Circulating lipid levels are influenced by both genetic and environmental factors. While vegetarianism has been linked to improved lipid profiles, it remains unclear whether these beneficial effects persist across individuals with varying genetic capacity for lipid metabolism. We hypothesized that genetic capacity and vegetarianism interact to influence the circulating levels of four lipids, including total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TG). Our study included UK Biobank participants of European (EUR, n = 182,300), Central/South Asian (CSA, n = 2,627), African (n = 2,143), and East Asian (n = 1,031) ancestry. Utilizing polygenic scores (PGS) for four circulating lipids, we employed multivariable regression models to assess PGS-by-vegetarianism interactions for each lipid. Vegetarianism is associated with reduced levels of TC, LDL cholesterol, and HDL cholesterol, and with elevated levels of TG in the EUR cohort (p-value < 0.001). The same significant association patterns were observed for HDL cholesterol and TG in the CSA cohort. We did not detect significant PGS-by-vegetarianism interactions for any lipid traits (Interaction p-value > 0.05). There is a lack of evidence supporting that PGS modifies the associations between vegetarianism and lipid levels, nor that vegetarianism alters the effects of PGS on lipid levels. Vegetarianism is associated with reduced TC, LDL cholesterol, and HDL cholesterol, as well as elevated TG among EUR participants, with similar patterns for HDL cholesterol and TG in CSA participants. These association effects of vegetarianism on circulating lipids are similar across individuals with varying genetic capacity for lipid metabolism.

Individuals of African ancestry carrying APOL1 (apolipoprotein L1) high-risk genotypes face a markedly increased risk of kidney failure, yet tools to identify those individuals likely to progress to chronic kidney disease are lacking. Here we profiled plasma proteomes of 851 Penn Medicine BioBank participants of African ancestry (285 males and 566 females) with APOL1 high-risk genotypes and preserved estimated glomerular filtration rate (eGFR) (≥60 ml min-1 1.73 m-2). Using elastic net Cox regression adjusted for age, sex, eGFR and albuminuria, we derived a nine-protein APOL1 Proteomic Risk Score (APRS) that predicts a composite outcome of ≥40% eGFR decline, kidney failure or death. APRS achieved a time-dependent area under the receiver operating characteristic curve (tAUC) of 86.5%, outperforming the Kidney Failure Risk Equation (66.1%) and polygenic risk scores, with 10-year event rates of 62.5% versus 3.3% across risk quintiles. External validation in Atherosclerosis Risk in Communities and UK Biobank cohorts confirmed robust accuracy (tAUC 82-85%) and consistent performance across demographic and clinical subgroups. Plasma levels of APRS component proteins correlated with kidney tissue fibrosis and tubular injury pathways, indicating strong biological plausibility. By enabling early and accurate prediction of disease progression in APOL1 high-risk individuals, APRS bridges the gap between genetic susceptibility and clinical translation. This scalable and biologically informed approach provides a precision medicine framework for early intervention and may accelerate development of APOL1-targeted therapies to reduce kidney disease disparities.

Transcriptome-wide association study of cardiovascular outcomes in chronic kidney disease: The chronic renal insufficiency cohort.

Objective : Suicidal thoughts and behaviors (STB) constitute high public health concerns. Understanding the longitudinal trajectories of STB from adolescence to adulthood as a function of sex, ancestry, and genetic liability would improve our knowledge and the design of population-based prevention/intervention. Methods : We used data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) and included participants of European (EA, N = 4,905) and African (AA, N = 1,654) ancestry. We evaluated the growth trajectories of suicide ideation and suicide attempt from age 12 to 40 separately in participants of EA and AA and assessed the roles of sex and genetic liability, indexed using polygenic scores (PGS). Results : Quadratic growth models including an age-by-sex interaction fit the data best in both ancestral groups. Results indicated an overall decrease of STB from adolescence to adulthood, a stabilization between ages 25–35, and a tendency to increase after age 35. Sex differences were evidenced by higher baseline levels of STB and sharper decreases across ages in females. Including PGS improved the model fit and was related to baseline levels of STB. Conclusions : Adolescence constitutes a high-risk period for the development of STB, particularly in females and those with high genetic liability. Though we observed a stabilization of STB in adulthood, another risk period may arise after age 35.

Genomic Study of Resilience to Posttraumatic Stress Disorder in the Million Veteran Program.

