Role of the X Chromosome in Alzheimer Disease Genetics.

Importance: The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD. Objectives: To perform the first large-scale X chromosome-wide association study (XWAS) of AD. Design, Setting, and Participants: This was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available. Main Outcome and Measures: Risk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome-wide (P < 1 × 10-5) and genome-wide (P < 5 × 10-8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects. Results: Analyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome-wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk. Conclusion and Relevance: This large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid ß accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.

Biological Insights from Schizophrenia-associated Loci in Ancestral Populations.

Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals - near PLXNA4 , PMAIP1 , and TRPA1 - are the first to be independently identified in populations of predominantly African ancestry. Joint analyses of African, European, and East Asian ancestries across 86,981 cases and 303,771 controls, yielded 376 distinct autosomal loci, which were refined to 708 putatively causal variants via multi-ancestry fine-mapping. Utilizing single-cell functional genomic data from human brain tissue and two complementary approaches, transcriptome-wide association studies and enhancer-promoter contact mapping, we identified a consensus set of 94 genes across ancestries and pinpointed the specific cell types in which they act. We identified reproducible associations of schizophrenia polygenic risk scores with schizophrenia diagnoses and a range of other mental and physical health problems. Our study addresses a longstanding gap in the generalizability of research findings for schizophrenia across ancestral populations, underlining shared biological underpinnings of schizophrenia across global populations in the presence of broadly divergent risk allele frequencies.

No Replication of Alzheimer's Disease Genetics as a Moderator of Combat Exposure's Association with PTSD risk in 138,592 Combat Veterans.

Large-scale cohort and epidemiological studies suggest that posttraumatic stress disorder (PTSD) confers risk for late-onset Alzheimer's disease (AD) and related dementias (ADRD); however, the basis for this association remains unclear. Several prior studies of military Veterans have reported that carriers of the apolipoprotein E (APOE) ε4 gene variant are at heightened risk for the development of PTSD following combat exposure, suggesting that PTSD and ADRD may share some genetic risk. This cohort study was designed to further examine the hypothesis that ADRD genetic risk also confers risk for PTSD. To do so, we examined APOE ε4 and ε2 genotypes, an AD polygenic risk score (PRS), and other Veteran-relevant risk factors for PTSD in age-stratified groups of individuals of European (n = 123,372) and African (n = 15,220) ancestry in the US Department of Veterans Affairs' Million Veteran Program. Analyses revealed no significant main effect associations between the APOE ε4 (or ε2) genotype or the AD PRS on PTSD severity or diagnosis. There were also no significant interactions between measures of AD genetic risk and either combat exposure severity or history of head injury in association with PTSD in any age group. We conclude that the association between PTSD and the primary ADRD genetic risk factor, APOE ε4, that was reported previously was not replicable in the largest relevant dataset in the world. Thus, the epidemiological association between PTSD and ADRD is not likely to be driven by the major genetic factors underlying ADRD risk.

Associations Of Vitamin D-Related Biomarkers With Hypertension And The Renin-Angiotensin System In Men And Women.

BACKGROUND: Vitamin D may prevent the development of hypertension through down-regulation of renin-angiotensin system. However, epidemiologic studies assessing the interrelation of vitamin D-related biomarkers with hypertension are sparse. METHODS: We examined the prospective associations between vitamin D-related biomarkers and risk of hypertension in a nested case-control study. In each of the Women's Health Study (WHS) and Physicians' Health Study (PHS) II, 500 incident hypertension cases and 500 age and race matched controls were randomly selected. Baseline plasma 25(OH)-vitamin D [25(OH)D], parathyroid hormone (PTH), and total renin concentrations were measured. RESULTS: Among controls, 25(OH)D and PTH were inversely correlated, but neither was correlated with total renin. In the crude model, there was a trend of association between increasing quintiles of 25(OH)D and lower risk of hypertension in women, with relative risks and 95% CIs of 1.00, 1.24 (0.84-1.83), 0.82 (0.53-1.25), 0.75 (0.48-1.16), and 0.81 (0.52-1.27) (p, trend: 0.07). Adjustment for body mass index and other hypertension risk factors eliminated this association (RR of 5th quintile: 1.03). No associations were found in men. Baseline PTH and ratio of 25(OH)D to PTH were not associated with risk of hypertension in women or men. When men and women were included in the same model, vitamin D insufficiency (defined as 25(OH)D <20 ng/mL) also was not associated with increased risk of hypertension. No interactions were found across subgroups. CONCLUSIONS: Our study found no association of baseline plasma 25(OH)D or PTH with risk of hypertension or total renin concentration in middle-aged and older men and women.

Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol.

AIMS: Elevated Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, but the mechanisms of risk are debated. Studies have found inconsistent associations between Lp(a) and measurements of atherosclerosis. We aimed to assess the relationship between Lp(a), low-density lipoprotein cholesterol (LDL-C) and coronary artery plaque severity. METHODS: The study population consisted of participants of the Million Veteran Program who have undergone an invasive angiogram. The primary exposure was genetically predicted Lp(a), estimated by a polygenic score. Genetically predicted LDL-C was also assessed for comparison. The primary outcome was coronary artery plaque severity, categorized as normal, non-obstructive disease, 1-vessel disease, 2-vessel disease, and 3-vessel or left main disease. RESULTS: Among 18,927 adults of genetically inferred European ancestry and 4,039 adults of genetically inferred African ancestry, we observed consistent associations between genetically predicted Lp(a) and obstructive coronary plaque, with effect sizes trending upward for increasingly severe categories of disease. Associations were independent of risk factors, clinically measured LDL-C and genetically predicted LDL-C. However, we did not find strong or consistent evidence for an association between genetically predicted Lp(a) and risk for non-obstructive plaque. CONCLUSIONS: Genetically predicted Lp(a) is positively associated with coronary plaque severity independent of LDL-C, consistent with Lp(a) promoting atherogenesis. However, the effects of Lp(a) may be greater for progression of plaque to obstructive disease than for the initial development of non-obstructive plaque. A limitation of this study is that Lp(a) was estimated using genetic markers and could not be directly assayed, nor could apo(a) isoform size.

This study assessed the association between genetic propensity towards higher lipoprotein(a) [Lp(a)] in the blood and the severity of coronary artery plaque seen on clinical angiograms, independent of other factors, including low-density lipoprotein cholesterol (LDL-C). The study was conducted in a large U.S. population using data from the Million Veteran Program. Genetically predicted high Lp(a) was associated with obstructive coronary plaque, but it was not associated with non-obstructive coronary plaque. This association was independent of LDL-C, and the association was greater for more severe forms of disease.The mechanisms of association between Lp(a) and cardiovascular events are debated. Prior studies have shown that Lp(a) does not associate with early markers of atherosclerosis. Our analyses support the idea that Lp(a) plays less of a role in early plaque initiation but plays a significant role in the progression of plaque towards more severe disease, independent of LDL-C.

Measuring Frailty Using Self-Report or Automated Tools to Identify Risk of Cardiovascular Events and Mortality: The Million Veteran Program.

BACKGROUND: Frailty, a syndrome of physiologic vulnerability, increases cardiovascular disease (CVD) risk. Whether in person or automated frailty tools are ideal for identifying CVD risk remains unclear. We calculated 3 distinct frailty scores and examined their associations with mortality and CVD events in the Million Veteran Program, a prospective cohort of nearly 1 million US veterans. METHODS AND RESULTS: Veterans aged ≥50 years and enrolled from 2011 to 2018 were included. Two frailty indices (FI) based on the deficit accumulation theory were calculated: the questionnaire-based 36-item Million Veteran Program-FI and 31-item Veterans Affairs-FI using claims data. We calculated Fried physical frailty using the self-reported, 3-item Study of Osteoporotic Fractures. Multivariable-adjusted Cox models examined the association of frailty by each score with primary (all-cause and CVD mortality) and secondary (myocardial infarction, stroke, and heart failure) outcomes. In 190 688 veterans (69±9 years, 94% male, 85% White), 33, 233 (17%) all-cause and 10 115 (5%) CVD deaths occurred. Using Million Veteran Program-FI, 29% were robust, 42% pre-frail, and 29% frail. Frailty prevalence increased by age group (27% in 50-59 to 42% in ≥90 years). Using the Million Veteran Program-FI, over 6±2 years, frail veterans had a higher hazard of all-cause (hazard ratio [HR], 3.05 [95% CI, 2.95-3.16]) and CVD mortality (HR, 3.65 [95% CI, 3.43-3.90]). Findings were concordant for the Veterans Affairs-FI and Study of Osteoporotic Fractures frailty definitions, and remained significant even among younger veterans aged 50-59 years. CONCLUSIONS: Irrespective of frailty measure, frailty is associated with a higher risk of all-cause mortality and adverse CVD events. Further study of frailty in veterans aged <60 years old is warranted.

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries.

