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3,287 results on '"Nelson, B."'

1. Geospatial investigations in Colombia reveal variations in the distribution of mood and psychotic disorders

Author

Janet Song, Mauricio Castaño Ramírez, Justin T. Okano, Susan K. Service, Juan de la Hoz, Ana M. Díaz-Zuluaga, Cristian Vargas Upegui, Cristian Gallago, Alejandro Arias, Alexandra Valderrama Sánchez, Terri Teshiba, Chiara Sabatti, Ruben C. Gur, Carrie E. Bearden, Javier I. Escobar, Victor I. Reus, Carlos Lopez Jaramillo, Nelson B. Freimer, Loes M. Olde Loohuis, and Sally Blower

Subjects
Medicine
Abstract

Abstract Background Geographical variations in mood and psychotic disorders have been found in upper-income countries. We looked for geographic variation in these disorders in Colombia, a middle-income country. We analyzed electronic health records from the Clínica San Juan de Dios Manizales (CSJDM), which provides comprehensive mental healthcare for the one million inhabitants of Caldas. Methods We constructed a friction surface map of Caldas and used it to calculate the travel-time to the CSJDM for 16,295 patients who had received an initial diagnosis of mood or psychotic disorder. Using a zero-inflated negative binomial regression model, we determined the relationship between travel-time and incidence, stratified by disease severity. We employed spatial scan statistics to look for patient clusters. Results We show that travel-times (for driving) to the CSJDM are less than 1 h for ~50% of the population and more than 4 h for ~10%. We find a distance-decay relationship for outpatients, but not for inpatients: for every hour increase in travel-time, the number of expected outpatient cases decreases by 20% (RR = 0.80, 95% confidence interval [0.71, 0.89], p = 5.67E-05). We find nine clusters/hotspots of inpatients. Conclusions Our results reveal inequities in access to healthcare: many individuals requiring only outpatient treatment may live too far from the CSJDM to access healthcare. Targeting of resources to comprehensively identify severely ill individuals living in the observed hotspots could further address treatment inequities and enable investigations to determine factors generating these hotspots.

Published
2024
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2. Prototyping a Serial Number Based Authentication Model for a Computer in a Wireless Local Area Network

Author

Chebor, John C., Karume, Simon M., Masese, Nelson B., and Kipkebut, Andrew

Subjects
Computer Science - Cryptography and Security, Computer Science - Networking and Internet Architecture
Abstract

With the increase of wireless LAN usage in homes and enterprises due to its numerous benefits, authenticating the ever increasing number of devices and their users has become a challenge to proprietors of such kind networks. A MAC address, a physical network address that is used as basis for this study, has a copy of its value in the system software that can be spoofed and altered rendering the address not unique, not secure and unreliable. On the contrary, a computers serial number is hard-coded in the system hardware only and therefore cannot be spoofed and altered making it unique, secure and reliable. The research, therefore, was aimed at designing a model that demonstrates how a computers serial number can be used for authenticating a computer in a wireless local area network. In order to achieve the research objective, the study examined the inbuilt access and use of a computers serial number prototype model as an alternative method of authenticating devices in a network. Design science research methodology that involved design and development, demonstration and model evaluation was employed. A Serial Number Based Authentication Prototype or SNAP was therefore designed using state chart and flow chart diagrams based on dynamic programming, developed over evolutionary prototyping and test run on a static experimental design using Java Development Kit and MySQL platforms to demonstrate, as proof of concept, that a computers serial number can be used to authenticate a computer in a wireless local area network. From the test runs whose outcomes were the binary values yes or no, it was found out that SNAP can actually allow or deny, enable or disable a computer in a network based on the computers serial number. The researcher therefore, recommends that the prototype be scaled up, then adopted as a network device authentication method., Comment: 13 pages, 11 figures

Published
2022
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3. Echocardiographic estimation of pulmonary vascular resistance in advanced lung disease.