Type 2 diabetes complications manifest across various organs, but are fundamentally rooted in vascular dysfunction. This study aims to identify plasma protein signatures that improve prediction of macrovascular and microvascular complications in type 2 diabetes over classical clinical factors, assess the stability of their prognostic performance over time, and explore the cross-ancestry generalizability of the developed models. We analysed 2,923 plasma proteins in 917 European-ancestry UK Biobank participants with prevalent type 2 diabetes but no prior vascular disease at baseline. The primary outcomes were time to first macrovascular or microvascular complication, identified through ICD-10 codes during a mean follow-up of 10.41 years. Protein selection was performed using clinical-variables-prioritized LASSO Cox regression across 100 resamples to identify proteins offering predictive value beyond established clinical markers. Stably selected proteins were then integrated with and evaluated against clinical-only models using optimism-corrected C-index, time-dependent AUC and Brier score. We also conducted exploratory analyses to assess model generalizability in 116 European genetic outliers and in 80 Asian and 54 African ancestry participants within the UK Biobank. For macrovascular outcomes, 37 proteins were selected, led by LRRC37A2, NT-proBNP, CHGA, APOD and STAB2. For microvascular complications, 9 proteins were selected, led by IL15, FAM3C and TNFSF11, with overall more moderate stability across resampling. The proteomics-integrated models significantly improved prediction of type 2 diabetes vascular complications beyond clinical markers (Harrell’s C: macrovascular 0.72 vs. 0.60; microvascular 0.67 vs. 0.62) and demonstrated stable prognostic accuracy over 10 years for macrovascular outcomes. In exploratory generalizability analyses, predictive gains of proteomics integration were maintained in European genetic outliers but diminished in African and Asian participants. Integrating proteomics with clinical data enhances risk prediction of type 2 diabetes vascular complications, especially for macrovascular outcomes. However, less precise prediction for microvascular complications and preliminary evidence of limited cross-ancestry generalizability highlight the need to expand targeted biomarker panels and quantification in larger, more ancestry-diverse cohorts to ensure effective and equitable clinical implementation of proteomics.

The inclusion of polygenic scores (PGS) from genetically correlated traits such as Major Depressive Disorder (MDD) and alcohol use disorder (AUD) may improve the prediction of these outcomes and their comorbidity. Despite the importance of this work, few studies have evaluated the efficacy of this possibility. The current study evaluates the use of MDD and AUD PGS individually and together to improve the prediction of MDD, AUD, and comorbid MDD-AUD using a sample of European, African, or Admixed American Ancestry participants from the National Longitudinal Study of Adolescent to Adult Health (N = 7,965). Cross-ancestry MDD and AUD PGS were created using PRS-CSx. The best fitting model of comorbid MDD-AUD in the whole sample included PGS for MDD and AUD (PGSMDD OR: 1.26, 95% CI 1.16–1.35, p = 2.69 × 10− 6; PGSAUD OR: 1.77, 95% CI 1.66–1.87, p = 3.49 × 10− 28), explaining an additional 4.88% of variance compared to a model only including sociodemographic covariates. For MDD, the best fitting model included the MDD PGS (OR: 1.25, 95% CI 1.17–1.33, p = 2.05 × 10− 8), explaining an additional 0.65% of variance. For AUD, the best fitting model included the AUD PGS (OR: 1.37, 95% CI 1.32–1.43, p = 1.25 × 10−28), which explained an additional 1.52% of variance. Inclusion of both PGS did not significantly improve the prediction of individual MDD or AUD. Inclusion of PGS for MDD and AUD significantly improved prediction for comorbid MDD-AUD, but not in MDD or AUD. These results help clarify the role of utilizing genetically correlated PGS in improving prediction of MDD, AUD, and comorbid MDD-AUD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10519-026-10263-3.