BACKGROUND: Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. METHODS: This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. FINDINGS: Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I2=61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I2=59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I2=68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. INTERPRETATION: The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. FUNDING: The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre.

Estimating the Effect of Bariatric Surgery on Cardiovascular Events Using Observational Data?

BACKGROUND: Observational studies have reported strongly protective effects of bariatric surgery on cardiovascular disease, but with oversimplified definitions of the intervention, eligibility criteria, and follow-up, which deviate from those in a randomized trial. We describe an attempt to estimate the effect of bariatric surgery on cardiovascular disease without introducing these sources of bias, which may not be entirely possible with existing observational data. METHODS: We propose two target trials among persons with diabetes: (1) bariatric operation (vs. no operation) among individuals who have undergone preoperative preparation (lifestyle modifications and screening) and (2) preoperative preparation and a bariatric operation (vs. neither preoperative nor operative component). We emulated both target trials using observational data of US veterans. RESULTS: Comparing bariatric surgery with no surgery (target trial #1; 8,087 individuals), the 7-year cardiovascular risk was 18.0% (95% CI = 6.9, 32.7) in the surgery group and 18.9% (95% CI = 17.7, 20.1) in the no-surgery group (risk difference -0.9, 95% CI = -12.0, 14.0). Comparing preoperative components plus surgery vs. neither (target trial #2; 10,065 individuals), the 7-year cardiovascular risk was 17.4% (95% CI = 13.6, 22.0) in the surgery group and 18.8% (95% CI = 17.8, 19.9) in the no-surgery group (risk difference -1.4, 95% CI = -5.1, 3.2). Body mass index and hemoglobin A1c were reduced with bariatric interventions in both emulations. CONCLUSIONS: Within limitations of available observational data, our estimates do not provide evidence that bariatric surgery reduces cardiovascular disease and support equipoise for a randomized trial of bariatric surgery for cardiovascular disease prevention.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

Natural Language Processing Algorithm to Extract Multiple Myeloma Stage From Oncology Notes in the Veterans Affairs Healthcare System.

PURPOSE: Stage in multiple myeloma (MM) is an essential measure of disease risk, but its measurement in large databases is often lacking. We aimed to develop and validate a natural language processing (NLP) algorithm to extract oncologists' documentation of stage in the national Veterans Affairs (VA) Healthcare System. METHODS: Using nationwide electronic health record (EHR) and cancer registry data from the VA Corporate Data Warehouse, we developed and validated a rule-based NLP algorithm to extract oncologist-determined MM stage. To that end, a clinician annotated MM stage within over 5,000 short snippets of clinical notes, and annotated MM stage at MM treatment initiation for 200 patients. These were allocated into snippet- and patient-level development and validation sets. We developed MM stage extraction and roll-up algorithms within the development sets. After the algorithms were finalized, we validated them using standard measures in held-out validation sets. RESULTS: We developed algorithms for three different MM staging systems that have been in widespread use (Revised International Staging System [R-ISS], International Staging System [ISS], and Durie-Salmon [DS]) and for stage reported without a clearly defined system. Precision and recall were uniformly high for MM stage at the snippet level, ranging from 0.92 to 0.99 for the different MM staging systems. Performance in identifying for MM stage at treatment initiation at the patient level was also excellent, with precision of 0.92, 0.96, 0.90, and 0.86 and recall of 0.99, 0.98, 0.94, and 0.92 for R-ISS, ISS, DS, and unclear stage, respectively. CONCLUSION: Our MM stage extraction algorithm uses rule-based NLP and data aggregation to accurately measure MM stage documented in oncology notes and pathology reports in VA's national EHR system. It may be adapted to other systems where MM stage is recorded in clinical notes.

Initiation of Statins for Primary Prevention in Heart Failure With Preserved Ejection Fraction.

