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1. Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program.

Author: Allison E Ashley-Koch, Nathan A Kimbrel, Xue J Qin, Jennifer H Lindquist, Melanie E Garrett, Michelle F Dennis, Lauren P Hair, Jennifer E Huffman, Daniel A Jacobson, Ravi K Madduri, Hilary Coon, Anna R Docherty, Jooeun Kang, Niamh Mullins, Douglas M Ruderfer, VA Million Veteran Program (MVP), MVP Suicide Exemplar Workgroup, International Suicide Genetics Consortium, Philip D Harvey, Benjamin H McMahon, David W Oslin, Elizabeth R Hauser, Michael A Hauser, and Jean C Beckham
Subjects: Genetics, QH426-470
Abstract: Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q's
Published: 2023
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2. A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.

Author: Sridharan Raghavan, Jie Huang, Catherine Tcheandjieu, Jennifer E Huffman, Elizabeth Litkowski, Chang Liu, Yuk-Lam A Ho, Haley Hunter-Zinck, Hongyu Zhao, Eirini Marouli, Kari E North, VA Million Veteran Program, Ethan Lange, Leslie A Lange, Benjamin F Voight, J Michael Gaziano, Saiju Pyarajan, Elizabeth R Hauser, Philip S Tsao, Peter W F Wilson, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, Yan V Sun, and Themistocles L Assimes
Subjects: Genetics, QH426-470
Abstract: BackgroundHeight has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Methods and findingsAnalyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.ConclusionsWe conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
Published: 2022
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3. Short-term effects of fine particulate matter and ozone on the cardiac conduction system in patients undergoing cardiac catheterization

Author: Siqi Zhang, Susanne Breitner, Wayne E Cascio, Robert B Devlin, Lucas M Neas, David Diaz-Sanchez, William E Kraus, Joel Schwartz, Elizabeth R Hauser, Annette Peters, and Alexandra Schneider
Subjects: Air pollution, Electrocardiogram, PR interval, QT interval, QRS interval, Toxicology. Poisons, RA1190-1270, Industrial hygiene. Industrial welfare, HD7260-7780.8
Abstract: Abstract Background Air pollution-induced changes in cardiac electrophysiological properties could be a pathway linking air pollution and cardiovascular events. The evidence of air pollution effects on the cardiac conduction system is incomplete yet. We investigated short-term effects of particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) and ozone (O3) on cardiac electrical impulse propagation and repolarization as recorded in surface electrocardiograms (ECG). Methods We analyzed repeated 12-lead ECG measurements performed on 5,332 patients between 2001 and 2012. The participants came from the Duke CATHGEN Study who underwent cardiac catheterization and resided in North Carolina, United States (NC, U.S.). Daily concentrations of PM2.5 and O3 at each participant’s home address were predicted with a hybrid air quality exposure model. We used generalized additive mixed models to investigate the associations of PM2.5 and O3 with the PR interval, QRS interval, heart rate-corrected QT interval (QTc), and heart rate (HR). The temporal lag structures of the associations were examined using distributed-lag models. Results Elevated PM2.5 and O3 were associated with four-day lagged lengthening of the PR and QRS intervals, and with one-day lagged increases in HR. We observed immediate effects on the lengthening of the QTc interval for both PM2.5 and O3, as well as delayed effects for PM2.5 (lagged by 3 – 4 days). The associations of PM2.5 and O3 with the PR interval and the association of O3 with the QRS interval persisted until up to seven days after exposure. Conclusions In patients undergoing cardiac catheterization, short-term exposure to air pollution was associated with increased HR and delays in atrioventricular conduction, ventricular depolarization and repolarization.
Published: 2018
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4. APOL1 risk alleles among individuals with CKD in Northern Tanzania: A pilot study.

Author: John W Stanifer, Francis Karia, Venance Maro, Kajiru Kilonzo, Xuejun Qin, Uptal D Patel, and Elizabeth R Hauser
Subjects: Medicine, Science
Abstract: INTRODUCTION:In sub-Saharan Africa, approximately 100 million people have CKD, yet genetic risk factors are not well-understood. Despite the potential importance of understanding APOL1 risk allele status among individuals with CKD, little genetic research has been conducted. Therefore, we conducted a pilot study evaluating the feasibility of and willingness to participate in genetic research on kidney disease, and we estimated APOL1 risk allele frequencies among individuals with CKD. METHODS:In 2014, we conducted a community-based field study evaluating CKD epidemiology in northern Tanzania. We assessed for CKD using urine albumin and serum creatinine to estimate GFR. We invited participants with CKD to enroll in an additional genetic study. We obtained dried-blood spots on filter cards, from which we extracted DNA using sterile punch biopsies. We genotyped for two single nucleotide polymorphisms (SNPs) defining the APOL1 G1 risk allele and an insertion/deletion polymorphism defining the G2 risk allele. Genotyping was performed in duplicate. RESULTS:We enrolled 481 participant, 57 (12%) of whom had CKD. Among these, enrollment for genotyping was high (n = 48; 84%). We extracted a median of 19.4 ng of DNA from each dried-blood spot sample, and we genotyped the two APOL1 G1 SNPs and the APOL1 G2 polymorphism. Genotyping quality was high, with all duplicated samples showing perfect concordance. The frequency of APOL1 risk variants ranged from 7.0% to 11.0%, which was similar to previously-reported frequencies from the general population of northern Tanzania (p>0.2). DISCUSSION:In individuals with CKD from northern Tanzania, we demonstrated feasibility of genotyping APOL1 risk alleles. We successfully genotyped three risk variants from DNA extracted from filter cards, and we demonstrated a high enrollment for participation. In this population, more extensive genetic studies of kidney disease may be well-received and will be feasible.
Published: 2017
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5. A genome-wide trans-ethnic interaction study links the PIGR-FCAMR locus to coronary atherosclerosis via interactions between genetic variants and residential exposure to traffic.

Author: Cavin K Ward-Caviness, Lucas M Neas, Colette Blach, Carol S Haynes, Karen LaRocque-Abramson, Elizabeth Grass, Z Elaine Dowdy, Robert B Devlin, David Diaz-Sanchez, Wayne E Cascio, Marie Lynn Miranda, Simon G Gregory, Svati H Shah, William E Kraus, and Elizabeth R Hauser
Subjects: Medicine, Science
Abstract: Air pollution is a worldwide contributor to cardiovascular disease mortality and morbidity. Traffic-related air pollution is a widespread environmental exposure and is associated with multiple cardiovascular outcomes such as coronary atherosclerosis, peripheral arterial disease, and myocardial infarction. Despite the recognition of the importance of both genetic and environmental exposures to the pathogenesis of cardiovascular disease, studies of how these two contributors operate jointly are rare. We performed a genome-wide interaction study (GWIS) to examine gene-traffic exposure interactions associated with coronary atherosclerosis. Using race-stratified cohorts of 538 African-Americans (AA) and 1562 European-Americans (EA) from a cardiac catheterization cohort (CATHGEN), we identify gene-by-traffic exposure interactions associated with the number of significantly diseased coronary vessels as a measure of chronic atherosclerosis. We found five suggestive (P
Published: 2017
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6. Genetic Variants in the Bone Morphogenic Protein Gene Family Modify the Association between Residential Exposure to Traffic and Peripheral Arterial Disease.

Author: Cavin K Ward-Caviness, Lucas M Neas, Colette Blach, Carol S Haynes, Karen LaRocque-Abramson, Elizabeth Grass, Elaine Dowdy, Robert B Devlin, David Diaz-Sanchez, Wayne E Cascio, Marie Lynn Miranda, Simon G Gregory, Svati H Shah, William E Kraus, and Elizabeth R Hauser
Subjects: Medicine, Science
Abstract: There is a growing literature indicating that genetic variants modify many of the associations between environmental exposures and clinical outcomes, potentially by increasing susceptibility to these exposures. However, genome-scale investigations of these interactions have been rarely performed particularly in the case of air pollution exposures. We performed race-stratified genome-wide gene-environment interaction association studies on European-American (EA, N = 1623) and African-American (AA, N = 554) cohorts to investigate the joint influence of common single nucleotide polymorphisms (SNPs) and residential exposure to traffic ("traffic exposure")-a recognized vascular disease risk factor-on peripheral arterial disease (PAD). Traffic exposure was estimated via the distance from the primary residence to the nearest major roadway, defined as the nearest limited access highways or major arterial. The rs755249-traffic exposure interaction was associated with PAD at a genome-wide significant level (P = 2.29x10-8) in European-Americans. Rs755249 is located in the 3' untranslated region of BMP8A, a member of the bone morphogenic protein (BMP) gene family. Further investigation revealed several variants in BMP genes associated with PAD via an interaction with traffic exposure in both the EA and AA cohorts; this included interactions with non-synonymous variants in BMP2, which is regulated by air pollution exposure. The BMP family of genes is linked to vascular growth and calcification and is a novel gene family for the study of PAD pathophysiology. Further investigation of BMP8A using the Genotype Tissue Expression Database revealed multiple variants with nominally significant (P < 0.05) interaction P-values in our EA cohort were significant BMP8A eQTLs in tissue types highlight relevant for PAD such as rs755249 (tibial nerve, eQTL P = 3.6x10-6) and rs1180341 (tibial artery, eQTL P = 5.3x10-6). Together these results reveal a novel gene, and possibly gene family, associated with PAD via an interaction with traffic air pollution exposure. These results also highlight the potential for interactions studies, particularly at the genome scale, to reveal novel biology linking environmental exposures to clinical outcomes.
Published: 2016
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7. Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship.

