomization analyses indicated potentially protective effects of gut microbiota. DISCUSSION: Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.

Genetics↗

PubMed2026

Monogenic ALB Variants as Determinants of Severe Hypercholesterolemia: A Population-Based Cohort Study.

BACKGROUND: Hypoalbuminemia is associated with several risk factors for myocardial infarction, including hypercholesterolemia, liver disease, kidney disease, and diabetes. Homozygosity of loss-of-function (LoF) variants in the ALB gene, which encodes albumin, is a known cause of congenital hypoalbuminemia. Studies have also shown that heterozygous ALB LoF variants are associated with increases in low-density lipoprotein cholesterol (LDL-C), comparable to those seen in familial hypercholesterolemia. OBJECTIVES: This study examined the effect of ALB LoF variants and other causes of low albumin on LDL-C levels in 2 population biobanks. METHODS: This study used data from 2 large cohorts with linked electronic health record and genetic information: Geisinger's MyCode Community Health Initiative, a health care population based in Pennsylvania, USA; and the National Institutes of Health All of Us Research Program, a nationwide epidemiologic cohort. LDL-C values were adjusted for lipid-lowering medication use. Myocardial infarction diagnoses were extracted from electronic health records using International Classification of Diseases codes. A polygenic score for serum albumin was calculated for participants of European ancestry. Linear regression models were used to estimate associations, and results were meta-analyzed across cohorts using fixed-effects models. RESULTS: Among 155,530 MyCode and 405,701 All of Us adult participants, 77 individuals (1 of 7,289) carried an ALB LoF variant. Among noncarriers, a 1 g/dL decrease in serum albumin was associated with a 10.9 mg/dL (95% CI:, 10.4-11.4) decrease in LDL-C. In contrast, ALB LoF variants were associated with a 0.69 g/dL (95% CI: 0.60-0.78) reduction in serum albumin and a 38.3 mg/dL (95% CI: 28.2-48.5) increase in LDL-C. Paradoxically, whereas monogenic determinants of hypoalbuminemia were associated with increased LDL-C, polygenic determinants of lower albumin were associated with a 0.22 mg/dL (95% CI: 0.17-0.26) decrease in LDL-C per decile. CONCLUSIONS: ALB LoF variants represent a previously underrecognized monogenic cause of elevated LDL-C, with effect sizes slightly less than canonical familial hypercholesterolemia variants. The divergent effects of ALB-mediated vs polygenic or physiological reductions in albumin on LDL-C suggest distinct underlying mechanisms.

Humans↗

PubMed2022

Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk.

Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage using Cox regression analysis. Statins were prescribed at least once to 75 973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (-3.47, -3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein levels [-0.05 mg/dl per year, (-0.07, -0.02)], showed concordant lipidomic effects on other lipid traits as statin use and was associated with a lower risk for incident myocardial infarction [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.

Cerebral Hemorrhage↗

PubMed2026

Blood Pressure Genetic Risk and Incident Hypertension at 2 to 7 Years Post Partum.