Background: Statins are highly effective for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and mortality. Data on the benefit of statins in adults with heart failure with preserved ejection fraction (HFpEF) and without ASCVD are limited. Objectives: The purpose of this study was to determine whether statins are associated with a lower risk of mortality and major adverse cardiovascular events (MACE) in HFpEF. Methods: Veterans Health Administration data from 2002 to 2016, linked to Medicare and Medicaid claims and pharmaceutical data, were collected. Patients had a new HFpEF diagnosis and no known ASCVD or prior statin use at baseline. Cox proportional hazards models were fit to evaluate the association of new statin use with outcomes (all-cause mortality and MACE). Propensity score overlap weighting (PSW) was used to balance baseline characteristics. Results: Among 7,970 Veterans, 47% initiated a statin over a mean 6.0-year follow-up. At HFpEF diagnosis, mean age was 69 ± 12 years, 96% were male, 67% were White, 14% were Black, and mean EF was 60% ± 6%. Before PSW, statin users were younger with more prevalent metabolic syndrome, arthritis, and other chronic conditions. All characteristics were balanced after PSW. There were 5,314 deaths and 4,859 MACE events. After PSW, the hazard for all-cause mortality for statin users vs nonusers was 22% lower (HR: 0.78; 95% CI: 0.73-0.83). The HR for MACE was 0.79 (95% CI: 0.74-0.84), 0.69 (95% CI: 0.60-0.80) for all-cause hospitalization, and 0.72 (95% CI: 0.59-0.88) for HF hospitalization. Conclusions: New statin use was associated with reduced all-cause mortality, MACE, and hospitalization in Veterans with HFpEF without prevalent ASCVD.

Identification and correction for collider bias in a genome-wide association study of diabetes-related heart failure.

Type 2 diabetes (T2D) is a major risk factor for heart failure (HF) and has elevated incidence among individuals with HF. Since genetics and HF can independently influence T2D, collider bias may occur when T2D (i.e., collider) is controlled for by design or analysis. Thus, we conducted a genome-wide association study (GWAS) of diabetes-related HF with correction for collider bias. We first performed a GWAS of HF to identify genetic instrumental variables (GIVs) for HF and to enable bidirectional Mendelian randomization (MR) analysis between T2D and HF. We identified 61 genomic loci, significantly associated with all-cause HF in 114,275 individuals with HF and over 1.5 million controls of European ancestry. Using a two-sample bidirectional MR approach with 59 and 82 GIVs for HF and T2D, respectively, we estimated that T2D increased HF risk (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.10), while HF also increased T2D risk (OR 1.60, 95% CI 1.36-1.88). Then we performed a GWAS of diabetes-related HF corrected for collider bias due to the study design of index cases. After removing the spurious association of TCF7L2 locus due to collider bias, we identified two genome-wide significant loci close to PITX2 (chromosome 4) and CDKN2B-AS1 (chromosome 9) associated with diabetes-related HF in the Million Veteran Program and replicated the associations in the UK Biobank. Our MR findings provide strong evidence that HF increases T2D risk. As a result, collider bias leads to spurious genetic associations of diabetes-related HF, which can be effectively corrected to identify true positive loci.

Accelerating Genome- and Phenome-Wide Association Studies using GPUs - A case study using data from the Million Veteran Program.

The expansion of biobanks has significantly propelled genomic discoveries yet the sheer scale of data within these repositories poses formidable computational hurdles, particularly in handling extensive matrix operations required by prevailing statistical frameworks. In this work, we introduce computational optimizations to the SAIGE (Scalable and Accurate Implementation of Generalized Mixed Model) algorithm, notably employing a GPU-based distributed computing approach to tackle these challenges. We applied these optimizations to conduct a large-scale genome-wide association study (GWAS) across 2,068 phenotypes derived from electronic health records of 635,969 diverse participants from the Veterans Affairs (VA) Million Veteran Program (MVP). Our strategies enabled scaling up the analysis to over 6,000 nodes on the Department of Energy (DOE) Oak Ridge Leadership Computing Facility (OLCF) Summit High-Performance Computer (HPC), resulting in a 20-fold acceleration compared to the baseline model. We also provide a Docker container with our optimizations that was successfully used on multiple cloud infrastructures on UK Biobank and All of Us datasets where we showed significant time and cost benefits over the baseline SAIGE model.

Healthy lifestyle and prostate cancer risk in the Million Veteran Program.

BACKGROUND: This study aims to assess the impact of healthy lifestyle on prostate cancer (PCa) risk in a diverse population. METHODS: Data for 281,923 men from the Million Veteran Program (MVP), a nationwide, health system-based cohort study, were analyzed. Self-reported information at enrollment included smoking status, exercise, diet, family history of PCa, and race/ethnicity. Body mass index (BMI) was obtained from clinical records. Genetic risk was assessed via a validated polygenic score. Cox proportional hazards models were used to assess associations with PCa outcomes. RESULTS: After accounting for ancestry, family history, and genetic risk, smoking was associated with an increased risk of metastatic PCa (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.64-2.02; p < 10-16) and fatal PCa (HR, 2.73; 95% CI, 2.36-3.25; p < 10-16). Exercise was associated with a reduced risk of fatal PCa (HR, 0.86; 95% CI, 0.76-0.98; p = .03). Higher BMI was associated with a slightly reduced risk of fatal PCa, and diet score was not independently associated with any end point. Association with exercise was strongest among those who had nonmetastatic PCa at MVP enrollment. Absolute reductions in the risk of fatal PCa via lifestyle factors were greatest among men of African ancestry (1.7% for nonsmokers vs. 6.1% for smokers) or high genetic risk (1.4% for nonsmokers vs. 4.3% for smokers). CONCLUSIONS: Healthy lifestyle is minimally related to the overall risk of developing PCa but is associated with a substantially reduced risk of dying from PCa. In multivariable analyses, both exercise and not smoking remain independently associated with reduced metastatic and fatal PCa.