X chromosome-wide association studies (XWAS) have successfully identified risk loci on the X chromosome associated with Parkinson’s disease (PD) susceptibility. However, only three such studies have been completed to date. Here, we present the first XWAS using an African cohort, comprising 690 PD cases and 826 controls. We applied an established XWAS workflow to perform male- and female-stratified analyses, as well as a combined meta-analysis. The male-stratified analysis identified five significant variants, including one lead locus (rs200539602), while the female-stratified analysis revealed 29 significant variants and two lead loci (rs2499550 and rs58045540), where rs2499550 is an upstream variant of the protein-coding gene FAAH2. The remaining female-stratified significant variants are expression quantitative trait loci for SPIN2A, SPIN2B, and SPIN3, which are highly expressed in the brain and nerve tissues, making them strong candidates for further investigation. One previously reported PD XWAS locus (rs28602900) was also replicated at a significance threshold of 0.05. The meta-analysis identified five variants surpassing chromosome-wide significance, including two lead loci (rs140715059 and rs141026964), the latter has no significant expression quantitative trait locus information but lies closest to the protein-coding gene MAGEC2, which may warrant further follow-up. None of the meta-analysis signals replicated in prior neurodegenerative disease XWAS. Overall, this study provides novel insights into the contribution of the X chromosome to PD susceptibility and represents the first PD XWAS to include participants of African ancestry, highlighting the importance of extending genetic studies to diverse populations.

BackgroundAs biobank‐scale cohorts emerge, there has been a great increase in the number of dementia cases available for genetic meta‐analyses, resulting in a substantial increase in the number of dementia risk variants identified and replicated. Although also increasing, the number of non‐European ancestry participants in most of these studies is still substantially lower. Although primarily European ancestry (EUR), the Million Veteran Program (MVP) contains a substantial proportion of African (AFR) and Hispanic (HIS) ancestry participants. Here, we analyzed three dementia phenotypes in MVP, and meta‐analyzed them with publicly available dementia summary statistics.MethodsThree phenotypes were analyzed in MVP (Table 1): 1) Alzheimer's disease and related dementias (ADRD), defined by two or more ADRD treatment codes in electronic medical records (EMR); 2) prescriptions for medications to treat dementia (e.g. cholinesterase inhibitors), also from EMR; 3) maternal and paternal proxy dementia as reported in MVP surveys. These analyses were independent, with non‐overlapping case/control sets. We first performed GWAS of these phenotypes within MVP ancestry groups (EUR, AFR, HIS), adjusting for sex and ancestry principal components. These were used along with Bellenguez et al. 2022, and AFR statistics from Kunkle et al. 2021 to generate a EUR MVP meta‐analysis, an MVP/Bellenguez EUR meta‐analysis, and a cross‐ancestry meta‐analysis using MR Mega. Novel regions were defined as genome‐wide significant (GWS) loci at least 250KB from the peak SNP in previous GWASs, and if within 1MB of that SNP, had a pairwise r2<0.2.ResultsWe identified 19 novel, GWS regions in EUR, five in MVP EUR, and 14 in the meta‐analysis (Table 2). We identified 11 novel regions in the cross‐ancestry meta. Two genes, PAX7 and PTPRD (not novel, but previously only observed in HIS), were unique to the AFR and HIS cohorts (Table 3).ConclusionThe MVP‐specific genes may be involved in processes related to more general (not AD specific) dementia pathways or have stronger effects in males. Several of the novel genes identified in EUR and cross‐ancestry meta‐analysis are involved in neuronal development and function or have been linked to cognitive outcomes.

African Americans are at increased risk for chronic kidney disease (CKD) in part due to Apolipoprotein L1 gene (APOL1) high-risk genotypes. Recently, a study from West Africa reported an association between monoallelic genotypes and risk of CKD and focal segmental glomerulosclerosis (FSGS). We here study the association of biallelic and monoallelic genotypes with CKD, proteinuria, and FSGS in participants in a hospital-based cohort in the Southeastern United States. We conducted a case-control study of African Ancestry participants from the Vanderbilt University Medical Center Biobank (n=23, 857). The primary outcome was CKD defined as: persistent GFR < 60 ml/min, end stage kidney disease (ESKD), biopsy-proven FSGS or urine protein-to-creatinine ratio of >700 mg/g or albumin-to-creatinine ratio of >420 mg/g. Secondary outcomes were proteinuria and FSGS outcomes separately. The primary exposure was APOL1 monoallelic genotype (1 copy of a risk allele versus none). APOL1 biallelic genotypes was studied as a secondary exposure. Sequential logistic regression models were performed adjusting for potential confounders. Among 23,857 participants, 5,784 had CKD, 1,533 had proteinuria, and 80 had biopsy-proven FSGS, 44.5% had one risk allele (monoallelic) and 13.6% had two risk alleles (biallelic). Biallelic carriers had higher odds of CKD than those with one or no risk alleles (adjusted odds ratio ( aOR ), 1.72; 95% confidence interval [CI], 1.57-1.89), proteinuria aOR = 2.02 (95% CI, 1.77-2.31), and FSGS aOR = 17.48 (95%CI 10.53-29.02). Monoallelic carriers (G0/G1 or G0/G2) had a small increase in odds of CKD ( aOR = 1.08, 95% CI 1.00-1.16, p=0.04), which was driven by the G0/G2 genotype ( aOR = 1.11, 95% CI 1.01-1.23, p=0.03). Monoallelic carriers (G0/G1 or G0/G2) had higher odds of proteinuria ( aOR = 1.23; 95% CI, 1.09-1.39) and G0/G1 had higher odds of FSGS (14 cases) ( aOR = 2.83; 95% CI, 1.18-6.79). In our study, monoallelic APOL1 genotypes were associated with 23% higher odds of proteinuria and 3-fold higher odds of FSGS for G0/G1. A modest increase odd for CKD of 8%, which may reflect CKD phenotypic heterogeneity. Our study supports the observations from a West Africa cohort in a US based cohort and adds the association of APOL1 monoallelic genotypes with proteinuria.

