J Michael Gaziano

• Brigham and Women's Hospital

Physical activity (PA) is one of the most fundamental of all traits in the animal kingdom, has pervasive health benefits, and is genetically influenced. Using data from the Million Veteran Program (MVP), we conducted genetic analyses of leisure, work, and home-time PA. For leisure, for individuals of European (EUR) ancestry, n=189,812 and SNP-based...

Antidepressants are among the most-prescribed drugs worldwide, and selective serotonin reuptake inhibitors (SSRIs) are among the most prescribed antidepressants, most commonly used for major depression. We sought to increase our understanding of the biological relationships between SSRI use and a range of psychiatric traits by conducting Genome Wid...

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to m...

Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the t...

Large biobanks, including the Million Veteran Program (MVP), the UK Biobank, and FinnGen, provide genetic association results for more than 1,000,000 individuals for hundreds of phenotypes. To select targets for pharmaceutical development, as well as to improve the understanding of existing targets, we harmonized these studies, and performed two-sa...

The adoption of EHRs has expanded opportunities to leverage data-driven algorithms in clinical care and research. A major bottleneck in effectively conducting multi-institutional EHR studies is the data heterogeneity across systems with numerous codes that either do not exist or represent different clinical concepts across institutions. The need fo...

237 Background: Polygenic scores are strongly associated with age at diagnosis of prostate cancer (PCa) but have not been clearly shown to discriminate between indolent and aggressive PCa. P-CARE (Prostate CAncer integrated Risk Evaluation) is an integrated model that combines a 601-variant polygenic hazard score (PHS601), genetic ancestry, and fam...

Background Coronary artery disease is a leading cause of morbidity and mortality in the United States. Coronary artery disease can lead to major complications including myocardial infarction (MI). The association of dietary cholesterol with coronary artery disease remains inconsistent. We examined the relation of dietary cholesterol with the incide...

To address the concern that polygenic hazard scores for prostate cancer (PCa) might not distinguish between indolent and aggressive disease, we performed case-only analyses using a 601-variant polygenic score (PHS601). We hypothesized that among men who eventually developed PCa, those with higher PHS were more likely to develop aggressive disease....

Background The X‐chromosome remains largely unexplored in Alzheimer’s disease (AD). To address this gap, we performed the first large‐scale X chromosome‐wide association study (XWAS) of AD. Method The study overview is shown in Figure 1A. We performed a meta‐analysis of XWAS in case‐control, family‐based, population‐based, and longitudinal AD‐rela...

To broaden our understanding of bradyarrhythmias and conduction disease, we performed common variant genome-wide association analyses in up to 1.3 million individuals and rare variant burden testing in 460,000 individuals for sinus node dysfunction (SND), distal conduction disease (DCD) and pacemaker (PM) implantation. We identified 13, 31 and 21 c...

Rationale: Older adults make up the majority of patients with advanced non-small cell lung cancer (NSCLC) and often carry multiple other comorbidities (multimorbidity) when initiating treatment. The nature and impact of multimorbidity remain largely unknown, given the limitations of standard count-based comorbidity indices in aging patients and th...

Objective Event capture in clinical trials is resource-intensive, and electronic medical records (EMRs) offer a potential solution. This study develops algorithms for EMR-based death and hospitalization capture and compares them with traditional event capture methods. Materials and Methods We compared the effectiveness of EMR-based event capture a...

To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts...

Importance The American Heart Association proposed Life’s Essential 8 (LE8) as an enhanced measurement tool for cardiovascular health. Objective To examine the association of LE8 with risk of atherosclerotic cardiovascular disease (ASCVD) incidence and prognosis in veterans. Design, Setting, and Participants This was a prospective cohort study of...

Background Cancer-associated thrombosis (CAT) is a leading cause of death in patients diagnosed with cancer. However, pharmacologic thromboprophylaxis use in cancer patients must be carefully evaluated due to a 2-fold increased risk of experiencing a major bleeding event within this population. The electronic health record CAT (EHR-CAT) risk assess...

Background: US Veterans have a high burden of cardiovascular disease (CVD). While cholesterol management is one of the most effective approaches for reducing CVD burden, over two-thirds of Veterans with atherosclerotic cardiovascular disease (ASCVD) are not optimally managed. Aims: To evaluate LDL-C monitoring, lipid lowering therapy (LLT) use, and...

Background: Heart failure (HF) is a life-threatening aging-related syndrome with growing impact on the global population. It is estimated that >8 million adults in the US will be living with HF by 2030. HF with preserved EF (HFpEF), defined by an ejection fraction ≥50%, frequently has delayed diagnosis and limited treatment options. HFpEF progressi...