IMPORTANCE: Hypertensive disorders of pregnancy (HDP; ie, preeclampsia/eclampsia and gestational hypertension) are associated with earlier development of chronic hypertension. Whether genetic risk for high systolic blood pressure (SBP) can stratify risk of new-onset hypertension after pregnancy is unclear. OBJECTIVE: To test the association of genetic risk for high SBP with new-onset hypertension at 2 to 7 years after delivery, independent of clinical characteristics and HDP history. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study of women enrolled during pregnancy between 2010 and 2013 and followed up at 2 to 7 years post partum. Included in the study were genotyped participants without pregestational chronic hypertension in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) Heart Health Study. The setting included 8 US clinical sites. Study data were analyzed from October 2024 to January 2026. EXPOSURES: SBP genetic risk was calculated using a genome-wide SBP polygenic score and categorized as low (bottom quintile), intermediate (quintiles 2-4) or high (top quintile). MAIN OUTCOMES AND MEASURES: The primary outcome was stage 1+ hypertension (≥130/80 mm Hg or use of antihypertensive medication) at 2 to 7 years post partum. Logistic regression tested the association of SBP genetic risk with development of hypertension, adjusted for sociodemographic factors, prepregnancy diabetes, first-trimester BP, HDP history, and postpartum body mass index (BMI). Key secondary analyses were stratified by HDP history and compared population attributable risk for high SBP genetic risk, HDP history, and postpartum BMI. RESULTS: Among 2852 participants (mean [SD] age, 30.8 [5.5] years; 353 [12.4%] with prior HDP), 509 (17.8%) developed hypertension by 2 to 7 years (mean [SD], 3.2 [0.9] years) after delivery. SBP genetic risk was independently associated with incident hypertension (high vs low SBP genetic risk: adjusted odds ratio [aOR], 1.50; 95% CI, 1.09-2.07; P = .01). In stratified analyses, SBP genetic risk was associated with incident hypertension in those without prior HDP (aOR, 1.25; 95% CI, 1.12-1.40 per SD; P < .001) but not in those with prior HDP (aOR, 1.01; 95% CI, 0.79-1.28 per SD; P = .92; P for interaction = .10). High SBP genetic risk, HDP history, and BMI greater than or equal to 25 (calculated as weight in kilograms divided by height in meters squared) accounted for 4.7%, 10.8%, and 41.5%, respectively, of population attributable risk for hypertension. CONCLUSIONS AND RELEVANCE: Results of this cohort study reveal that higher SBP genetic risk was independently associated with higher risk of developing new-onset hypertension 2 to 7 years after delivery. However, HDP history and elevated BMI were more important contributors to hypertension risk.

Humans↗

PubMed2026

Accelerated Biological Aging Increases the Risk of Head and Neck Cancer: Insights From Genetic Instruments of Epigenetic Clocks.

Epigenetic clocks are robust biomarkers of biological aging and have been associated with cancer susceptibility. However, the relationship between genetically predicted epigenetic age acceleration and head and neck cancer risk remains unclear. Using a large case-control study of 2189 head and neck squamous cell carcinoma (HNSCC) cases and 2189 age- and sex-matched controls, we investigated the associations between polygenic scores (PGSs) for multiple epigenetic clocks and HNSCC risk, and evaluated their potential causal roles using two-sample Mendelian randomization (MR). Genome-wide association study (GWAS)-identified single nucleotide polymorphisms (SNPs) associated with four epigenetic clocks (HannumAge, HorvathAge, GrimAge, and PhenoAge) were used to construct clock-specific PGSs. Logistic regression models were applied to assess associations between PGSs and HNSCC risk, while MR analyses, including inverse-variance weighted (IVW), weighted median, and MR-Egger methods, were used to infer potential causal relationships. Among the 48 epigenetic clock-associated SNPs, 12 showed nominal associations with HNSCC risk, and one variant (rs2275558 in PBX1) remained significant after Bonferroni correction (OR = 0.67, 95% CI: 0.60-0.76). PGSs for all four epigenetic clocks were higher in cases than in controls. In logistic regression analyses, each standard deviation increase in HannumAge PGS was associated with a 25% higher risk of HNSCC (OR = 1.25, 95% CI: 1.10-1.41), whereas HorvathAge, GrimAge, and PhenoAge PGSs showed weaker positive associations (ORs ranging from 1.06 to 1.10). Individuals in the highest PGS quartile for all four epigenetic clocks exhibiting 14%-25% higher risk than those in the lower three quartiles. MR analyses supported potential causal effects of genetically predicted HannumAge (IVW OR = 1.24 per SD increase, 95% CI: 1.09-1.42) and GrimAge (IVW OR = 1.23 per SD increase, 95% CI: 0.98-1.56) on HNSCC risk, with consistent estimates in weighted median analyses. Our results highlight biological aging as a potential etiologic mechanism for HNSCC and suggest that epigenetic clock-related genetic profiles may improve HNSCC risk stratification.

Humans↗

PubMed2026

Can Psychiatric Genetics Advance Without Incorporating a Life Course Perspective?