INTRODUCTIONAlzheimer's disease (AD) has genetic and environmental risk factors, including cigarette smoking. Gene–environment interactions may explain AD missing heritability.METHODSLifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome‐wide single nucleotide polymorphism (SNP)‐by‐smoking interaction and smoking‐stratified association studies. For top‐ranked loci, brain‐derived bulk and single nuclei RNA‐sequencing were used for differential expression and colocalization analyses.RESULTSAmong smokers only, there was a genome‐wide significant association in the APAF1/ANKS1B region (rs12368451; odds ratio = 1.19, 95% confidence interval: [1.12, 1.27], p = 3.0 × 10−8). Rs12368451 had expression quantitative trait locus (eQTL) activity that differed by smoking status and brain cell types but showed the most significant posterior probability (PP = 0.15) for being causal via ANKS1B expression in oligodendrocytes among smokers.DISCUSSIONPotentially causal in smokers via eQTL activity, the top SNP may alter expression of ANKS1B, which encodes amyloid beta precursor protein intracellular domain associated‐1, known to regulate amyloid beta plaques.HighlightsAmong smokers only, a novel chromosome 12 single nucleotide polymorphism (SNP) near ANKS1B was associated with Alzheimer's disease.Evidence came from European and African ancestry cohorts.RNA‐sequencing analyses implicated the top SNP as causal via ANKS1B expression in oligodendrocytes.A genome‐wide African ancestry–specific significant SNP–smoking interaction was observed on chromosome 6 in SLC22A23.

This study aims to identify new genetic loci associated with primary open-angle glaucoma (POAG) and explore shared genetic risk factors across African, European, and Admixed American/Latino populations. Genome-wide Association Study (GWAS) utilizing data from the All of Us Research Program. The study included 374,254 participants, with 4,305 individuals diagnosed with POAG and 369,949 controls. Participants were categorized by ancestry: European, African, and Admixed American/Latino. We used short-read sequencing data and applied strict quality control measures (MAF > 0.01, INFO > 0.8). GWAS were conducted for each ancestry group using a logistic mixed model, adjusting for age, sex, and the top 11 principal components. A fixed-effect meta-analysis combined the results across ancestries. Genome-wide significance was set at p<5×10−8. The primary outcome measures were the identification of genetic loci associated with POAG, and the analysis of transcription factors linked to these loci in relevant tissues. In the European cohort, we identified four novel loci associated with POAG, linked to the TUT4, RYK, MOXD1, and UBAP2 genes, as well as the previously known TMCO1 locus. In the African cohort, we found five new loci, including TSPAN17, SLC16A7, LOC100506869, LINC02388, and LOC107984606. For the Admixed American/Latino cohort, we identified GATA5, FAM135B, and LINC00871 genes as novel loci. Our analysis identified three novel loci in individuals of European ancestry, mapped to the genes TUT4, RYK, and MOXD1. In addition, five novel loci were detected in the GWAS of African ancestry participants, and four novel loci were identified in individuals of Admixed American/Latino ancestry. These findings indicate that the genetic determinants contributing to POAG may differ across populations, underscoring the importance of accounting for population-specific genetic architectures in the study of complex traits. Given the substantial variation in POAG prevalence among ancestries, it is plausible that certain genetic variants exert ancestry-specific effects. Consequently, conducting ancestry-stratified GWAS is essential for elucidating these unique genetic contributions.