Author

DesJardin, Jacqueline T, Svetlichnaya, Yana, Kolaitis, Nicholas A, Hays, Steven R, Kukreja, Jasleen, Schiller, Nelson B, Zier, Lucas S, Singer, Jonathan P, and De Marco, Teresa

Subjects
chronic obstructive pulmonary disease, hemodynamics, interstitial lung disease, lung transplant, pulmonary hypertension, Cardiovascular, Bioengineering, Heart Disease, Lung, Clinical Research, Respiratory, Good Health and Well Being, Cardiorespiratory Medicine and Haematology
Abstract

Noninvasive assessment of pulmonary hemodynamics is often performed by echocardiographic estimation of the pulmonary artery systolic pressure (ePASP), despite limitations in the advanced lung disease population. Other noninvasive hemodynamic variables, such as echocardiographic pulmonary vascular resistance (ePVR), have not been studied in this population. We performed a retrospective analysis of 147 advanced lung disease patients who received both echocardiography and right heart catheterization for lung transplant evaluation. The ePVR was estimated by four previously described equations. Noninvasive and invasive hemodynamic parameters were compared in terms of correlation, agreement, and accuracy. The ePVR models strongly correlated with invasively determined PVR and had good accuracy with biases of

Published
2023

4. Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Author

Yin, Xianyong, Bose, Debraj, Kwon, Annie, Hanks, Sarah C, Jackson, Anne U, Stringham, Heather M, Welch, Ryan, Oravilahti, Anniina, Silva, Lilian Fernandes, FinnGen, Locke, Adam E, Fuchsberger, Christian, Service, Susan K, Erdos, Michael R, Bonnycastle, Lori L, Kuusisto, Johanna, Stitziel, Nathan O, Hall, Ira M, Morrison, Jean, Ripatti, Samuli, Palotie, Aarno, Freimer, Nelson B, Collins, Francis S, Mohlke, Karen L, Scott, Laura J, Fauman, Eric B, Burant, Charles, Boehnke, Michael, Laakso, Markku, and Wen, Xiaoquan

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Medical Biochemistry and Metabolomics, Nutrition, Biotechnology, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Bilirubin, Carnitine, Genome-Wide Association Study, Glycerophospholipids, Humans, Male, Metabolomics, Quantitative Trait Loci, Solute Carrier Family 22 Member 5, Transcriptome, FinnGen, colocalizataion, genome-wide association study, metabolomics, transcriptome-wide association study, transcriptomics, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.

Published
2022

5. Association of Systemic Vascular Resistance Analog and Cardiovascular Outcomes: The Heart and Soul Study

Author

Lu, Dai‐Yin, Fang, Qizhi, Bibby, Dwight, Arora, Bhaskar, and Schiller, Nelson B

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Heart Disease, Clinical Research, Cardiovascular, Hypertension, Aged, Coronary Artery Disease, Female, Heart Failure, Heart Ventricles, Humans, Male, Middle Aged, Prognosis, Vascular Resistance, blood pressure, child, CIs, coronary artery disease, follow-up studies, humans, male sex, prognosis, follow‐up studies, Cardiorespiratory Medicine and Haematology, Cardiovascular medicine and haematology
Abstract

Background Systemic vascular resistance (SVR) is an integral component of the hemodynamic profile. Previous studies have demonstrated a close correlation between an estimated SVR analog (eSVR) based on echocardiographic methods and SVR by direct hemodynamic measurement. However, the prognostic impact of eSVR remains unestablished. Methods and Results Study participants with established coronary artery disease from the Heart and Soul Study formed this study cohort. We defined Doppler-derived eSVR as the ratio of systolic blood pressure to left ventricular outflow tract velocity time integral. Study participants were separated based on baseline eSVR tertile:

Published
2022

6. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Author

Palmer, Duncan S, Howrigan, Daniel P, Chapman, Sinéad B, Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco PM, Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden P, Craddock, Nicholas, Curtis, David, Di Florio, Arianna, Dickerson, Faith, Freimer, Nelson B, Goes, Fernando S, Jia, Xiaoming, Jones, Ian, Jones, Lisa, Jonsson, Lina, Kahn, Rene S, Landén, Mikael, Locke, Adam E, McIntosh, Andrew M, McQuillin, Andrew, Morris, Derek W, O’Donovan, Michael C, Ophoff, Roel A, Owen, Michael J, Pedersen, Nancy L, Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan W, Solomonson, Matthew, Clair, David St, Stahl, Eli A, Vreeker, Annabel, Walters, James TR, Wang, Weiqing, Watts, Nicholas A, Yolken, Robert, Zandi, Peter P, and Neale, Benjamin M

Subjects
Biotechnology, Human Genome, Clinical Research, Serious Mental Illness, Schizophrenia, Brain Disorders, Bipolar Disorder, Mental Health, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, A Kinase Anchor Proteins, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Exome Sequencing, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Published
2022

7. Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Author

Trubetskoy, Vassily, Pardiñas, Antonio F, Qi, Ting, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Bigdeli, Tim B, Bryois, Julien, Chen, Chia-Yen, Dennison, Charlotte A, Hall, Lynsey S, Lam, Max, Watanabe, Kyoko, Frei, Oleksandr, Ge, Tian, Harwood, Janet C, Koopmans, Frank, Magnusson, Sigurdur, Richards, Alexander L, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Grove, Jakob, Kim, Minsoo, Li, Zhiqiang, Voloudakis, Georgios, Zhang, Wen, Adams, Mark, Agartz, Ingrid, Atkinson, Elizabeth G, Agerbo, Esben, Al Eissa, Mariam, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z, Alptekin, Köksal, Als, Thomas D, Amin, Farooq, Arolt, Volker, Arrojo, Manuel, Athanasiu, Lavinia, Azevedo, Maria Helena, Bacanu, Silviu A, Bass, Nicholas J, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Benyamin, Beben, Bergen, Sarah E, Blasi, Giuseppe, Bobes, Julio, Bonassi, Stefano, Braun, Alice, Bressan, Rodrigo Affonseca, Bromet, Evelyn J, Bruggeman, Richard, Buckley, Peter F, Buckner, Randy L, Bybjerg-Grauholm, Jonas, Cahn, Wiepke, Cairns, Murray J, Calkins, Monica E, Carr, Vaughan J, Castle, David, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond CK, Chaumette, Boris, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cohen, David, Consoli, Angèle, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Davidson, Michael, Davis, Kenneth L, de Haan, Lieuwe, Degenhardt, Franziska, DeLisi, Lynn E, Demontis, Ditte, Dickerson, Faith, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G, Fañanás, Lourdes, Faraone, Stephen V, Fiorentino, Alessia, Forstner, Andreas, Frank, Josef, Freimer, Nelson B, Fromer, Menachem, Frustaci, Alessandra, Gadelha, Ary, Genovese, Giulio, and Gershon, Elliot S

Subjects
Brain Disorders, Human Genome, Mental Health, Schizophrenia, Serious Mental Illness, Biotechnology, Neurosciences, Genetics, Aetiology, 2.1 Biological and endogenous factors, Alleles, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Indonesia Schizophrenia Consortium, PsychENCODE, Psychosis Endophenotypes International Consortium, SynGO Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

Published
2022

8. Rare coding variants in ten genes confer substantial risk for schizophrenia.

Author

Singh, Tarjinder, Poterba, Timothy, Curtis, David, Akil, Huda, Al Eissa, Mariam, Barchas, Jack D, Bass, Nicholas, Bigdeli, Tim B, Breen, Gerome, Bromet, Evelyn J, Buckley, Peter F, Bunney, William E, Bybjerg-Grauholm, Jonas, Byerley, William F, Chapman, Sinéad B, Chen, Wei J, Churchhouse, Claire, Craddock, Nicholas, Cusick, Caroline M, DeLisi, Lynn, Dodge, Sheila, Escamilla, Michael A, Eskelinen, Saana, Fanous, Ayman H, Faraone, Stephen V, Fiorentino, Alessia, Francioli, Laurent, Gabriel, Stacey B, Gage, Diane, Gagliano Taliun, Sarah A, Ganna, Andrea, Genovese, Giulio, Glahn, David C, Grove, Jakob, Hall, Mei-Hua, Hämäläinen, Eija, Heyne, Henrike O, Holi, Matti, Hougaard, David M, Howrigan, Daniel P, Huang, Hailiang, Hwu, Hai-Gwo, Kahn, René S, Kang, Hyun Min, Karczewski, Konrad J, Kirov, George, Knowles, James A, Lee, Francis S, Lehrer, Douglas S, Lescai, Francesco, Malaspina, Dolores, Marder, Stephen R, McCarroll, Steven A, McIntosh, Andrew M, Medeiros, Helena, Milani, Lili, Morley, Christopher P, Morris, Derek W, Mortensen, Preben Bo, Myers, Richard M, Nordentoft, Merete, O'Brien, Niamh L, Olivares, Ana Maria, Ongur, Dost, Ouwehand, Willem H, Palmer, Duncan S, Paunio, Tiina, Quested, Digby, Rapaport, Mark H, Rees, Elliott, Rollins, Brandi, Satterstrom, F Kyle, Schatzberg, Alan, Scolnick, Edward, Scott, Laura J, Sharp, Sally I, Sklar, Pamela, Smoller, Jordan W, Sobell, Janet L, Solomonson, Matthew, Stahl, Eli A, Stevens, Christine R, Suvisaari, Jaana, Tiao, Grace, Watson, Stanley J, Watts, Nicholas A, Blackwood, Douglas H, Børglum, Anders D, Cohen, Bruce M, Corvin, Aiden P, Esko, Tõnu, Freimer, Nelson B, Glatt, Stephen J, Hultman, Christina M, McQuillin, Andrew, Palotie, Aarno, Pato, Carlos N, Pato, Michele T, Pulver, Ann E, and St Clair, David