Author: Jennifer R Dungan, Xuejun Qin, Benjamin D Horne, John F Carlquist, Abanish Singh, Melissa Hurdle, Elizabeth Grass, Carol Haynes, Simon G Gregory, Svati H Shah, Elizabeth R Hauser, and William E Kraus
Subjects: Medicine, Science
Abstract: Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two LSAMP SNPs-rs1462845 and rs6788787-using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; n = 2,224) and the Intermountain Heart Collaborative Study (IMHC; n = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (HR = 1.11, 95%CI = 1.01-1.22, p = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (HR = 0.80, 95% CI = 0.69-0.92, p = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (HR = 1.29, 95% CI = 1.08-1.55, p = 0.00456; replication HR = 1.25, 95% CI = 1.05-1.49, p = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype ('A/A') fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.
Published: 2016
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8. High heritability of metabolomic profiles in families burdened with premature cardiovascular disease

Author: Svati H Shah, Elizabeth R Hauser, James R Bain, Michael J Muehlbauer, Carol Haynes, Robert D Stevens, Brett R Wenner, Z Elaine Dowdy, Christopher B Granger, Geoffrey S Ginsburg, Christopher B Newgard, and William E Kraus
Subjects: acylcarnitines, amino acids, heritability, cardiovascular disease, metabolomics, Biology (General), QH301-705.5, Medicine (General), R5-920
Abstract: Abstract Integration of genetic and metabolic profiling holds promise for providing insight into human disease. Coronary artery disease (CAD) is strongly heritable, but the heritability of metabolomic profiles has not been evaluated in humans. We performed quantitative mass spectrometry‐based metabolic profiling in 117 individuals within eight multiplex families from the GENECARD study of premature CAD. Heritabilities were calculated using variance components. We found high heritabilities for amino acids (arginine, ornithine, alanine, proline, leucine/isoleucine, valine, glutamate/glutamine, phenylalanine and glycine; h2=0.33–0.80, P=0.005–1.9 × 10−16), free fatty acids (arachidonic, palmitic, linoleic; h2=0.48–0.59, P=0.002–0.00005) and acylcarnitines (h2=0.23–0.79, P=0.05–0.0000002). Principal components analysis was used to identify metabolite clusters. Reflecting individual metabolites, several components were heritable, including components comprised of ketones, β‐hydroxybutyrate and C2‐acylcarnitine (h2=0.61); short‐ and medium‐chain acylcarnitines (h2=0.39); amino acids (h2=0.44); long‐chain acylcarnitines (h2=0.39) and branched‐chain amino acids (h2=0.27). We report a novel finding of high heritabilities of metabolites in premature CAD, establishing a possible genetic basis for these profiles. These results have implications for understanding CAD pathophysiology and genetics.
Published: 2009
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9. Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

Author: William E Kraus, Deborah M Muoio, Robert Stevens, Damian Craig, James R Bain, Elizabeth Grass, Carol Haynes, Lydia Kwee, Xuejun Qin, Dorothy H Slentz, Deidre Krupp, Michael Muehlbauer, Elizabeth R Hauser, Simon G Gregory, Christopher B Newgard, and Svati H Shah
Subjects: Genetics, QH426-470
Abstract: Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.
Published: 2015
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10. A functional polymorphism in the 5HTR2C gene associated with stress responses also predicts incident cardiovascular events.

Author: Beverly H Brummett, Michael A Babyak, Rong Jiang, Svati H Shah, Richard C Becker, Carol Haynes, Megan Chryst-Ladd, Damian M Craig, Elizabeth R Hauser, Ilene C Siegler, Cynthia M Kuhn, Abanish Singh, and Redford B Williams
Subjects: Medicine, Science
Abstract: Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. Study population consisted of 6,126 Caucasian participants (4,036 [65.9%] males and 2,090 [34.1%] females). A total of 1,769 events occurred (1,544 deaths and 225 MIs; median follow-up time = 5.3 years, interquartile range = 3.3-8.2). Unadjusted Cox time-to-event regression models showed, compared to Cys23 G carriers, males hemizygous for Ser23 C and females homozygous for Ser23C were at increased risk for the composite endpoint of all-cause death or MI: Hazard Ratio (HR) = 1.47, 95% confidence interval (CI) = 1.17, 1.84, p = .0008. Adjusting for age, rs6318 genotype was not related to body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection fraction in either males or females. After adjustment for these covariates the estimate for the two Ser23 C groups was modestly attenuated, but remained statistically significant: HR = 1.38, 95% CI = 1.10, 1.73, p = .005. These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease.
Published: 2013
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11. Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.

Author: Svati H Shah, Neil J Freedman, Lisheng Zhang, David R Crosslin, David H Stone, Carol Haynes, Jessica Johnson, Sarah Nelson, Liyong Wang, Jessica J Connelly, Michael Muehlbauer, Geoffrey S Ginsburg, David C Crossman, Christopher J H Jones, Jeffery Vance, Michael H Sketch, Christopher B Granger, Christopher B Newgard, Simon G Gregory, Pascal J Goldschmidt-Clermont, William E Kraus, and Elizabeth R Hauser
Subjects: Genetics, QH426-470
Abstract: Neuropeptide Y (NPY) is a strong candidate gene for coronary artery disease (CAD). We have previously identified genetic linkage to familial CAD in the genomic region of NPY. We performed follow-up genetic, biostatistical, and functional analysis of NPY in early-onset CAD. In familial CAD (GENECARD, N = 420 families), we found increased microsatellite linkage to chromosome 7p14 (OSA LOD = 4.2, p = 0.004) in 97 earliest age-of-onset families. Tagged NPY SNPs demonstrated linkage to CAD of a 6-SNP block (LOD = 1.58-2.72), family-based association of this block with CAD (p = 0.02), and stronger linkage to CAD in the earliest age-of-onset families. Association of this 6-SNP block with CAD was validated in: (a) 556 non-familial early-onset CAD cases and 256 controls (OR 1.46-1.65, p = 0.01-0.05), showing stronger association in youngest cases (OR 1.84-2.20, p = 0.0004-0.09); and (b) GENECARD probands versus non-familial controls (OR 1.79-2.06, p = 0.003-0.02). A promoter SNP (rs16147) within this 6-SNP block was associated with higher plasma NPY levels (p = 0.04). To assess a causal role of NPY in atherosclerosis, we applied the NPY1-receptor-antagonist BIBP-3226 adventitially to endothelium-denuded carotid arteries of apolipoprotein E-deficient mice; treatment reduced atherosclerotic neointimal area by 50% (p = 0.03). Thus, NPY variants associate with atherosclerosis in two independent datasets (with strong age-of-onset effects) and show allele-specific expression with NPY levels, while NPY receptor antagonism reduces atherosclerosis in mice. We conclude that NPY contributes to atherosclerosis pathogenesis.
Published: 2009
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12. GATA2 is associated with familial early-onset coronary artery disease.

Author: Jessica J Connelly, Tianyuan Wang, Julie E Cox, Carol Haynes, Liyong Wang, Svati H Shah, David R Crosslin, A Brent Hale, Sarah Nelson, David C Crossman, Christopher B Granger, Jonathan L Haines, Christopher J H Jones, Jeffery M Vance, Pascal J Goldschmidt-Clermont, William E Kraus, Elizabeth R Hauser, and Simon G Gregory
Subjects: Genetics, QH426-470
Abstract: The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance.
Published: 2006
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13. Associations between neighborhood socioeconomic cluster and hypertension, diabetes, myocardial infarction, and coronary artery disease within a cohort of cardiac catheterization patients

Author: David Diaz-Sanchez, Anne M. Weaver, William E. Kraus, Elizabeth R. Hauser, Lucas M. Neas, Radhika Dhingra, Robert B. Devlin, Cavin K. Ward-Caviness, Laura McGuinn, and Wayne E. Cascio
Subjects: medicine.medical_specialty, Cardiac Catheterization, business.industry, Public health, Myocardial Infarction, Coronary Artery Disease, medicine.disease, Health equity, Article, Coronary artery disease, Social Class, Socioeconomic Factors, Residence Characteristics, Cohort, Epidemiology, Hypertension, medicine, Diabetes Mellitus, Humans, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, Socioeconomic status, Body mass index, Demography
Abstract: Background Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. Methods We used Ward’s Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. Results Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. Conclusions We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.
Published: 2021

14. The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes

Author: Rong Jiang, Elizabeth R. Hauser, Lydia Coulter Kwee, Svati H. Shah, Jessica A. Regan, Janet L. Huebner, Virginia B. Kraus, William E. Kraus, and Cavin K. Ward-Caviness
Subjects: Cardiac Catheterization, Cardiovascular Diseases, Genetics, Humans, Stroke Volume, DNA Methylation, Molecular Biology, Genetics (clinical), Ventricular Function, Left, Developmental Biology, Epigenesis, Genetic
Abstract: Background Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures. Methods We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach. Results PhenoAA (HR = 1.05, P P P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065). Conclusions Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks.
Published: 2022

15. Declining autozygosity over time: an exploration in over 1 million individuals from three diverse cohorts

Author: Sarah M.C. Colbert, Frank R. Wendt, Gita A. Pathak, Drew A. Helmer, Elizabeth R. Hauser, Matthew C. Keller, Renato Polimanti, and Emma C. Johnson
Subjects: Genetics, Genetics (clinical)
Abstract: We hypothesized that overall autozygosity is decreasing over generational time. In this report, we present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us and the Million Veteran Program, N=82,474 and 622,497, respectively) and one from the UK (UK Biobank, N=380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope=-0.029, se=0.009, p=6.03e-4). Using a chi-square difference test, we determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope=-0.058, se=0.015, p=1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope=-0.001, se=0.008, p=0.945). We also found that the association between autozygosity and year of birth in the overall meta-analysis was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope=-0.011, se=0.008, p=0.167), suggesting that increases in education and income may partially account for decreasing levels of autozygosity over time. To our knowledge, this is the largest demonstration of decreasing autozygosity over time in a modern sample (birth years 1904-2003), and we speculate that this trend can be attributed to increases in population size, urbanization and panmixia, with differences in demographic and sociocultural processes leading to country-specific differences in the rate of decline.
Published: 2022

16. Ten or More Cumulative Lifetime Adenomas Are Associated with Increased Risk for Advanced Neoplasia and Colorectal Cancer