Abstract Background and Aims Two variants in APOL1 drive progressive, proteinuric nephropathies called APOL1-mediated kidney disease (AMKD). Inaxaplin, an oral inhibitor of APOL1, reduced proteinuria by 47.6% in persons with 2 APOL1 variants and focal segmental glomerulosclerosis (FSGS) in a Phase 2 study. We report interim data from an APOL1 genotyping study, describe the Phase 2/3 inaxaplin trial (AMPLITUDE) design in a broader AMKD population, and provide interim baseline data from the Phase 2 component of AMPLITUDE. Methods Our genotyping study is enrolling up to 4000 participants of recent African ancestry with FSGS or nondiabetic kidney disease and UPCR ≥0.5 g/g. One blood sample is collected to verify APOL1 genotype by polymerase chain reaction to describe the genetic prevalence of AMKD and inform eligibility for clinical trials. Our Phase 2/3, randomized, double-blind, placebo-controlled, adaptive trial is enrolling persons without diabetes (Phase 2: 18 to 65 years; Phase 3: 10 to 65 years) with 2 APOL1 variants, UPCR ≥0.7 to &amp;lt;10 g/g, and eGFR ≥25 to &amp;lt;75 mL/min/1.73 m2. In the Phase 2 component, participants received inaxaplin (different doses) or placebo for 12 weeks to select a dose for evaluation of inaxaplin efficacy/safety in ∼400 participants in Phase 3. For the final analysis, the primary endpoint will be reduction in rate of decline of kidney function (eGFR slope) by inaxaplin versus placebo; secondary endpoint is time to composite clinical outcome (sustained decline of ≥30% from baseline in eGFR, onset of ESKD, or death). Final analysis will occur when ≥2 years of eGFR data and ∼187 composite clinical outcomes are obtained. Results The genotyping study interim analysis included 2866 participants of whom 674 (23.5%) have 2 APOL1 variants; 164 of the 674 (24.3%) participants are from Europe. Of the 674 participants with 2 APOL1 variants in this study, 36 enrolled in the completed Phase 2 component of AMPLITUDE. In the AMPLITUDE trial, we selected a 45 mg inaxaplin once daily dose for Phase 3 after the Phase 2 efficacy/safety data had been reviewed by an independent data monitoring committee. Among 64 participants dosed, 34 (53.1%), 24 (37.5%), and 6 (9.4%) have G1/G1, G1/G2, or G2/G2 genotypes, respectively. The mean (SD) age was 42.7 (11.0) years and mean (SD) baseline eGFR was 42.8 (14.0) mL/min/1.73 m2. Phase 3 is ongoing in nine countries, including Belgium and France in Europe. Conclusions The high prevalence of two APOL1 variants in participants with recent African ancestry and proteinuric CKD reinforces the importance of APOL1 genotyping to optimize kidney disease management and enable referral to clinical trials of APOL1-targeted therapies. Our Phase 2/3 trial will evaluate the effects of inaxaplin on preserving kidney function and reducing proteinuria in a broad AMKD population.

BackgroundOlfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown. Therefore, here we aimed to elucidate its genetic architecture through a genome-wide association study meta-analysis (GWMA).MethodsThis GWMA included the participants of European ancestry (N = 22,730) enrolled in four different large population-based studies followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030). Olfactory dysfunction was assessed using a 12-item smell identification test.ResultsGWMA revealed a novel genome-wide significant locus (tagged by single nucleotide polymorphism rs11228623 at the 11q12 locus) associated with olfactory dysfunction. Gene-based analysis revealed a high enrichment for olfactory receptor genes in this region. Phenome-wide association studies demonstrated associations between genetic variants related to olfactory dysfunction and blood cell counts, kidney function, skeletal muscle mass, cholesterol levels and cardiovascular disease. Using individual-level data, we also confirmed and quantified the strength of these associations on a phenotypic level. Moreover, employing two-sample Mendelian Randomization analyses, we found evidence for causal associations between olfactory dysfunction and these phenotypes.ConclusionsOur findings provide novel insights into the genetic architecture of the sense of smell and highlight its importance for many aspects of human health. Moreover, these findings could facilitate the identification and monitoring of individuals at increased risk of olfactory dysfunction and associated diseases.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12863-025-01360-z.