Background: Patients are increasingly obtaining genetic health information and integrating it into their care with the help of their primary care provider (PCP). However, PCPs may not be adequately prepared to effectively utilize genetic results . Across the VA health system, the Million Veteran Program- Return of Actionable Results- Familial Hyper...

Importance Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have nephroprotective properties beyond those related to weight loss and glycemic control. Objective To investigate the association of genetically proxied GLP-1RAs with kidney disease progression. Design, Setting, and Participants This genetic association study assembled a nation...

Background Veterans of the 1990–1991 Gulf War have experienced excess health problems, most prominently the multisymptom condition Gulf War illness (GWI). The Department of Veterans Affairs (VA) Cooperative Studies Program #2006 “Genomics of Gulf War Illness in Veterans” project was established to address important questions concerning pathobiologi...

Purpose Physical activity (PA) can improve cancer survival; however, whether the timing of PA differentially affects mortality risk is unclear. We evaluated the association between PA levels pre- and post-diagnosis and mortality risk in the Women’s Health Study (WHS), Physicians’ Health Study (PHS)-I, and PHS-II prospective cohorts. Methods We cat...

Background. Mendelian randomization (MR) studies have been described as naturally occurring randomized controlled trials (RCTs). However, MR often deviates from appropriate RCT design principles and relies heavily on two-sample approaches. We used data from the Million Veteran Program (MVP) to empirically evaluate the impact of study design choices...

Objective We aimed to characterise self-reported military and occupational exposures including Agent Orange, chemical/biological warfare agents, solvents, fuels, pesticides, metals and burn pits among Veterans in the Department of Veterans Affairs Million Veteran Program (MVP). Methods MVP is an ongoing longitudinal cohort and mega-biobank of over...

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 (...

We performed large-scale genome-wide gene-sleep interaction analyses of lipid levels to identify novel genetic variants underpinning the biomolecular pathways of sleep-associated lipid disturbances and to suggest possible druggable targets. We collected data from 55 cohorts with a combined sample size of 732,564 participants (87% European ancestry)...

Background Dietary quality plays an important role in disease development and prognosis, and diet is also a key contributor to disparities in many chronic diseases and health conditions. Objectives This study aimed to assess racial and ethnic disparities experienced by veterans; we examined food intake and dietary quality across different racial a...

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 d...

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressu...

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 a...

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...

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 the risk of hyperten...

Objectives: This study aims to assess the impact of domain shift on chest X-ray classification accuracy and to analyze the influence of ground truth label quality and demographic factors such as age group, sex, and study year. Materials and Methods: We used a DenseNet121 model pretrained MIMIC-CXR dataset for deep learning-based multilabel classifi...

BACKGROUND Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke. METHODS We performed genome...

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the...

BACKGROUND Observational studies have estimated 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 studying the effect of bariatric surgery on cardiovascular disease witho...

Biobanks advance biomedical and clinical research by collecting and offering data and biological samples for numerous studies. However, the impact of these repositories varies greatly due to differences in their purpose, scope, governance, and data collected. Here, we computationally identified 2,663 biobanks and their textual mentions in 228,761 s...

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 elec...

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 comp...

Despite widespread use of drugs targeting traditional cardiovascular risk factors such as lipids and blood pressure, a high burden of coronary heart disease (CHD) remains, hence novel therapeutics are needed for people who harbor residual risk. Using transcriptomic and proteomic data to instrument 15,527 genes or proteins, we conducted systematic c...

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 inter...

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 histo...

1620 Background: We previously operationalized the NCCN list of high-risk medications in older adults into a measurable scale—Geriatric Oncology Potentially Inappropriate Medications (GO-PIMs)—to aid oncology teams in identifying PIMs and understand their impact (1). This scale revealed that PIMs were prevalent and associated with frailty in older...

1541 Background: Germline pathogenic alterations are found in approximately 10% of men with metastatic prostate cancer (mPC) and can inform precision therapy, surveillance, and cancer prevention for family. National guidelines recommend germline genetic testing be offered to all men with mPC, yet uptake of testing in the community has been document...

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-...

Simple Summary Improvements in lung cancer risk assessment to inform on the need for screening may be achieved through the use of biomarkers. Here, we report the findings of a validation study of a panel of four circulating protein biomarkers for the risk prediction of lung cancer in a cohort of pre-diagnostic plasmas obtained from the Physician’s...

BACKGROUND Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular...

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...

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...