Author: Laura W. Musselwhite, Brian Sullivan, Xuejun Qin, Dawn Provenzale, Ziad F. Gellad, Elizabeth R. Hauser, Thomas S. Redding, David G. Weiss, Christina D. Williams, David A. Lieberman, Ashton Madison, and Meghan C. O'Leary
Subjects: Villous adenoma, medicine.medical_specialty, education.field_of_study, Adenoma, Physiology, business.industry, Colorectal cancer, Population, Gastroenterology, Hepatology, medicine.disease, Logistic regression, Malignancy, digestive system diseases, Dysplasia, Internal medicine, medicine, education, business
Abstract: Colorectal cancer (CRC) screening guidelines recommend frequent colonoscopies and consideration of genetic testing in individuals with ≥10 cumulative adenomas. However, it is unclear how these guidelines apply to routine practice. We estimated the proportion of participants found to have ≥10 cumulative adenomas in a screening population and described their outcomes of advanced neoplasia (AN), CRC, and extra-colonic malignancy. We performed a secondary analysis of VA CSP#380, which includes 3121 veterans aged 50–75 who were followed up to 10 years after screening colonoscopy. We calculated the cumulative risk of ≥10 cumulative adenomas by Kaplan–Meier method. We compared baseline risk factors in those with and without ≥10 cumulative adenomas as well as the risk for AN (adenoma ≥1 cm, villous adenoma or high-grade dysplasia, or CRC) and extra-colonic malignancy by multivariate logistic regression. The cumulative risk of ≥10 cumulative adenomas over 10.5 years was 6.51% (95% CI 4.38%–9.62%). Age 60–69 or 70–75 at baseline colonoscopy was the only factors associated with the finding of ≥10 cumulative adenomas. Compared to those with 0–9 cumulative adenomas, participants with ≥10 cumulative adenomas were more likely to have had AN (OR 17.03; 95% CI 9.41–30.84), including CRC (OR 7.00; 95% CI 2.84–17.28), but not extra-colonic malignancies. Approximately 6.5% of participants in this screening population were found to have ≥10 cumulative adenomas over 10.5 years, which was uncommon before age 60. These participants were found to have AN and CRC significantly more often compared to those with lower cumulative adenomas.
Published: 2021

17. Establishment of multi-stage intravenous self-administration paradigms in mice

Author: Lauren M, Slosky, Andrea, Pires, Yushi, Bai, Nicholas B, Clark, Elizabeth R, Hauser, Joshua D, Gross, Fiona, Porkka, Yang, Zhou, Xiaoxiao, Chen, Vladimir M, Pogorelov, Krisztian, Toth, William C, Wetsel, Lawrence S, Barak, and Marc G, Caron
Subjects: Mice, Inbred C57BL, Mice, Drug-Seeking Behavior, Models, Animal, Animals, Administration, Intravenous, Self Administration
Abstract: Genetically tractable animal models provide needed strategies to resolve the biological basis of drug addiction. Intravenous self-administration (IVSA) is the gold standard for modeling psychostimulant and opioid addiction in animals, but technical limitations have precluded the widespread use of IVSA in mice. Here, we describe IVSA paradigms for mice that capture the multi-stage nature of the disorder and permit predictive modeling. In these paradigms, C57BL/6J mice with long-standing indwelling jugular catheters engaged in cocaine- or remifentanil-associated lever responding that was fixed ratio-dependent, dose-dependent, extinguished by withholding the drug, and reinstated by the presentation of drug-paired cues. The application of multivariate analysis suggested that drug taking in both paradigms was a function of two latent variables we termed incentive motivation and discriminative control. Machine learning revealed that vulnerability to drug seeking and relapse were predicted by a mouse's a priori response to novelty, sensitivity to drug-induced locomotion, and drug-taking behavior. The application of these behavioral and statistical-analysis approaches to genetically-engineered mice will facilitate the identification of neural circuits driving addiction susceptibility and relapse and focused therapeutic development.
Published: 2022

18. Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder

Author: Stephen K. Siecinski, Stephanie N. Giamberardino, Marina Spanos, Annalise C. Hauser, Jason R. Gibson, Tara Chandrasekhar, Maria del Pilar Trelles, Carol M. Rockhill, Michelle L. Palumbo, Allyson Witters Cundiff, Alicia Montgomery, Paige Siper, Mendy Minjarez, Lisa A. Nowinski, Sarah Marler, Lydia C. Kwee, Lauren C. Shuffrey, Cheryl Alderman, Jordana Weissman, Brooke Zappone, Jennifer E. Mullett, Hope Crosson, Natalie Hong, Sheng Luo, Lilin She, Manjushri Bhapkar, Russell Dean, Abby Scheer, Jacqueline L. Johnson, Bryan H. King, Christopher J. McDougle, Kevin B. Sanders, Soo‐Jeong Kim, Alexander Kolevzon, Jeremy Veenstra‐VanderWeele, Elizabeth R. Hauser, Linmarie Sikich, and Simon G. Gregory
Subjects: General Neuroscience, Neurology (clinical), Genetics (clinical)
Abstract: Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.
Published: 2022

19. Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation

Author: Francis J. Miller, Igor Nepliouev, Elizabeth R. Hauser, Tai-Qin Huang, Neil J. Freedman, Lisheng Zhang, Leigh Brian, Kamie P. Snow, Brandon M. Schickling, Jonathan A. Stiber, and Jiao-Hui Wu
Subjects: Vascular smooth muscle, Physiology, Myocytes, Smooth Muscle, Cell, Muscle, Smooth, Vascular, Mice, Physiology (medical), medicine, Animals, Cells, Cultured, Foam cell, Mice, Knockout, NADPH oxidase, biology, CD68, Chemistry, Neuropeptides, Transdifferentiation, Original Articles, Atherosclerosis, musculoskeletal system, Cell biology, Cross-Sectional Studies, medicine.anatomical_structure, KLF4, Cell Transdifferentiation, NADPH Oxidase 1, cardiovascular system, biology.protein, Cardiology and Cardiovascular Medicine, tissues
Abstract: Aims The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation and pro-inflammatory signaling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis. Methods and results SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a Western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn-/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 wk, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs was reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. Conclusions We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells. Translational perspective Drebrin is abundantly expressed in vascular smooth muscle cells (SMCs) and is up-regulated in human atherosclerosis. A hallmark of atherosclerosis is the accumulation of foam cells that secrete pro-inflammatory cytokines and contribute to plaque instability. A large proportion of these foam cells in humans derive from SMCs. We found that SMC Drebrin limits atherosclerosis by reducing SMC transdifferentiation to macrophage-like foam cells in a manner dependent on Nox1 and KLF4. For this reason, strategies aimed at augmenting SMC Drebrin expression in atherosclerotic plaques may limit atherosclerosis progression and enhance plaque stability by bridling SMC-to-foam-cell transdifferentiation.
Published: 2021

20. Characterizing chronological accumulation of comorbidities in healthy veterans: a computational approach

Author: Elizabeth R. Hauser, Terry Hyslop, David A. Lieberman, Ashton Madison, Brian Sullivan, Christina D. Williams, Meghan C. O'Leary, Julian C. Hong, Ziad F. Gellad, Thomas S. Redding, Xuejun Qin, A. Jasmine Bullard, Dawn Provenzale, David G. Weiss, and Kellie J. Sims
Subjects: Male, Risk, 0301 basic medicine, medicine.medical_specialty, Longitudinal study, Databases, Factual, Science, Myocardial Infarction, MEDLINE, Comorbidity, Disease, Article, Comorbidities, 03 medical and health sciences, 0302 clinical medicine, International Classification of Diseases, Health care, medicine, Humans, 030212 general & internal medicine, Renal Insufficiency, Chronic, Data mining, Veterans Affairs, Aged, Veterans, Aged, 80 and over, Multidisciplinary, business.industry, Middle Aged, medicine.disease, 030104 developmental biology, Relative risk, Emergency medicine, Cohort, Medicine, Female, Neural Networks, Computer, Cardiomyopathies, business
Abstract: Understanding patient accumulation of comorbidities can facilitate healthcare strategy and personalized preventative care. We applied a directed network graph to electronic health record (EHR) data and characterized comorbidities in a cohort of healthy veterans undergoing screening colonoscopy. The Veterans Affairs Cooperative Studies Program #380 was a prospective longitudinal study of screening and surveillance colonoscopy. We identified initial instances of three-digit ICD-9 diagnoses for participants with at least 5 years of linked EHR history (October 1999 to December 2015). For diagnoses affecting at least 10% of patients, we calculated pairwise chronological relative risk (RR). iGraph was used to produce directed graphs of comorbidities with RR > 1, as well as summary statistics, key diseases, and communities. A directed graph based on 2210 patients visualized longitudinal development of comorbidities. Top hub (preceding) diseases included ischemic heart disease, inflammatory and toxic neuropathy, and diabetes. Top authority (subsequent) diagnoses were acute kidney failure and hypertensive chronic kidney failure. Four communities of correlated comorbidities were identified. Close analysis of top hub and authority diagnoses demonstrated known relationships, correlated sequelae, and novel hypotheses. Directed network graphs portray chronologic comorbidity relationships. We identified relationships between comorbid diagnoses in this aging veteran cohort. This may direct healthcare prioritization and personalized care.
Published: 2021

21. Accelerated epigenetic age as a biomarker of cardiovascular sensitivity to traffic-related air pollution

Author: Radhika Dhingra, Lucas M. Neas, Erik Slawsky, Wayne E. Cascio, Rong Jiang, Robert B. Devlin, Lydia Coulter Kwee, Elizabeth R. Hauser, Anne M. Weaver, Cavin K. Ward-Caviness, Svati H. Shah, Kenneth Olden, Armistead G. Russell, William E. Kraus, and David Diaz-Sanchez
Subjects: Genetic Markers, Male, environmental sensitivity, Aging, Traffic-Related Pollution, Arterial disease, air pollution, Air pollution, Blood Pressure, medicine.disease_cause, Risk Assessment, Epigenesis, Genetic, Peripheral Arterial Disease, cardiovascular disease, Residence Characteristics, Environmental health, medicine, North Carolina, Humans, Epigenetics, Organ system, Aged, Vehicle Emissions, traffic, business.industry, Age Factors, Urban Health, Cell Biology, Chronological age, DNA methylation age, Environmental Exposure, DNA Methylation, Middle Aged, Heart Disease Risk Factors, Cohort, Biomarker (medicine), Female, business, Research Paper, Environmental Monitoring
Abstract: Background Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. Methods Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. Results We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. Conclusion Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.
Published: 2020

22. Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness

Author: Brian J. Andonian, Alec Koss, Timothy R. Koves, Elizabeth R. Hauser, Monica J. Hubal, David M. Pober, Janet M. Lord, Nancie J. MacIver, E. William St Clair, Deborah M. Muoio, William E. Kraus, David B. Bartlett, and Kim M. Huffman
Subjects: Arthritis, Rheumatoid, Oxidative Stress, Multidisciplinary, Cardiorespiratory Fitness, Humans, Pilot Projects, Muscle, Skeletal
Abstract: Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.
Published: 2022

23. High-Risk Adenomas at Screening Colonoscopy Remain Predictive of Future High-Risk Adenomas Despite an Intervening Negative Colonoscopy

Author: Samir Gupta, Julian C. Hong, Christina D. Williams, David A. Lieberman, Ziad F. Gellad, Ashton Madison, Xuejun Qin, Meghan C. OʼLeary, Brian Sullivan, Elizabeth R. Hauser, Thomas S. Redding, Kellie J. Sims, Dawn Provenzale, Douglas J. Robertson, and David G. Weiss
Subjects: Adenoma, Male, medicine.medical_specialty, Time Factors, Colorectal cancer, Population, Colonoscopy, Logistic regression, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Humans, education, Aged, Veterans, education.field_of_study, Hepatology, medicine.diagnostic_test, business.industry, Incidence, Incidence (epidemiology), Gastroenterology, Odds ratio, Middle Aged, medicine.disease, United States, Confidence interval, United States Department of Veterans Affairs, Logistic Models, 030220 oncology & carcinogenesis, Cohort, Female, 030211 gastroenterology & hepatology, Colorectal Neoplasms, business
Abstract: INTRODUCTION Limited data inform the current postpolypectomy surveillance guidelines, which suggest a shortened interval to third colonoscopy after a negative second examination if high-risk adenomas (HRA) were present on the initial screening colonoscopy. Therefore, we examined the risk of HRA at third colonoscopy stratified by findings on 2 previous examinations in a prospective screening colonoscopy cohort of US veterans. METHODS We identified participants who had 3 or more colonoscopies from CSP#380. We examined the risk of HRA on the third examination based on findings from the previous 2 examinations. Multivariate logistic regression was used to adjust for multiple covariates. RESULTS HRA were found at the third examination in 114 (12.8%) of 891 participants. Those with HRA on both previous examinations had the greatest incidence of HRA at third examination (14/56, 25.0%). Compared with those with no adenomas on both previous examinations, participants with HRA on the first examination remained at significantly increased risk for HRA at the third examination at 3 years after a negative second examination (odds ratio [OR] 3.41, 95% confidence interval [CI] 1.28-9.08), 5 years (OR 3.14, 95% CI 1.49-6.61), and 7 years (OR 2.89, 95% CI 1.08-7.74). DISCUSSION In a screening population, HRA on the first examination identified individuals who remained at increased risk for HRA at the third examination, even after a negative second examination. This finding supports current colorectal cancer surveillance guidelines, which suggest a shortened, 5-year time interval to third colonoscopy after a negative second examination if high-risk findings were present on the baseline examination.
Published: 2020

24. Genotyping Array Design and Data Quality Control in the Million Veteran Program

Author: John Concato, Timothy J. O'Leary, Mary Brophy, Lakshmi Radhakrishnan, Jie Huang, Purushotham Karnam, VA Million Veteran Program, Sun-Gou Ji, Haley Hunter-Zinck, Saiju Pyarajan, Man Li, Yunling Shi, Xin Gong, Jennifer Moser, Ronald M. Przygodzki, Philip S. Tsao, Elizabeth R. Hauser, Sumitra Muralidhar, Joel Gelernter, Paul Hsieh, John Michael Gaziano, Ning Sun, Poornima Devineni, Donald E. Humphries, Christopher J. O'Donnell, Hongyu Zhao, Teresa Webster, Themistocles L. Assimes, Grant D. Huang, Jeanette Schmidt, Andrew Liem, Cuiping Pan, and Bryan R Gorman
Subjects: Genetic Markers, Male, Quality Control, 0301 basic medicine, Genotype, Genetic genealogy, Genome-wide association study, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Ethnicity, Genetics, Humans, Medicine, Precision Medicine, Veterans Affairs, Genotyping, Genetics (clinical), Aged, Veterans, Aged, 80 and over, Whole Genome Sequencing, business.industry, Middle Aged, Precision medicine, Biobank, 030104 developmental biology, Data quality, Cohort, Female, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography
Abstract: The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other ‘omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP’s substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.
Published: 2020

25. Determinants of Dropout from and Variation in Adherence to an Exercise Intervention: The STRRIDE Randomized Trials

Author: Katherine A. Collins, Kim M. Huffman, Ruth Q. Wolever, Patrick J. Smith, Ilene C. Siegler, Leanna M. Ross, Elizabeth R. Hauser, Rong Jiang, John M. Jakicic, Paul T. Costa, and William E. Kraus
Subjects: Article
Abstract: PURPOSE. This study aimed to characterize the timing and self-reported determinants of exercise dropout among sedentary adults with overweight or obesity. We also sought to explore variations in adherence among individuals who completed a 6- to 8-month structured exercise intervention. METHODS. A total of 947 adults with dyslipidemia [STRRIDE I, STRRIDE AT/RT] or prediabetes [STRRIDE-PD] were enrolled to either control or to one of 10 exercise interventions, ranging from doses of 8–23 kcal/kg/week; intensities of 50%–75% V̇O2 peak; and durations of 6–8 months. Two groups included resistance training and one included dietary intervention (7% weight loss goal). Dropout was defined as an individual who withdrew from the study due a variety of determinants. Timing of intervention dropout was defined as the last session attended and categorized into phases. Exercise training adherence was calculated by dividing weekly minutes or total sets of exercise completed by weekly minutes or total sets of exercise prescribed. General linear models were used to characterize the associations between timing of dropout and determinant category. RESULTS. Compared to exercise intervention completers (n=652), participants who dropped out (n=295) were on average non-white (98% vs. 80%, p
Published: 2022

26. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author: Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards 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Artigas M., Van der Auwera S., Azevedo M.H., Bass N., Bau C.H.D., Baune B.T., Bellivier F., Berger K., Biernacka J.M., Bigdeli T.B., Binder E.B., Boehnke M., Boks M.P., Bosch R., Braff D.L., Bryant R., Budde M., Byrne E.M., Cahn W., Casas M., Castelao E., Cervilla J.A., Chaumette B., Cichon S., Corvin A., Craddock N., Craig D., Degenhardt F., Djurovic S., Edenberg H.J., Fanous A.H., Foo J.C., Forstner A.J., Frye M., Fullerton J.M., Gatt J.M., Gejman P.V., Giegling I., Grabe H.J., Green M.J., Grevet E.H., Grigoroiu-Serbanescu M., Gutierrez B., Guzman-Parra J., Hamilton S.P., Hamshere M.L., Hartmann A., Hauser J., Heilmann-Heimbach S., Hoffmann P., Ising M., Jones I., Jones L.A., Jonsson L., Kahn R.S., Kelsoe J.R., Kendler K.S., Kloiber S., Koenen K.C., Kogevinas M., Konte B., Krebs M.-O., Landen M., Lawrence J., Leboyer M., Lee P.H., Levinson D.F., Liao C., Lissowska J., Lucae S., Mayoral F., McElroy S.L., McGrath P., McGuffin P., McQuillin A., Medland S.E., Mehta D., Melle I., Milaneschi Y., Mitchell P.B., Molina E., Morken G., Mortensen P.B., Muller-Myhsok B., Nievergelt C., Nimgaonkar V., Nothen M.M., O'Donovan M.C., Ophoff R.A., Owen M.J., Pato C., Pato M.T., Penninx B.W.J.H., Pimm J., Pistis G., Potash J.B., Power R.A., Preisig M., Quested D., Ramos-Quiroga J.A., Reif A., Ribases M., Richarte V., Rietschel M., Rivera M., Roberts A., Roberts G., Rouleau G.A., Rovaris D.L., Rujescu D., Sanchez-Mora C., Sanders A.R., Schofield P.R., Schulze T.G., Scott L.J., Serretti A., Shi J., Shyn S.I., Sirignano L., Sklar P., Smeland O.B., Smoller J.W., Sonuga-Barke E.J.S., Spalletta G., Strauss J.S., Swiatkowska B., Trzaskowski M., Turecki G., Vilar-Ribo L., Vincent J.B., Volzke H., Walters J.T.R., Shannon Weickert C., Weickert T.W., Weissman M.M., Williams L.M., Wray N.R., Zai C.C., Ashley-Koch A.E., Beckham J.C., Hauser E.R., Hauser M.A., Kimbrel N.A., Lindquist J.H., McMahon B., Oslin D.W., Qin X., Mattheisen M., Abdellaoui A., Adams M.J., Agerbo E., Andlauer T.F.M., Bacanu S.-A., Baekvad-Hansen M., Beekman A.T.F., Bryois J., Buttenschon H.N., Bybjerg-Grauholm J., Cai N., Christensen J.H., Clarke T.-K., Colodro-Conde L., Couvy-Duchesne B., Crawford G.E., Davies G., Derks E.M., Direk N., Dolan C.V., Dunn E.C., Eley T.C., Escott-Price V., Hassan Kiadeh F.F., Finucane H.K., Frank J., Gaspar H.A., Gill M., Goes F.S., Gordon S.D., Weinsheimer S.M., Wellmann J., Willemsen G., Wu Y., Xi H.S., Yang J., Zhang F., Arolt V., Boomsma D.I., Dannlowski U., de Geus E.J.C., Depaulo J.R., Domenici E., Domschke K., Esko T., Grove J., Hall L.S., Hansen C.S., Hansen T.F., Herms S., Hickie I.B., Homuth G., Horn C., Hottenga J.-J., Hougaard D.M., Howard D.M., Jansen R., Jorgenson E., Knowles J.A., Kohane I.S., Kraft J., Kretzschmar W.W., Kutalik Z., Li Y., Lind P.A., MacIntyre D.J., MacKinnon D.F., Maier R.M., Maier W., Marchini J., Mbarek H., Middeldorp C.M., Mihailov E., Milani L., Mondimore F.M., Montgomery G.W., Mostafavi S., Nauck M., Ng B., Nivard M.G., Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.
Subjects: LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract: Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551
Published: 2022

27. Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans

Author: Nathan A, Kimbrel, Allison E, Ashley-Koch, Xue J, Qin, Jennifer H, Lindquist, Melanie E, Garrett, Michelle F, Dennis, Lauren P, Hair, Jennifer E, Huffman, Daniel A, Jacobson, Ravi K, Madduri, Jodie A, Trafton, Hilary, Coon, Anna R, Docherty, Niamh, Mullins, Douglas M, Ruderfer, Philip D, Harvey, Benjamin H, McMahon, David W, Oslin, Jean C, Beckham, Elizabeth R, Hauser, Michael A, Hauser, and Robert, Striker
Subjects: Psychiatry and Mental health
Abstract: ImportanceSuicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.ObjectiveTo identify novel, replicable genomic risk loci for SITB.Design, Setting, and ParticipantsThis genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.Main Outcome and MeasuresSITB.ResultsA total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P −8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.Conclusions and RelevanceThe findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.
Published: 2023

28. Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci

Author: Adolfo Correa, David Van Den Berg, Sonja I. Berndt, Elizabeth R. Hauser, Anna Batorsky, Ethan M. Lange, Andrea A. Baccarelli, Leslie A. Lange, Fadi J. Charchar, Nora Franceschini, Steve Horvath, Mindy D. Szeto, James Eales, Stephan Beck, Xiao Jiang, Laura M. Raffield, Kathryn L. Evans, Russell P. Tracy, Andrew P. Morris, William E. Kraus, Xiaoguang Xu, Maciej Tomaszewski, Stephanie J. London, Daniel L. McCartney, Caroline Hayward, Hermant K Tiwari, Jerome I. Rotter, Josyf C. Mychaleckyj, Eric A. Whitsel, Mi Kyeong Lee, Peter Durda, Lifang Hou, Donna K. Arnett, Holly Kramer, Amit Patki, Marguerite R. Irvin, Riccardo E. Marioni, Rong Jiang, Yongmei Liu, Charles E Breeze, Svati H. Shah, and Stephen S. Rich
Subjects: Epigenomics, Kidney Disease, Kidney development, QH426-470, Kidney, Kidney Function Tests, Epigenesis, Genetic, 0302 clinical medicine, Genetics (clinical), Regulation of gene expression, Genetics, 0303 health sciences, DNA methylation, Epigenetic, 3. Good health, Phenotype, 030220 oncology & carcinogenesis, Medicine, Molecular Medicine, Glomerular Filtration Rate, Population, Quantitative Trait Loci, Clinical Sciences, Renal and urogenital, Context (language use), Biology, Quantitative Trait, 03 medical and health sciences, Quantitative Trait, Heritable, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Kidney function, Genetic, Humans, Epigenetics, Heritable, Molecular Biology, 030304 developmental biology, Research, Human Genome, Racial Groups, Genetic Variation, dNaM, Epigenome, Gene regulation, Genetics, Population, Gene Expression Regulation, TOPMed MESA Multi-Omics Working Group, CpG Islands, Epigenesis, Genome-Wide Association Study
Abstract: Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
Published: 2021

29. Association of Gulf War Illness with Characteristics in Deployed vs. Non-Deployed Gulf War Era Veterans in the Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis

Author: Linh M. Duong, Alice B. S. Nono Djotsa, Jacqueline Vahey, Lea Steele, Rachel Quaden, Kelly M. Harrington, Sarah T. Ahmed, Renato Polimanti, Elani Streja, John Michael Gaziano, John Concato, Hongyu Zhao, Krishnan Radhakrishnan, Elizabeth R. Hauser, Drew A. Helmer, Mihaela Aslan, and Elizabeth J. Gifford
Subjects: gulf war, Health, Toxicology and Mutagenesis, Public Health, Environmental and Occupational Health, veteran, Toxicology, gulf war illness, chronic multisymptom illness, post-deployment health surveys, health outcomes, Cross-Sectional Studies, Military Personnel, Good Health and Well Being, Humans, Persian Gulf Syndrome, Veterans
Abstract: Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990–1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA’s Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990–1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018–2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx−], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx−, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.
Published: 2022

30. Gene–Toxicant Interactions in Gulf War Illness: Differential Effects of the PON1 Genotype

Author: Kellie J. Sims, Blair Chesnut, Jimmy T. Efird, Saiju Pyarajan, Annjanette Stone, Elizabeth R. Hauser, Elizabeth J. Gifford, Christina D. Williams, Stephen H. Boyle, Julie Upchurch, Crystal Stafford, and Jacqueline Vahey
Subjects: Candidate gene, medicine.medical_specialty, Single-nucleotide polymorphism, Neurosciences. Biological psychiatry. Neuropsychiatry, Gulf War illness, chemistry.chemical_compound, GWI, Internal medicine, Genotype, Medicine, SNP, Gene, veteran health, pesticides, pyridostigmine bromide, gene–environment interactions, PON1, business.industry, General Neuroscience, humanities, chemistry, Cohort, business, Toxicant, RC321-571
Abstract: About 25–35% of United States veterans who fought in the 1990–1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene–toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1, were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.
Published: 2021
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31. Screening Colonoscopy Findings Are Associated With Noncolorectal Cancer Mortality

Author: Brian A. Sullivan, Xuejun Qin, Cameron Miller, Elizabeth R. Hauser, Thomas S. Redding, Ziad F. Gellad, Ashton N. Madison, Laura W. Musselwhite, Jimmy T. Efird, Kellie J. Sims, Christina D. Williams, David Weiss, David Lieberman, and Dawn Provenzale
Subjects: Adenoma, Gastroenterology, Humans, Mass Screening, Colonoscopy, Colorectal Neoplasms, Early Detection of Cancer
Abstract: Controversy exists regarding the impact of various risk factors on noncolorectal cancer (CRC) mortality in healthy screening populations. We examined the impact of known CRC risk factors, including baseline colonoscopy findings, on non-CRC mortality in a screening population.Cooperative Studies Program (CSP) #380 is comprised of 3,121 veterans aged 50-75 years who underwent screening colonoscopy from 1994 to 97 and were then followed for at least 10 years or until death. Hazard ratios (HRs) for risk factors on non-CRC mortality were estimated by multivariate Cox proportional hazards.Current smoking (HR 2.12, 95% confidence interval [CI] 1.78-2.52, compared with nonsmokers) and physical activity (HR 0.89, 95% CI 0.84-0.93) were the modifiable factors most associated with non-CRC mortality in CSP#380. In addition, compared with no neoplasia at baseline colonoscopy, non-CRC mortality was higher in participants with ≥3 small adenomas (HR 1.43, 95% CI 1.06-1.94), advanced adenomas (HR 1.32, 95% CI 0.99-1.75), and CRC (HR 2.95, 95% CI 0.98-8.85). Those with 1-2 small adenomas were not at increased risk for non-CRC mortality (HR 1.15, 95% CI 0.94-1.4).In a CRC screening population, known modifiable risk factors were significantly associated with 10-year non-CRC mortality. Furthermore, those who died from non-CRC causes within 10 years were more likely to have had high-risk findings at baseline colonoscopy. These results suggest that advanced colonoscopy findings may be a risk marker of poor health outcomes. Integrated efforts are needed to motivate healthy lifestyle changes during CRC screening, particularly in those with high-risk colonoscopy findings and unaddressed risk factors.
Published: 2021

32. Gene-Toxicant Interactions in Gulf War Illness: Differential Effects of the

Author: Jacqueline, Vahey, Elizabeth J, Gifford, Kellie J, Sims, Blair, Chesnut, Stephen H, Boyle, Crystal, Stafford, Julie, Upchurch, Annjanette, Stone, Saiju, Pyarajan, Jimmy T, Efird, Christina D, Williams, and Elizabeth R, Hauser
Subjects: GWI, pesticides, gene–environment interactions, PON1, humanities, Article, veteran health, Gulf War illness, pyridostigmine bromide
Abstract: About 25–35% of United States veterans who fought in the 1990–1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene–toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1, were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.
Published: 2021

33. A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program

Author: Sridharan, Raghavan, Jie, Huang, Catherine, Tcheandjieu, Jennifer E, Huffman, Elizabeth, Litkowski, Chang, Liu, Yuk-Lam A, Ho, Haley, Hunter-Zinck, Hongyu, Zhao, Eirini, Marouli, Kari E, North, Ethan, Lange, Leslie A, Lange, Benjamin F, Voight, J Michael, Gaziano, Saiju, Pyarajan, Elizabeth R, Hauser, Philip S, Tsao, Peter W F, Wilson, Kyong-Mi, Chang, Kelly, Cho, Christopher J, O'Donnell, Yan V, Sun, and Themistocles L, Assimes
Subjects: Adult, Cancer Research, Atrial Fibrillation, Hypertension, Genetics, Humans, Genetic Predisposition to Disease, Molecular Biology, Polymorphism, Single Nucleotide, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Genome-Wide Association Study, Veterans
Abstract: Background Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Methods and findings Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. Conclusions We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
Published: 2021

34. Exposures to low-levels of fine particulate matter are associated with acute changes in heart rate variability, cardiac repolarization, and circulating blood lipids in coronary artery disease patients

Author: Jaime E. Mirowsky, Martha Sue Carraway, Radhika Dhingra, Haiyan Tong, Lucas Neas, David Diaz-Sanchez, Wayne E. Cascio, Martin Case, James L. Crooks, Elizabeth R. Hauser, Z. Elaine Dowdy, William E. Kraus, and Robert B. Devlin
Subjects: Male, Air Pollutants, Coronary Artery Disease, Environmental Exposure, Lipids, Biochemistry, United States, Cholesterol, Ozone, Heart Rate, Air Pollution, Humans, Particulate Matter, Biomarkers, General Environmental Science
Abstract: Exposure to air pollution is a major risk factor for cardiovascular disease, disease risk factors, and mortality. Specifically, particulate matter (PM), and to some extent ozone, are contributors to these effects. In addition, exposures to these pollutants may be especially dangerous for susceptible populations. In this repeated-visit panel study, cardiovascular markers were collected from thirteen male participants with stable coronary artery disease. For 0-4 days prior to the health measurement collections, daily concentrations of fine PM (PM
Published: 2022