The prevalence of myopia varies significantly across the globe. This may be a consequence of differences in exposure to lifestyle risk factors or differences in genetic susceptibility across ancestry groups. "Trans-ancestry genetic correlation" quantifies the similarity in genetic predisposition to a trait or disease between different populations. We estimated the trans-ancestry genetic correlation of refractive error across Europeans, South Asians, East Asians, and Africans using recently developed approaches. Two methods were applied: (1) trans-ancestry genetic correlation with unbalanced data resources (TAGC-UDR) and (2) trans-ancestry bivariate genomic-relatedness-based restricted maximum-likelihood (TAB-GREML). TAGC-UDR analyses were carried out for UK Biobank participants of European (n = 3500), East Asian (n = 972), South Asian (n = 4303), and African (n = 3877) ancestry. TAB-GREML analyses were carried out for participants of European (n = 10,000), South Asian (n = 4303), and African (n = 3877) ancestry. TAGC-UDR analyses suggested the trans-ancestry genetic correlation of refractive error was in the range 0.7-1.0 for the European versus African, European versus East Asian, and European versus South Asian ancestry pairs. The TAB-GREML estimates were consistent with the TAGC-UDR findings. Precision of the estimates was limited, reflecting the modest sample sizes of the non-European samples. These results support and extend previous work suggesting that genetic susceptibility to refractive error is largely shared across Europeans, Africans, and South Asians. This suggests geographical differences in myopia prevalence are mostly driven by lifestyle factors or rare genetic variants not considered in the current work.

BackgroundCannabis use has gained legal and societal acceptance in many locations worldwide in recent years, with consequent increases in both cannabis lifetime use (CanLU) and cannabis use disorder (CanUD). Both CanLU and CanUD are genetically influenced, and knowledge of the specifics of how genes affect risk for these traits can help improve our understanding of their biology, and how they relate genetically to other traits. This talk will summarize our work on these traits.Aims & ObjectivesThe availability of large biobank samples such as the Million Veteran Program and AllOfUs (in the US) and the UK Biobank (in the UK) has made it feasible to conduct powerful genetic studies of these traits. We completed multi-ancestral GWAS analyses of CanLU and CanUD and considered their relationships to a range of psychiatric, substance use, and medical traits, and to each other.MethodWe used genomewide association analysis, linkage disequilibrium score regression, genomic structural equation modeling (gSEM), and Mendelian randomization (MR).ResultsWe identified multiple associated risk loci in European and African ancestry participants. Patterns of genetic correlation tended to differ between CanLU and CanUD, with the latter trait tending to be associated with deleterious traits to a greater extent than CanLU. MR results showed causal effects for CanUD and CanLU on opioid use disorder, problematic alcohol use, and smoking traits. Many of these relationships were bidirectional. gSEM supported that CanLU and CanUD load onto different genetic factors; CanUD clustered with other use disorders and CanLU, with impulsivity-related traits. CanUD, compared to CanLU, also showed more bidirectional causal effects with a range of psychiatric phenotypes.Discussion & ConclusionsCanUD and CanLU have complex genetic architectures, with features in common with each other and with other substance use traits, as well as distinct features. Knowledge of this genetic architecture opens the possibility of drug repurposing in the interest of improving treatment. CanUD and cannabis use can increase the risk of developing other substance use disorders, psychiatric disorders, and medical disorders. These relationships will increase in importance and in terms of their consequences on public health as use and abuse of cannabis increase in many worldwide populations.