Subjects
Humans, Genetic Predisposition to Disease, Receptors, N-Methyl-D-Aspartate, Case-Control Studies, Schizophrenia, Mutation, Exome, Neurodevelopmental Disorders, Human Genome, Biotechnology, Mental Health, Neurosciences, Brain Disorders, Genetics, Serious Mental Illness, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, General Science & Technology
Abstract

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

Published
2022

9. Epigenetic clock and methylation studies in vervet monkeys.

Author

Jasinska, Anna J, Haghani, Amin, Zoller, Joseph A, Li, Caesar Z, Arneson, Adriana, Ernst, Jason, Kavanagh, Kylie, Jorgensen, Matthew J, Mattison, Julie A, Wojta, Kevin, Choi, Oi-Wa, DeYoung, Joseph, Li, Xinmin, Rao, Andrew W, Coppola, Giovanni, Freimer, Nelson B, Woods, Roger P, and Horvath, Steve

Subjects
Animals, Mammals, Macaca mulatta, DNA Methylation, Epigenesis, Genetic, Longevity, Epigenomics, Chlorocebus aethiops, Aging, DNA methylation, Development, Epigenetic clock, Monkey, Vervet, Genetics, Biotechnology, Digestive Diseases, Underpinning research, 1.1 Normal biological development and functioning
Abstract

DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.

Published
2022

10. Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

Author

Chani J. Hodonsky, Adam W. Turner, Mohammad Daud Khan, Nelson B. Barrientos, Ruben Methorst, Lijiang Ma, Nicolas G. Lopez, Jose Verdezoto Mosquera, Gaëlle Auguste, Emily Farber, Wei Feng Ma, Doris Wong, Suna Onengut-Gumuscu, Maryam Kavousi, Patricia A. Peyser, Sander W. van der Laan, Nicholas J. Leeper, Jason C. Kovacic, Johan L.M. Björkegren, and Clint L. Miller

Subjects
eQTL, genetic diversity, coronary artery, RNA-seq, fine-mapping, gene regulation, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract

Summary: Genome-wide association studies (GWASs) have identified hundreds of risk loci for coronary artery disease (CAD). However, non-European populations are underrepresented in GWASs, and the causal gene-regulatory mechanisms of these risk loci during atherosclerosis remain unclear. We incorporated local ancestry and haplotypes to identify quantitative trait loci for expression (eQTLs) and splicing (sQTLs) in coronary arteries from 138 ancestrally diverse Americans. Of 2,132 eQTL-associated genes (eGenes), 47% were previously unreported in coronary artery; 19% exhibited cell-type-specific expression. Colocalization revealed subgroups of eGenes unique to CAD and blood pressure GWAS. Fine-mapping highlighted additional eGenes, including TBX20 and IL5. We also identified sQTLs for 1,690 genes, among which TOR1AIP1 and ULK3 sQTLs demonstrated the importance of evaluating splicing to accurately identify disease-relevant isoform expression. Our work provides a patient-derived coronary artery eQTL resource and exemplifies the need for diverse study populations and multifaceted approaches to characterize gene regulation in disease processes.