35. Longitudinal assessment of colonoscopy adverse events in the prospective Cooperative Studies Program no. 380 colorectal cancer screening and surveillance cohort

Author: Elizabeth A. Kobe, Brian A. Sullivan, Xuejun Qin, Thomas S. Redding, Elizabeth R. Hauser, Ashton N. Madison, Cameron Miller, Jimmy T. Efird, Ziad F. Gellad, David Weiss, Kellie J. Sims, Christina D. Williams, David A. Lieberman, and Dawn Provenzale
Subjects: Risk Factors, Gastroenterology, Humans, Mass Screening, Radiology, Nuclear Medicine and imaging, Colonoscopy, Prospective Studies, Colorectal Neoplasms, Early Detection of Cancer
Abstract: Data are limited regarding colonoscopy risk during long-term, programmatic colorectal cancer screening and follow-up. We aimed to describe adverse events during follow-up in a colonoscopy screening program after the baseline examination and examine factors associated with increased risk.Cooperative Studies Program no. 380 includes 3121 asymptomatic veterans aged 50 to 75 years who underwent screening colonoscopy between 1994 and 1997. Periprocedure adverse events requiring significant intervention were defined as major events (other events were minor) and were tracked during follow-up for at least 10 years. Multivariable odds ratios (ORs) were calculated for factors associated with risk of follow-up adverse events.Of 3727 follow-up examinations in 1983 participants, adverse events occurred in 105 examinations (2.8%) in 93 individuals, including 22 major and 87 minor events (examinations may have had1 event). Incidence of major events (per 1000 examinations) remained relatively stable over time, with 6.1 events at examination 2, 4.8 at examination 3, and 7.2 at examination 4. Examinations with major events included 1 perforation, 3 GI bleeds requiring intervention, and 17 cardiopulmonary events. History of prior colonoscopic adverse events was associated with increased risk of events (major or minor) during follow-up (OR, 2.7; 95% confidence interval, 1.6-4.6).Long-term programmatic screening and surveillance was safe, as major events were rare during follow-up. However, serious cardiopulmonary events were the most common major events. These results highlight the need for detailed assessments of comorbid conditions during routine clinical practice, which could help inform individual decisions regarding the utility of ongoing colonoscopy follow-up.
Published: 2022

36. Corrigendum: Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease

Author: Jennifer R. Dungan, Xue Qin, Melissa Hurdle, Carol S. Haynes, Elizabeth R. Hauser, and William E. Kraus
Subjects: age-related disease, genome-wide association study, Genetics, Molecular Medicine, QH426-470, candidate gene analyses, coronary artery disease, Genetics (clinical), survival analysis
Published: 2021

37. A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci

Author: Nathan A, Kimbrel, Allison E, Ashley-Koch, Xue J, Qin, Jennifer H, Lindquist, Melanie E, Garrett, Michelle F, Dennis, Lauren P, Hair, Jennifer E, Huffman, Daniel A, Jacobson, Ravi K, Madduri, Jodie A, Trafton, Hilary, Coon, Anna R, Docherty, Jooeun, Kang, Niamh, Mullins, Douglas M, Ruderfer, Philip D, Harvey, Benjamin H, McMahon, David W, Oslin, Elizabeth R, Hauser, Michael A, Hauser, and Jean C, Beckham
Subjects: Black or African American, Genetic Loci, Humans, Genetic Predisposition to Disease, Suicide, Attempted, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study, Veterans
Abstract: To identify pan-ancestry and ancestry-specific loci associated with attempting suicide among veterans, we conducted a genome-wide association study (GWAS) of suicide attempts within a large, multi-ancestry cohort of U.S. veterans enrolled in the Million Veterans Program (MVP). Cases were defined as veterans with a documented history of suicide attempts in the electronic health record (EHR; N = 14,089) and controls were defined as veterans with no documented history of suicidal thoughts or behaviors in the EHR (N = 395,064). GWAS was performed separately in each ancestry group, controlling for sex, age and genetic substructure. Pan-ancestry risk loci were identified through meta-analysis and included two genome-wide significant loci on chromosomes 20 (p = 3.64 × 10
Published: 2021

38. Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990–1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006

Author: Daniel F. Levey, Stacey B. Whitbourne, Alysia D. Maffucci, Elizabeth R. Hauser, Mihaela Aslan, Rebecca B. McNeil, John Concato, Dawn Provenzale, Jacqueline Vahey, Krishnan Radhakrishnan, Joel Gelernter, Rachel Quaden, John Michael Gaziano, Renato Polimanti, Drew A. Helmer, Grant D. Huang, Kelly M. Harrington, and Hongyu Zhao
Subjects: medicine.medical_specialty, phenotyping, Genomic data, Neurosciences. Biological psychiatry. Neuropsychiatry, Genomics, Disease, Gulf war, exposures, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Health care, medicine, genomics, Psychiatry, Persian Gulf War deployment status, Veterans Affairs, 030304 developmental biology, Persian, 0303 health sciences, business.industry, General Neuroscience, Medical record, 030210 environmental & occupational health, language.human_language, humanities, U.S. veteran, Gulf War Illness, language, business, Psychology, RC321-571
Abstract: Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.
Published: 2021

39. Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease

Author: Jennifer R. Dungan, Xue Qin, Melissa Hurdle, Carol S. Haynes, Elizabeth R. Hauser, and William E. Kraus
Subjects: 0301 basic medicine, Oncology, Candidate gene, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, QH426-470, 030204 cardiovascular system & hematology, survival analysis, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Risk of mortality, Genetics, SNP, candidate gene analyses, Genetics (clinical), Survival analysis, Original Research, age-related disease, genome-wide association study, business.industry, Correction, medicine.disease, 030104 developmental biology, Molecular Medicine, business, coronary artery disease
Abstract: ObjectiveCoronary artery disease (CAD) is an age-associated condition that greatly increases the risk of mortality. The purpose of this study was to identify gene variants associated with all-cause mortality among individuals with clinically phenotyped CAD using a genome-wide screening approach.Approach and ResultsWe performed discovery (n = 684), replication (n = 1,088), and meta-analyses (N = 1,503) for association of genomic variants with survival outcome using secondary data from White participants with CAD from two GWAS sub-studies of the Duke Catheterization Genetics Biorepository. We modeled time from catheterization to death or last follow-up (median 7.1 years, max 12 years) using Cox multivariable regression analysis. Target statistical screening thresholds were p × 10–8 for the discovery phase and Bonferroni-calculated p-values for the replication (p < 5.3 × 10–4) and meta-analysis (p < 1.6 × 10–3) phases. Genome-wide analysis of 785,945 autosomal SNPs revealed two SNPs (rs13007553 and rs587936) that had the same direction of effect across all three phases of the analysis, with suggestive p-value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, LINC01250, which resides between MYTIL and EIPR1, conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17–1.86, p(adj) = 1.07 × 10–3 (discovery), p(adj) = 0.03 (replication), p(adj) = 9.53 × 10–5 (meta-analysis)]. MYT1L is involved in neuronal differentiation. TSSC1 is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to DAB2IP was associated with increased survival time [HR 0.65, 95% CI 0.51–0.83, p(adj) = 4.79 × 10–4 (discovery), p(adj) = 0.02 (replication), p(adj) = 2.25 × 10–5 (meta-analysis)]. DAB2IP is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. DAB2IP has multiple lines of evidence for protection against atherosclerosis.ConclusionReplicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci LINC01250 (rs13007553) and biologically relevant candidate DAB2IP (rs587936). These candidates did not overlap with validated longevity candidate genes. Future research could further define the role of common variants in survival outcomes for people with CAD and, ultimately, improve longitudinal outcomes for these patients.
Published: 2021

40. Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity in Genome-wide Association Studies

Author: Themistocles L. Assimes, P. S. Sriram, Qin Hui, Stephen Mastorides, Zuhair Ballas, Yan V. Sun, Hua Tang, Marijana Vujkovic, Ronald G Washburn, Samuel M. Aguayo, Jennifer Moser, Gwenevere Anderson, Mary A. Whooley, Sumitra Muralidhar, Agnes Wallbom, Adriana M. Hung, Xuan-Mai T. Nguyen, Huaying Fang, Jennifer Greco, Rachel B. Ramoni, Amparo Gutierrez, Saiju Pyarajan, Stuart R. Warren, Rob Striker, Pran Iruvanti, Mark B. Hamner, Scott L. DuVall, Elizabeth R. Hauser, Christopher J. O'Donnell, Donald E. Humphries, Jon B. Klein, Nora R. Ratcliffe, John M. Wells, Maureen Murdoch, Gerardo Villareal, Laurence Kaminsky, Peter W. F. Wilson, Mary E. Oehlert, Mary Brophy, Stacey B. Whitbourne, Louis J. Dell’Italia, Grant D. Huang, Ronald Fernando, Dean P. Argyres, Jie Huang, Hongyu Zhao, Scott Kinlay, Kelly Cho, Jeff Whittle, Scott M. Damrauer, Jacqueline Honerlaw, Sunil K. Ahuja, Laurence Meyer, Brooks Robey, John B. Harley, Gretchen Gibson, John Concato, Rachel McArdle, David Cohen, Krisann K. Oursler, Robin A. Hurley, Sujata Bhushan, Salvador Gutierrez, D Jhala, John J. Callaghan, Ron B. Schifman, Nhan Do, Junzhe Xu, Jim Breeling, Jessica V. Brewer, Elif Sonel, Kyong-Mi Chang, Peter W.F. Wilson, Brady Stephens, Shahpoor Shayan, Philip S. Tsao, Joseph Fayad, Michael Godschalk, Jack H. Lichy, Scott Sherman, Shing Shing Yeh, Alan Swann, Michael Rauchman, Samir Gupta, Satish C. Sharma, Edward Boyko, J. Michael Gaziano, Julie Lynch, Timothy R. Morgan, Jean C. Beckham, Todd Stapley, Malcolm Buford, Richard J. Servatius, Hermes Florez, and Kathlyn Sue Haddock
Subjects: 0303 health sciences, Genetic diversity, Support Vector Machine, Genetic genealogy, Racial Groups, Ethnic group, Genome-wide association study, Article, Genetic architecture, Machine Learning, 03 medical and health sciences, Race (biology), 0302 clinical medicine, Evolutionary biology, Ethnicity, Genetics, Trait, Humans, Psychology, Algorithms, 030217 neurology & neurosurgery, Genetics (clinical), Genome-Wide Association Study, 030304 developmental biology, Genetic association
Abstract: Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.
Published: 2019