Objective To examine the causal relationship between alcohol use and dementia risk across multiple ancestry groups. Design We triangulated evidence from observational and univariable and multivariable Mendelian randomization. Setting and participants Cross-ancestry observational analyses were conducted in two large prospective studies: the US Milli...

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 (...

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 3...

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist t...

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...

Introduction Beta-carotene (BC) protects the body against free radicals that may damage the kidney and lead to the development of acute kidney injury and chronic kidney disease (CKD). Previous studies in animal models have demonstrated a potential protective effect of 30 mg/kg BC supplementation on renal ischemia or reperfusion injury and subsequen...

We used expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) to conduct genome-wide Mendelian randomization (MR) using 27,799 cases of heart failure (HF) with reduced ejection fraction (HFrEF), 27,579 cases of HF with preserved ejection fraction (HFpEF), and 367,267 control individuals from the Million Veteran Prog...

Introduction: Lifetime risk of prostate cancer (PCa) is strongly associated with three factors: ancestry, family history, and genetics. We previously developed a polygenic hazard score (PHS) for PCa comprised of 290 common genetic variants (PHS290). When accounting for family history and ancestry (self-reported or genetically determined), PHS290 re...

Background: Heart failure (HF) is a life-threatening syndrome with growing impact on the global population. It is estimated that >8 million people in the US will be living with HF by 2030. Aging is a major risk factor for HF. Age-at-onset (AAO) is one of the critical traits in cohort studies of age-related diseases. Large-scale genome-wide associat...

Background: Limited and inconsistent observational data are available on the association of potato consumption with risk of hypertension. Objective: To test the hypothesis that consumption of total; combined baked, boiled, and mashed; and fried potatoes is associated with incidence of hypertension and that dietary pattern (assessed using the plant-...

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self...

Objective Development of clinical phenotypes from electronic health records (EHRs) can be resource intensive. Several phenotype libraries have been created to facilitate reuse of definitions. However, these platforms vary in target audience and utility. We describe the development of the Centralized Interactive Phenomics Resource (CIPHER) knowledge...

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 control...

Objective The development of clinical research informatics tools and workflow processes associated with re-engaging biobank participants has become necessary as genomic repositories increasingly consider the return of actionable research results. Materials and Methods Here we describe the development and utility of an informatics application for p...

Importance Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is a commonly used estimate of obesity, which is a complex trait affected by genetic and lifestyle factors. Marked weight gain and loss could be associated with adverse biological processes. Objective To evaluate the association between BMI vari...

60 Background: Germline pathogenic alterations are found in approximately 10% of men with metastatic prostate cancer (mPC) and can inform precision therapy, surveillance, and cancer prevention for family. National guidelines recommend germline genetic testing be offered to all men with mPC, yet uptake of testing in the community has been documented...

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke. Methods: We performed genom...

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 f...

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990–1991 Persian Gulf War (GW). Eligible Veterans were invited via mail to complete a survey assessing health conditions as well as GW-sp...

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (...

Introduction Frailty, a syndrome of physiologic vulnerability, increases cardiovascular disease (CVD) risk. Which frailty tool is ideal for risk stratification remains unclear. We calculated three frailty scores from the Million Veteran Program (MVP) and examined their association with mortality and CVD in older Veterans. Methods Participants were...

Background Observational studies are used for estimating vaccine effectiveness under real-world conditions. The practical performance of two common approaches – cohort and test-negative designs – need to be compared for Covid-19 vaccines. Methods We compared the cohort and test-negative designs to estimate the effectiveness of the BNT162b2 vaccine...

Background There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk. Methods The study included 185,323 Million Ve...

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; Ea...

Background Statins are part of long‐term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown. Methods This was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002‐2012, followed through 2...

Importance There are limited data for the utility of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and death in adults with chronic kidney disease (CKD). Objective To evaluate the association of statin use with all-cause mortality and major adverse cardiovascular events (MACE) among US veterans older than 65 year...

Electronic health record (EHR) data are increasingly used to support real-world evidence studies but are limited by the lack of precise timings of clinical events. Here, we propose a label-efficient incident phenotyping (LATTE) algorithm to accurately annotate the timing of clinical events from longitudinal EHR data. By leveraging the pre-trained s...

Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27–46% of the risk of age-related chronic imbalance...

Aims We sought to identify factors associated with right ventricular (RV) dysfunction and elevated pulmonary artery systolic pressure (PASP) and association with adverse outcomes in peripartum cardiomyopathy (PPCM). Methods and results We conducted a multi‐centre cohort study to identify subjects with PPCM with the following criteria: left ventric...

As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by m...