Published
2024
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11. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

Author

Yin, Xianyong, Chan, Lap Sum, Bose, Debraj, Jackson, Anne U, VandeHaar, Peter, Locke, Adam E, Fuchsberger, Christian, Stringham, Heather M, Welch, Ryan, Yu, Ketian, Fernandes Silva, Lilian, Service, Susan K, Zhang, Daiwei, Hector, Emily C, Young, Erica, Ganel, Liron, Das, Indraniel, Abel, Haley, Erdos, Michael R, Bonnycastle, Lori L, Kuusisto, Johanna, Stitziel, Nathan O, Hall, Ira M, Wagner, Gregory R, Kang, Jian, Morrison, Jean, Burant, Charles F, Collins, Francis S, Ripatti, Samuli, Palotie, Aarno, Freimer, Nelson B, Mohlke, Karen L, Scott, Laura J, Wen, Xiaoquan, Fauman, Eric B, Laakso, Markku, and Boehnke, Michael

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Medical Biochemistry and Metabolomics, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Alleles, Finland, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Phenotype, Polymorphism, Single Nucleotide, FinnGen
Abstract

Few studies have explored the impact of rare variants (minor allele frequency

Published
2022

12. Reduced etch lag and high aspect ratios by deep reactive ion etching (DRIE)

Author

Gerlt, M. S., Läubli, N. F., Manser, M., Nelson, B. J., and Dual, J.

Subjects
Physics - Plasma Physics, Physics - Applied Physics
Abstract

Deep reactive ion etching (DRIE) with the Bosch process is one of the key procedures used to manufacture micron-sized structures for MEMS and microfluidic applications in silicon and, hence, of increasing importance for miniaturization in biomedical research. While guaranteeing high aspect ratio structures and providing high design flexibility, the etching procedure suffers from reactive ion etching lag and often relies on complex oxide masks to enable deep etching. In this work, we introduce an optimized Bosch process that reduces the etch lag to below 1.5 %. Furthermore, we improved a three-step Bosch process, allowing the fabrication of structures with 6 micrometre thickness at depths up to 180 micrometre while maintaining their stability.

Published
2021
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13. On the structure of Ag-containing sol-gel bioactive glasses: A surface crystal growth of metallic silver removes its network modifier role in the glass structure

Author

Roger Borges, Juliana S.S. Oliveira, Antônia P. Queiroz, Telma Zambanini, Akiko M. Hanashiro, Nelson B. Lima, José F. Schneider, and Juliana Marchi

Subjects
Silver, Bioactive glass, Sol-gel synthesis, Structural characterization, Clay industries. Ceramics. Glass, TP785-869
Abstract

Ag-containing bioactive glasses (Ag-BG) have been extensively studied as a bactericidal biomaterial, produced mainly by the sol-gel method over the last decades. According to the literature, sol-gel-derived Ag-BG may show metallic or ionic silver species in the glass structure. However, most of these works lack detailed information about how the addition of silver affects the glass network. In this study, we systematically produced sol-gel derived 58S glasses containing different quantities of Ag2O (1, 5, and 10 wt%), yielding glasses with different proportions of silver species (Ag0 or Ag+1). Results from X-ray diffraction and scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS) evidenced the progressive formation of silver crystals due to the addition of silver in the glass structure. 29Si and 31P nuclear magnetic resonance and photoelectronic X-ray spectroscopies evidenced a glass depolymerization caused by Ag1+ addition in the glass structure. On the other hand, the presence of silver crystals (Ag0) removes the network modifier role of silver, yielding glasses with higher network connectivity. A possible mechanism to explain the formation of silver crystals was proposed based on surface nucleation and growth. Finally, we suggest understanding Ag1+ or Ag0 formation as a solution to design glasses with tuned bactericidal properties.

Published
2023
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14. Evaluating the mouse neural precursor line, SN4741, as a suitable proxy for midbrain dopaminergic neurons

Author

Rachel J. Boyd, Sarah A. McClymont, Nelson B. Barrientos, Paul W. Hook, William D. Law, Rebecca J. Rose, Eric L. Waite, Jay Rathinavelu, Dimitrios Avramopoulos, and Andrew S. McCallion