41. Association of long-term PM2.5 exposure with traditional and novel lipid measures related to cardiovascular disease risk

Author: Wayne E. Cascio, Joel Schwartz, Elizabeth R. Hauser, Alexandra Schneider, Lucas M. Neas, Robert W. McGarrah, Robert B. Devlin, David Diaz-Sanchez, Laura McGuinn, Qian Di, Cavin K. Ward-Caviness, and William E. Kraus
Subjects: Cardiac Catheterization, medicine.medical_specialty, 010504 meteorology & atmospheric sciences, Apolipoprotein B, medicine.medical_treatment, Blood lipids, 010501 environmental sciences, complex mixtures, 01 natural sciences, Article, Diabetes mellitus, Internal medicine, North Carolina, medicine, Humans, Fine Particulate Matter, Lipids, Cardiovascular Disease, Air Pollution, lcsh:Environmental sciences, 0105 earth and related environmental sciences, General Environmental Science, Cardiac catheterization, lcsh:GE1-350, biology, business.industry, Environmental Exposure, medicine.disease, Cross-Sectional Studies, Cardiovascular Diseases, Cohort, Disease risk, biology.protein, Particulate Matter, lipids (amino acids, peptides, and proteins), business, Body mass index, Lipoprotein
Abstract: Background: Fine particulate matter (PM2.5) exposure is associated with increased morbidity and mortality, particularly for cardiovascular disease. The association between long-term exposure to PM2.5 and measures of lipoprotein subfractions remains unclear. Therefore, we examined associations between long-term PM2.5 exposure and traditional and novel lipoprotein measures in a cardiac catheterization cohort in North Carolina. Methods: This cross-sectional study included 6587 patients who had visited Duke University for a cardiac catheterization between 2001 and 2010 and resided in North Carolina. We used estimates of daily PM2.5 concentrations on a 1 km-grid based on satellite measurements. PM2.5 predictions were matched to the address of each patient and averaged for the year prior to catheterization date. Serum lipids included HDL, LDL, and triglyceride-rich particle, and apolipoprotein B concentrations (HDL-P, LDL-P, TRL-P, and apoB, respectively). Linear and quantile regression models were used to estimate change in lipoprotein levels with each μg/m3 increase in annual average PM2.5. Models were adjusted for age, sex, race/ethnicity, history of smoking, area-level education, urban/rural status, body mass index, and diabetes. Results: For a 1-μg/m3 increment in PM2.5 exposure, we observed increases in total and small LDL-P, LDL-C, TRL-P, apoB, total cholesterol, and triglycerides. The percent change from the mean outcome level was 2.00% (95% CI: 1.38%, 2.64%) for total LDL-P and 2.25% (95% CI: 1.43%, 3.06%) for small LDL-P. Conclusion: Among this sample of cardiac catheterization patients residing in North Carolina, long-term PM2.5 exposure was associated with increases in several lipoprotein concentrations. This abstract does not necessarily reflect U.S. EPA policy. Keywords: Fine particulate matter, Lipids, Cardiovascular disease, Air pollution
Published: 2019

42. Evaluation of PM(2.5) air pollution sources and cardiovascular health

Author: Elizabeth R. Hauser, Wayne E. Cascio, David Diaz-Sanchez, Erik Slawsky, Armistead G. Russell, Cavin K. Ward-Caviness, William E. Kraus, Ran Huang, Lucas M. Neas, Robert B. Devlin, and Anne M. Weaver
Subjects: Ammonium bisulfate, Global and Planetary Change, medicine.medical_specialty, Epidemiology, business.industry, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Public Health, Environmental and Occupational Health, Odds ratio, medicine.disease, Logistic regression, Pollution, Coronary artery disease, chemistry.chemical_compound, chemistry, Internal medicine, Cohort, medicine, Cardiology, Myocardial infarction, Original Research Article, Risk factor, business, Cardiac catheterization
Abstract: Long-term air pollution exposure, notably fine particulate matter, is a global contributor to morbidity and mortality and a known risk factor for coronary artery disease (CAD) and myocardial infarctions (MI). Knowledge of impacts related to source-apportioned PM(2.5) is limited. New modeling methods allow researchers to estimate source-specific long-term impacts on the prevalence of CAD and MI. The Catheterization Genetics (CATHGEN) cohort consists of patients who underwent a cardiac catheterization at Duke University Medical Center between 2002 and 2010. Severity of coronary blockage was determined by coronary angiography and converted into a binary indicator of clinical CAD. History of MI was extracted from medical records. Annual averages of source specific PM(2.5) were estimated using an improved gas-constrained source apportionment model for North Carolina from 2002 to 2010. We tested six sources of PM(2.5) mass for associations with CAD and MI using mixed effects multivariable logistic regression with a random intercept for county and multiple adjustments. PM(2.5) fractions of ammonium bisulfate and ammonium nitrate were associated with increased prevalence of CAD (odds ratio [OR] 1.20; 95% CI = 1.11, 1.22 and OR 1.18; 95% CI = 1.05, 1.32, respectively). PM(2.5) from ammonium bisulfate and ammonium nitrate were also associated with increased prevalence of MI (OR 1.20; 95% CI = 1.10, 1.29 and OR 1.35; 95% CI = 1.20, 1.53, respectively). Greater PM(2.5) concentrations of ammonium bisulfate and ammonium nitrate are associated with greater MI and CAD prevalence. The association with bisulfate suggests aerosol acidity may play a role. Our findings suggest analyses of source specific PM(2.5) mass can reveal novel associations.
Published: 2021

43. Th17 Immunity in the Colon Is Controlled by Two Novel Subsets of Colon-Specific Mononuclear Phagocytes

Author: Hsin-I. Huang, Mark L. Jewell, Nourhan Youssef, Min-Nung Huang, Elizabeth R. Hauser, Brian E. Fee, Nathan P. Rudemiller, Jamie R. Privratsky, Junyi J. Zhang, Estefany Y. Reyes, Donghai Wang, Gregory A. Taylor, Michael D. Gunn, Dennis C. Ko, Donald N. Cook, Vidyalakshmi Chandramohan, Steven D. Crowley, and Gianna Elena Hammer
Subjects: Mice, 129 Strain, Th17 immunity, CD14, Immunology, Lipopolysaccharide Receptors, Antigen-Presenting Cells, Gene Expression, Mice, Transgenic, Biology, Immunity, Intestine, Small, medicine, Animals, Immunology and Allergy, Macrophage, dendritic cells, Antigen-presenting cell, Receptor, Anaphylatoxin C5a, intestine, Original Research, Mice, Knockout, Phagocytes, colon, CD24 Antigen, Mononuclear phagocyte system, Dendritic cell, RC581-607, Small intestine, macrophages, medicine.anatomical_structure, Interferon Regulatory Factors, Cytokines, Th17 Cells, Immunologic diseases. Allergy, small intestine, IRF4
Abstract: Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.
Published: 2021

44. A large-scale multi-ethnic genome-wide association study of coronary artery disease

Author: Joshua C. Bis, Kari E. North, Christopher A. Haiman, Mariaelisa Graff, Charles Kooperberg, Steven Buyske, Loic Le Marchand, Saiju Pyarajan, Yingchang Lu, Huaying Fang, Yuk-Lam Ho, Ian B. Stanaway, Shefali S. Verma, Kyung Min Lee, Peter W.F. Wilson, Shining Ma, Yan V. Sun, Ozan Dikilitas, Stephen Waldo, Daniel J. Rader, Hampton L. Leonard, Sekar Kathiresan, Christopher P. O'Donnell, Fei Chen, Kaoru Ito, Xiang Zhu, Elizabeth R. Hauser, Kyong-Mi Chang, Gail P. Jarvik, Botong Shen, Luca A. Lotta, Peter D. Reaven, Rachel L. Kember, Danish Saleheen, Genevieve L. Wojcik, Yoichiro Kamatani, Jeffrey Haessler, Sridharan Raghavan, Kumardeep Chaudhary, Kenneth M. Kaufman, Marijana Vujkovic, Jennifer Lee, Scott M. Damrauer, Kazuyoshi Ishigaki, Jie Huang, Austin T. Hilliard, Ron Do, Shoa L. Clarke, Noah Tsao, Derek Klarin, Kelly Cho, Jennifer E. Huffman, Donald R. Miller, J. Michael Gaziano, Bahram Namjou, Satoshi Koyama, Leslie A. Lange, Alexander G. Bick, Valerio Napolioni, Bryan R Gorman, Pradeep Natarajan, Scott J. Hebbring, Lynne R. Wilkens, Ruth J. F. Loos, P.S. Tsao, Benjamin F. Voight, Catherine Tcheandjieu, Mary Plomondon, Aris Baras, Hua Tang, Themistocles L. Assimes, Adam S. Gordon, Marylyn D. Ritchie, Ayush Giri, Michael G. Levin, Nasa Sinnott-Armstrong, Rebecca J Song, Christy L. Avery, Thomas Maddox, Marie Verbanck, Iftikhar J. Kullo, and Julie Lynch
Subjects: Coronary artery disease, Scale (ratio), business.industry, Ethnic group, Medicine, Genome-wide association study, Computational biology, business, medicine.disease
Abstract: Coronary artery disease (CAD) is a leading cause of death, yet its genetic determinants are not fully elucidated. We report a multi-ethnic genome-wide association study of CAD involving nearly a quarter of a million cases, incorporating the largest cohorts to date of Whites, Blacks, and Hispanics from the Million Veteran Program with existing studies including CARDIoGRAMplusC4D, UK Biobank, and Biobank Japan. We verify substantial and nearly equivalent heritability of CAD across multiple ancestral groups, discover 107 novel loci including the first nine on the X-chromosome, identify the first eight genome-wide significant loci among Blacks and Hispanics, and demonstrate that two common haplotypes are largely responsible for the risk stratification at the well-known 9p21 locus in most populations except those of African origin where both haplotypes are virtually absent. We identify 15 loci for angiographically derived burden of coronary atherosclerosis, which robustly overlap with the strongest and earliest loci reported to date for clinical CAD. Phenome-wide association analyses of novel loci and externally validated polygenic risk scores (PRS) augment signals from the insulin resistance cluster of risk factors and consequences, extend previously established pleiotropic associations of loci with traditional risk factors to include smoking and family history, and confirm a substantially reduced transferability of existing PRS to Blacks. Downstream integrative genomic analyses reinforce the critical role of endothelial, fibroblast, and smooth muscle cells within the coronary vessel wall in CAD susceptibility. Our study highlights the value of a multi-ethnic design in efficiently characterizing the genetic architecture of CAD across all human populations.
Published: 2021