Genome-wide association study of the common retinal disorder epiretinal membrane: Significant risk loci in each of three American populations.

Epiretinal membrane (ERM) is a common retinal condition characterized by the presence of fibrocellular tissue on the retinal surface, often with visual distortion and loss of visual acuity. We studied European American (EUR), African American (AFR), and Latino (admixed American, AMR) ERM participants in the Million Veteran Program (MVP) for genome-wide association analysis-a total of 38,232 case individuals and 557,988 control individuals. We completed a genome-wide association study (GWAS) in each population separately, and then results were meta-analyzed. Genome-wide significant (GWS) associations were observed in all three populations studied: 31 risk loci in EUR subjects, 3 in AFR, and 2 in AMR, with 48 in trans-ancestry meta-analysis. Many results replicated in the FinnGen sample. Several GWS variants associate to alterations in gene expression in the macula. ERM showed significant genetic correlation to multiple traits. Pathway enrichment analyses implicated collagen and collagen-adjacent mechanisms, among others. This well-powered ERM GWAS identified novel genetic associations that point to biological mechanisms for ERM.

Genome-Wide Analysis to Assess if Heavy Alcohol Consumption Modifies the Association between SNPs and Pancreatic Cancer Risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10-8 in the meta-analysis; Pinteraction = 2.1 × 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer. IMPACT: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers.

Design and pilot results from the Million Veteran Program Return Of Actionable Results (MVP-ROAR) Study.

BACKGROUND: As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition. METHODS: The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months. RESULTS: The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; P = .03). The ongoing RCT will determine between-arm differences in this primary outcome. CONCLUSION: While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT04178122.

Agent orange exposure and prostate cancer risk in the million veteran program.

BACKGROUND: The US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk. PATIENTS AND METHODS: Participants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. RESULTS AND INTERPRETATION: On univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09, <10-6) but not with metastatic PCa (HR: 1.07, 95% CI: 0.98-1.15, p = 0.10) or PCa death (HR: 1.02, 95% CI: 0.83-1.23, p = 0.09). Similar results were found when accounting for genetic risk. Agent Orange exposure history may not improve modern PCa risk stratification.

The Role of X Chromosome in Alzheimer's Disease Genetics.

Importance: The X chromosome has remained enigmatic in Alzheimer's disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD. Objectives: Perform the first large-scale X chromosome-wide association study (XWAS) of AD. Primary analyses are non-stratified, while secondary analyses evaluate sex-stratified effects. Design: Meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium (ADGC) and Alzheimer's Disease Sequencing Project (ADSP), the UK Biobank (UKB), the Finnish health registry (FinnGen), and the US Million Veterans Program (MVP). Risk for AD evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Setting: Genetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Summary statistics for multi-tissue expression and protein quantitative trait loci (QTL) available from published studies, enabling follow-up genetic colocalization analyses. Participants: 1,629,863 eligible participants were selected from referred and volunteer samples, of which 477,596 were excluded for analysis exclusion criteria. Number of participants who declined to participate in original studies was not available. Main Outcome and Measures: Risk for AD (odds ratio; OR) with 95% confidence intervals (CI). Associations were considered at X-chromosome-wide (P-value<1e-5) and genome-wide (P-value<5e-8) significance. Results: Analyses included 1,152,284 non-Hispanic White European ancestry subjects (57.3% females), including 138,558 cases. 6 independent genetic loci passed X-chromosome-wide significance, with 4 showing support for causal links between the genetic signal for AD and expression of nearby genes in brain and non-brain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR=1.054, 95%-CI=[1.035, 1.075]) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Conclusion and Relevance: We performed the first large-scale XWAS of AD and identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid beta accumulation. Overall, this study significantly advances our knowledge of AD genetics and may provide novel biological drug targets.