Subjects
Parkinson disease, Mouse-derived cell lines, Immortalized cell lines, Chromatin accessibility, RNA-seq, ATAC-seq, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract To overcome the ethical and technical limitations of in vivo human disease models, the broader scientific community frequently employs model organism-derived cell lines to investigate disease mechanisms, pathways, and therapeutic strategies. Despite the widespread use of certain in vitro models, many still lack contemporary genomic analysis supporting their use as a proxy for the affected human cells and tissues. Consequently, it is imperative to determine how accurately and effectively any proposed biological surrogate may reflect the biological processes it is assumed to model. One such cellular surrogate of human disease is the established mouse neural precursor cell line, SN4741, which has been used to elucidate mechanisms of neurotoxicity in Parkinson disease for over 25 years. Here, we are using a combination of classic and contemporary genomic techniques – karyotyping, RT-qPCR, single cell RNA-seq, bulk RNA-seq, and ATAC-seq – to characterize the transcriptional landscape, chromatin landscape, and genomic architecture of this cell line, and evaluate its suitability as a proxy for midbrain dopaminergic neurons in the study of Parkinson disease. We find that SN4741 cells possess an unstable triploidy and consistently exhibits low expression of dopaminergic neuron markers across assays, even when the cell line is shifted to the non-permissive temperature that drives differentiation. The transcriptional signatures of SN4741 cells suggest that they are maintained in an undifferentiated state at the permissive temperature and differentiate into immature neurons at the non-permissive temperature; however, they may not be dopaminergic neuron precursors, as previously suggested. Additionally, the chromatin landscapes of SN4741 cells, in both the differentiated and undifferentiated states, are not concordant with the open chromatin profiles of ex vivo, mouse E15.5 forebrain- or midbrain-derived dopaminergic neurons. Overall, our data suggest that SN4741 cells may reflect early aspects of neuronal differentiation but are likely not a suitable proxy for dopaminergic neurons as previously thought. The implications of this study extend broadly, illuminating the need for robust biological and genomic rationale underpinning the use of in vitro models of molecular processes.

Published
2023
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15. Multi-ancestry genetic analysis of gene regulation in coronary arteries prioritizes disease risk loci

Author

Hodonsky, Chani J., Turner, Adam W., Khan, Mohammad Daud, Barrientos, Nelson B., Methorst, Ruben, Ma, Lijiang, Lopez, Nicolas G., Mosquera, Jose Verdezoto, Auguste, Gaëlle, Farber, Emily, Ma, Wei Feng, Wong, Doris, Onengut-Gumuscu, Suna, Kavousi, Maryam, Peyser, Patricia A., van der Laan, Sander W., Leeper, Nicholas J., Kovacic, Jason C., Björkegren, Johan L.M., and Miller, Clint L.

Published
2024
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16. Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Author

Lam, Max, Chen, Chia-Yen, Ge, Tian, Xia, Yan, Hill, David W, Trampush, Joey W, Yu, Jin, Knowles, Emma, Davies, Gail, Stahl, Eli A, Huckins, Laura, Liewald, David C, Djurovic, Srdjan, Melle, Ingrid, Christoforou, Andrea, Reinvang, Ivar, DeRosse, Pamela, Lundervold, Astri J, Steen, Vidar M, Espeseth, Thomas, Räikkönen, Katri, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Giegling, Ina, Konte, Bettina, Hartmann, Annette M, Roussos, Panos, Giakoumaki, Stella, Burdick, Katherine E, Payton, Antony, Ollier, William, Chiba-Falek, Ornit, Koltai, Deborah C, Need, Anna C, Cirulli, Elizabeth T, Voineskos, Aristotle N, Stefanis, Nikos C, Avramopoulos, Dimitrios, Hatzimanolis, Alex, Smyrnis, Nikolaos, Bilder, Robert M, Freimer, Nelson B, Cannon, Tyrone D, London, Edythe, Poldrack, Russell A, Sabb, Fred W, Congdon, Eliza, Conley, Emily Drabant, Scult, Matthew A, Dickinson, Dwight, Straub, Richard E, Donohoe, Gary, Morris, Derek, Corvin, Aiden, Gill, Michael, Hariri, Ahmad R, Weinberger, Daniel R, Pendleton, Neil, Bitsios, Panos, Rujescu, Dan, Lahti, Jari, Le Hellard, Stephanie, Keller, Matthew C, Andreassen, Ole A, Deary, Ian J, Glahn, David C, Huang, Hailiang, Liu, Chunyu, Malhotra, Anil K, and Lencz, Todd

Subjects
Humans, Nootropic Agents, Cognition, Schizophrenia, Genome-Wide Association Study, Transcriptome, Psychiatry, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

Published
2021

17. Health Equity Implications of Missing Data Among Youths With Childhood‐Onset Systemic Lupus Erythematosus: A Proof‐of‐Concept Study in the Childhood Arthritis and Rheumatology Research Alliance Registry