45. Eur Heart J

Author: Yoichiro Kamatani, Markus Scholz, Pin Huang, Marcus E. Kleber, Chang Liu, Aldons J. Lusis, Zhiheng Cai, Janet Gukasyan, Yi Han, Georgios J. Vlachojannis, W.H. Wilson Tang, Satoshi Koyama, Johan L.M. Björkegren, Margarete Mehrabian, David-Alexandre Trégouët, Hooman Allayee, Folkert W. Asselbergs, Peter Bazeley, Elizabeth R. Hauser, Casey E. Romanoski, Mohammad Daud Khan, Leo-Pekka Lyytikäinen, Riyaz S. Patel, Issei Komuro, Tuomo Nieminen, Stanley L. Hazen, Qiong Jia, Muredach P. Reilly, Redouane Aherrahrou, Xuling Chang, Jari Laurikka, James R. Hilser, Marion van Vugt, William E. Kraus, Clint L. Miller, Kaoru Ito, Jaana Hartiala, Marcus M. Seldin, Calvin Pan, Winfried März, Joachim Thiery, Jane F. Ferguson, Yan V. Sun, Chew-Kiat Heng, Pekka Kuukasjärvi, Mika Kähönen, Mete Civelek, Lindsey K. Stolze, S. Ram Kumar, Graciela E. Delgado, Nicholas L. Smith, Subarna Biswas, William S Schwartzman, Laurence J. Howe, Lijiang Ma, Rong Jiang, Adam W. Turner, Arshed A. Quyyumi, Terho Lehtimäki, Cardiology, Tampere University, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Genetic factors, Smooth muscle cell migration, SLC44A3, Myocardial Infarction/genetics, Context (language use), Locus (genetics), Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Bioinformatics, 3121 Internal medicine, Polymorphism, Single Nucleotide, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Japan, Risk Factors, Medicine, Humans, Genetic Predisposition to Disease, AcademicSubjects/MED00200, Myocardial infarction, Polymorphism, Coronary atherosclerosis, 030304 developmental biology, 0303 health sciences, business.industry, Coronary Artery Disease/genetics, Genetic Predisposition to Disease/genetics, Clnical Research, Endothelial Cells, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Polymorphism, Single Nucleotide/genetics, 3. Good health, Coronary arteries, Meta-analysis, Editorial, medicine.anatomical_structure, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business, Single Nucleotide/genetics, Genome-Wide Association Study
Abstract: Aims While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. Methods and results We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. Conclusions A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Published: 2021

46. Research tool for classifying Gulf War illness using survey responses: Lessons for writing replicable algorithms for symptom-based conditions

Author: Drew A. Helmer, Elizabeth J. Gifford, Elizabeth R. Hauser, Dawn Provenzale, Jacqueline Vahey, and Kellie J. Sims
Subjects: Male, Computer science, Flexibility (personality), Sample (statistics), General Medicine, General Biochemistry, Genetics and Molecular Biology, Gulf War, Cohort Studies, Biorepository, Test case, Documentation, Chronic Disease, Code (cryptography), Humans, Persian Gulf Syndrome, General Pharmacology, Toxicology and Pharmaceutics, Pseudocode, Algorithm, Veterans Affairs, Algorithms, Veterans
Abstract: Aims Gulf War illness (GWI), a chronic symptom-based disorder, affects up to 30% of Veterans who served in the 1990-1991 Gulf War1. Because no diagnostic test or code for GWI exists, researchers typically determine case status using self-reported symptoms and conditions according to Kansas2 and CDC3 criteria. No validated algorithm has been published and case definitions have varied slightly by study. This paper aims to standardize the application of the original CDC and Kansas case definitions by defining a framework for writing reliable code for complex case definitions, implementing this framework on a sample of 1343 Gulf War Veterans (GWVs), and validating the framework by applying the code to a sample of 41,077 GWVs. Main methods Methods were drawn from software engineering: write pseudocode, write test cases, and write code; then test code. Code was examined for accuracy, flexibility, replicability, and reusability. Key findings The pseudocode promoted understanding of the planned algorithm, encouraging discussion and leading to agreement on the case definition algorithms among all team members. The completed SAS code was written for and tested in the Gulf War Era Cohort and Biorepository (GWECB)4. This code was adapted and tested in the Million Veteran Program (MVP)5. The code was documented for reproducibility and reusability. Significance Ease of reuse suggests that this method could be used to standardize the application of other case definitions, reducing time and resources spent by each study team. Documentation, code, and test cases are available through the Department of Veterans Affairs (VA) Phenomics catalog6.
Published: 2021

47. Th17 immunity in the colon is controlled by two novel subsets of colon-specific mononuclear phagocytes

Author: Nourhan Youssef, Donald N. Cook, Gianna E. Hammer, Vidyalakshmi Chandramohan, Elizabeth R. Hauser, Gregory A. Taylor, Dennis C. Ko, Junyi J. Zhang, Steven D. Crowley, Hsin-I Huang, Nathan P. Rudemiller, Min-Nung Huang, Estefany Y. Reyes, Jamie R. Privratsky, Michael D. Gunn, Brian E. Fee, Donghai Wang, and Mark L. Jewell
Subjects: medicine.anatomical_structure, Immunity, CD14, Immunology, medicine, Macrophage, Dendritic cell, Mononuclear phagocyte system, Biology, Antigen-presenting cell, Small intestine, IRF4
Abstract: Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.
Published: 2021

48. Ten or More Cumulative Lifetime Adenomas Are Associated with Increased Risk for Advanced Neoplasia and Colorectal Cancer

Author: Brian A, Sullivan, Thomas S, Redding, Xuejun, Qin, Ziad F, Gellad, Elizabeth R, Hauser, Meghan C, O'Leary, Christina D, Williams, Laura W, Musselwhite, David, Weiss, Ashton N, Madison, David, Lieberman, and Dawn, Provenzale
Subjects: Adenoma, Risk Factors, Incidence, Colonic Neoplasms, Colonic Polyps, Humans, Colonoscopy, Colorectal Neoplasms, Early Detection of Cancer
Abstract: Colorectal cancer (CRC) screening guidelines recommend frequent colonoscopies and consideration of genetic testing in individuals with ≥10 cumulative adenomas. However, it is unclear how these guidelines apply to routine practice.We estimated the proportion of participants found to have ≥10 cumulative adenomas in a screening population and described their outcomes of advanced neoplasia (AN), CRC, and extra-colonic malignancy.We performed a secondary analysis of VA CSP#380, which includes 3121 veterans aged 50-75 who were followed up to 10 years after screening colonoscopy. We calculated the cumulative risk of ≥10 cumulative adenomas by Kaplan-Meier method. We compared baseline risk factors in those with and without ≥10 cumulative adenomas as well as the risk for AN (adenoma ≥1 cm, villous adenoma or high-grade dysplasia, or CRC) and extra-colonic malignancy by multivariate logistic regression.The cumulative risk of ≥10 cumulative adenomas over 10.5 years was 6.51% (95% CI 4.38%-9.62%). Age 60-69 or 70-75 at baseline colonoscopy was the only factors associated with the finding of ≥10 cumulative adenomas. Compared to those with 0-9 cumulative adenomas, participants with ≥10 cumulative adenomas were more likely to have had AN (OR 17.03; 95% CI 9.41-30.84), including CRC (OR 7.00; 95% CI 2.84-17.28), but not extra-colonic malignancies.Approximately 6.5% of participants in this screening population were found to have ≥10 cumulative adenomas over 10.5 years, which was uncommon before age 60. These participants were found to have AN and CRC significantly more often compared to those with lower cumulative adenomas.
Published: 2021

49. An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility

Author: Ephraim L. Tsalik, Alejandro L. Antonia, Liuyang Wang, Micah T. McClain, Elizabeth R. Hauser, Thomas J Balmat, Mark R. DeLong, Thomas W. Burke, Xiling Shen, Andy Ingham, Emily R Ko, Dennis C. Ko, Christopher W. Woods, Florica J Constantine, Geoffrey S. Ginsburg, and Ricardo Henao
Subjects: Multifactorial Inheritance, Linkage disequilibrium, Systems biology, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Computational biology, QH426-470, Biology, Polymorphism, Single Nucleotide, Article, colocalization, Linkage Disequilibrium, Transcriptome, gout, rs2869462, pleiotropy, Genetic variation, Genetics, rs505922, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Mechanism (biology), SARS-CoV-2, macular telangiectasia, PheWAS, COVID-19, rs12610495, idiopathic pulmonary fibrosis, Phenotype, Human genetics, Genetic architecture, Hi-HOST, Medicine, Molecular Medicine, LD-score, Databases, Nucleic Acid, Software, cross-phenotype association, Genome-Wide Association Study
Abstract: Background While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Results Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Conclusions Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb.
Published: 2020

50. 606: LONG TERM OUTCOMES OF INCIDENT COLORECTAL CANCER AND COLORECTAL CANCER MORTALITY 20 YEARS AFTER BASELINE SCREENING COLONOSCOPY IN CSP#380

Author: Brian Sullivan, Thomas S. Redding, Xuejun Qin, Andrew D. Thompson, Samir Gupta, Ranier Bustamante, Ashley Earles, David Weiss, Ashton Madison, Julie Upchurch, Jimmy T. Efird, Kellie J. Sims, Jason A. Dominitz, Christina D. Williams, Elizabeth R. Hauser, and David A. Lieberman
Subjects: Hepatology, Gastroenterology
Published: 2022

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