BackgroundAlzheimer’s disease (AD) risk variants have been identified in European ancestry cohorts that have stronger effects at certain ages, in individuals with a specific sex, or in those with specific isoforms of APOE, the strongest AD risk locus. However, sample sizes in African ancestry (AA) cohorts have been underpowered to perform stratified analyses.MethodsWe generated genome-wide association study datasets stratified by sex, age at onset (< 75 vs ≥ 75), and APOE-ε4 carrier status in AA cohorts from MVP and the Alzheimer’s Disease Genetics Consortium (ADGC). Outcomes in MVP were AD and related dementias (ADRD; n = 4073 cases and 19,648 controls) and proxy dementia (i.e., reported dementia in a parent, n = 6216 cases and 21,566 controls) while ADGC analyses examined AD (n = 2425 cases and 5069 controls). The proxy dementia GWASs were included in the sex-stratified meta-analysis corresponding to the sex of the affected parent. The top genes were tested for differential expression in AA brain tissue.ResultsIn addition to the APOE region, genome-wide significant associations were observed in an intergenic region near the EPHA5 gene (rs141838133, p = 2.19 × 10–8) in individuals with onset < 75 years, in GRIN3B near the known AD risk gene ABCA7 (rs115882880, p = 3.83 × 10–8) in females, and near TSPEAR (rs139130053, p = 4.27 × 10–8) in APOE-ε4 non-carriers. EPHA5 regulates glucose homeostasis, and ephrin receptors modify the strength of existing synapses in the brain and in pancreatic islets. It is unclear whether GRIN3B represents a locus distinct from ABCA7. Rs115882880 was a significant eQTL for GRIN3B but not ABCA7 in AA brain samples. TSPEAR regulates Notch signaling but has not been linked to neuronal function.ConclusionsAge, sex, and APOE-stratified analyses of dementia in AA participants from two cohorts revealed potential new associations. Stratified analyses may yield critical information about the genetic heterogeneity underlying dementia risk and lead to advances in precision medicine.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-025-01782-y.

OBJECTIVEGenetic risk scores (GRSs) for type 1 diabetes (T1D) may assist T1D classification and prediction but are often developed from European populations. To improve health outcomes, it is important to understand the performance and utility of GRSs in diverse ancestry populations.RESEARCH DESIGN AND METHODSWe assessed performance of three previously published T1D GRSs in differentiating people with and without Type 1 diabetes in African (with/without T1D=194/235), European (n=1109/125), and Hispanic (266/170) ancestry populations in the USA, and from Cameroon and Uganda (n=144/5001). The assessed GRSs were developed from European ancestry populations (GRS1, GRS2) and from an African ancestry population (AAGRS).RESULTSThe discriminative power, as measured by the area under the receiver operating characteristic curve (AUC), for GRS2 and AAGRS were equivalent on the African ancestry populations, and both outperformed the GRS1: the AUCs produced by the GRS2, AAGRS and GRS1 on Uganda/Cameroon data were 0.882 (0.845-0.914), 0.874 (0.838-0.907) and 0.816 (0.772-0.857) respectively. GRS2 outperformed the AAGRS and GRS1 on Hispanic and European populations. The GRS2 distributions varied by population, with lower average scores for African populations. If the same GRS2 risk thresholds of 11.5 were set for European and African populations, the sensitivities were 0.91 and 0.53, respectively.CONCLUSIONSThe GRS2 produced similar or improved discriminative power across the populations but the AAGRS matched performance on African ancestry participants with fewer single nucleotide polymorphisms. Varying GRS2 risk thresholds may be required for different populations due to the divergent distributions.

Array genotyping of transfusion-relevant blood cell antigens in 6946 ancestrally diverse study participants.

Activation of the renin-angiotensin-aldosterone system (RAAS) and African ancestry are both associated with increased end-organ damage in hypertension. An insertion (I)/deletion (D) polymorphism in the gene encoding the angiotensin-converting enzyme (ACE) has been associated with ACE activity. This study tested the hypothesis that ancestry or ACE I/D genotype affects the conversion of angiotensin (Ang) I to Ang II and blood pressure, renal plasma flow, and aldosterone during Ang I or II infusion. Ang I and Ang II were infused in graded doses from 1 to 20 ng/kg/min in a randomized, single-blind, crossover study in salt-replete normotensive participants of self-identified African (Black) or European (white) ancestry who were homozygous for the ACE I/I (7 Black, 8 white) or D/D (8 Black, 8 white) genotype. ACE activity was significantly increased in ACE D/D vs. ACE I/I individuals regardless of ancestry. The conversion of Ang I to Ang II was increased in Black compared to in white participants, independent of genotype. The pressor and aldosterone responses to Ang I and Ang II did not differ by ancestry or ACE I/D genotype. Basal renal plasma flow was increased in individuals of ACE D/D genotype independent of ancestry but the renal vasoconstrictor response to Ang I and Ang II did not differ by ACE genotype. The conversion of infused Ang I to Ang II is increased in Black compared to in white individuals. Increased Ang II could contribute to attenuated responses to RAAS interfering drugs and end-organ damage in individuals of African ancestry.