Psychiatric disorders unfold over the life course; however, genomic studies of these conditions overwhelmingly rely on phenotypes collected at a single time point, often in adulthood. Therefore, genome-wide association studies (GWASs) of psychiatric conditions may miss genetic variants with time-varying relevance to etiology, prevention, and treatment, such as those that influence trajectories of symptoms and behaviors, age at onset, course of treatment response, and the co-evolution of comorbidities. With recent advances in longitudinal biobanks and analytic tools, we posit that incorporating a life course perspective in psychiatric genetics will enable critically relevant insights into each of these areas of investigation. We propose that the current inconsistent portability of polygenic scores across age groups can be reconciled through the design of carefully considered longitudinal GWASs in age-diverse samples. Pioneering longitudinal GWASs in psychiatry have revealed novel genomic signals associated with time-dependent phenotypes that are distinct from those influencing lifetime diagnosis, suggesting that the study of longitudinal phenotypes will complement cross-sectional approaches and empower biological and therapeutic discoveries. Advances in post-GWAS functional annotation resources and analytic approaches now enable us to contextualize the genetic contributions to psychiatric disorders as dynamic age- and exposure-dependent processes. Although longitudinal GWASs pose unique challenges with regard to data availability, selection bias, and missing data, integrating temporality into psychiatric genetics at scale is now attainable and promises to reveal novel biology and therapeutic opportunities for psychiatric conditions.

Cohort study↗

PubMed2026

Alcohol use disorder and childhood adversity in the association between polygenic risk and suicidality.

OBJECTIVE: Suicidal ideation (SI) and suicide attempt (SA) are both influenced by genetic, behavioral, and environmental factors. Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may mediate or moderate the effects of genetic liability for suicidality. METHODS: Using data from 10,275 participants (43.8% female; 47.2% African-like genetic ancestry [AFR], 52.8% European-like genetic ancestry [EUR]), we tested whether polygenic scores (PGS) for SI and SA predicted lifetime suicidality outcomes. We evaluated whether AUD partially accounted for these associations and ACEs moderated the direct and indirect associations. RESULTS: The SA PGS was significantly associated with SA (AFR: b = 0.36, SE = 0.01; EUR: b = 0.17, SE = 0.01; both ps < 2e-16), but the SI PGS was not associated with SI (p > 0.55). AUD statistically mediated the association between the SA PGS and SA, accounting for approximately 2% of the total association in AFR individuals and 10% in EUR individuals (both ps < 2e-16). Notably, the proportion of the association that was accounted for by AUD decreased as ACEs exposure increased, from 4.30% to 0.54% in AFR individuals and from 13.31% to 3.44% in EUR individuals. In contrast, there was only very modest mediation and no moderated mediation for SI. CONCLUSIONS: Particularly among individuals with lower ACEs exposure, AUD accounted for a meaningful proportion of the association between genetic liability to SA and lifetime SA. These findings highlight different correlates across suicidality phenotypes and suggest potential clinical relevance for AUD in the association between genetic liability and SA.

Adult↗

PubMed2026

Perceived partner substance use, genetic predispositions, and their associations with problematic alcohol use, emotional well-being, and relationship quality.

BACKGROUND: Romantic relationships are important contexts for substance use and emotional well-being. We tested the hypotheses that (i) genetic predispositions for alcohol consumption would be positively associated with partner substance use, (ii) partner substance use would moderate genetic influences on one's own alcohol outcomes, and (iii) partner discordance in substance use would be associated with lower emotional well-being and relationship quality. METHODS: Analyses included 2,357 participants (Mage = 51.4, 58.2% female) from the Collaborative Studies on the Genetics of Alcoholism. Focal measures included participants' reports of their own and their current partner's past-year substance use (frequencies of alcohol use, heavy drinking, drunkenness, cannabis use, and nicotine use), emotional well-being, and relationship quality. Participants' genetic predispositions were indexed with genome-wide polygenic scores for alcohol consumption (PGSAlc). Participant-partner substance use discordance was calculated as the difference between the participant's and their partner's use for each substance use measure, separately. RESULTS: Participant PGSAlc was not significantly associated with partners' perceived substance use. Frequent perceived partner alcohol use and heavy drinking significantly amplified the association between PGSAlc and alcohol use or drunkenness. Frequent perceived partner drunkenness and cannabis use significantly attenuated the association between PGSAlc and heavy drinking or frequency of alcohol use. Participant-partner discordance for several substance use measures was significantly associated with lower emotional well-being and relationship quality, controlling for participant and partner substance use main effects. CONCLUSIONS: The results highlight the importance of partner substance use in etiological models of alcohol use, emotional health outcomes, and relationship quality.

Humans↗

PubMed2024

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Humans↗