Author

Woo, Jennifer M. P., Simmonds, Faith, Dennos, Anne, Son, Mary Beth F., Lewandowski, Laura B., Rubinstein, Tamar B., Abel, N., Abulaban, K., Adams, A., Adams, M., Agbayani, R., Aiello, J., Akoghlanian, S., Alejandro, C., Allenspach, E., Alperin, R., Alpizar, M., Amarilyo, G., Ambler, W., Anderson, E., Ardoin, S., Armendariz, S., Baker, E., Balboni, I., Balevic, S., Ballenger, L., Ballinger, S., Balmuri, N., Barbar‐Smiley, F., Barillas‐Arias, L., Basiaga, M., Baszis, K., Becker, M., Bell‐Brunson, H., Beltz, E., Benham, H., Benseler, S., Bernal, W., Beukelman, T., Bigley, T., Binstadt, B., Black, C., Blakley, M., Bohnsack, J., Boland, J., Boneparth, A., Bowman, S., Bracaglia, C., Brooks, E., Brothers, M., Brown, A., Brunner, H., Buckley, M., Buckley, M., Bukulmez, H., Bullock, D., Cameron, B., Canna, S., Cannon, L., Carper, P., Cartwright, V., Cassidy, E., Cerracchio, L., Chalom, E., Chang, J., Chang‐Hoftman, A., Chauhan, V., Chira, P., Chinn, T., Chundru, K., Clairman, H., Co, D., Confair, A., Conlon, H., Connor, R., Cooper, A., Cooper, J., Cooper, S., Correll, C., Corvalan, R., Costanzo, D., Cron, R., Curiel‐Duran, L., Curington, T., Curry, M., Dalrymple, A., Davis, A., Davis, C., Davis, C., Davis, T., De Benedetti, F., De Ranieri, D., Dean, J., Dedeoglu, F., DeGuzman, M., Delnay, N., Dempsey, V., DeSantis, E., Dickson, T., Dingle, J., Donaldson, B., Dorsey, E., Dover, S., Dowling, J., Drew, J., Driest, K., Du, Q., Duarte, K., Durkee, D., Duverger, E., Dvergsten, J., Eberhard, A., Eckert, M., Ede, K., Edelheit, B., Edens, C., Edens, C., Edgerly, Y., Elder, M., Ervin, B., Fadrhonc, S., Failing, C., Fair, D., Falcon, M., Favier, L., Federici, S., Feldman, B., Fennell, J., Ferguson, I., Ferguson, P., Ferreira, B., Ferrucho, R., Fields, K., Finkel, T., Fitzgerald, M., Fleming, C., Flynn, O., Fogel, L., Fox, E., Fox, M., Franco, L., Freeman, M., Fritz, K., Froese, S., Fuhlbrigge, R., Fuller, J., George, N., Gerhold, K., Gerstbacher, D., Gilbert, M., Gillispie‐Taylor, M., Giverc, E., Godiwala, C., Goh, I., Goheer, H., Goldsmith, D., Gotschlich, E., Gotte, A., Gottlieb, B., Gracia, C., Graham, T., Grevich, S., Griffin, T., Griswold, J., Grom, A., Guevara, M., Guittar, P., Guzman, M., Hager, M., Hahn, T., Halyabar, O., Hammelev, E., Hance, M., Hanson, A., Harel, L., Haro, S., Harris, J., Harry, O., Hartigan, E., Hausmann, J., Hay, A., Hayward, K., Heiart, J., Hekl, K., Henderson, L., Henrickson, M., Hersh, A., Hickey, K., Hill, P., Hillyer, S., Hiraki, L., Hiskey, M., Hobday, P., Hoffart, C., Holland, M., Hollander, M., Hong, S., Horwitz, M., Hsu, J., Huber, A., Huggins, J., Hui‐Yuen, J., Hung, C., Huntington, J., Huttenlocher, A., Ibarra, M., Imundo, L., Inman, C., Insalaco, A., Jackson, A., Jackson, S., James, K., Janow, G., Jaquith, J., Jared, S., Johnson, N., Jones, J., Jones, J., Jones, J., Jones, K., Jones, S., Joshi, S., Jung, L., Justice, C., Justiniano, A., Karan, N., Kaufman, K., Kemp, A., Kessler, E., Khalsa, U., Kienzle, B., Kim, S., Kimura, Y., Kingsbury, D., Kitcharoensakkul, M., Klausmeier, T., Klein, K., Klein‐Gitelman, M., Kompelien, B., Kosikowski, A., Kovalick, L., Kracker, J., Kramer, S., Kremer, C., Lai, J., Lam, J., Lang, B., Lapidus, S., Lapin, B., Lasky, A., Latham, D., Lawson, E., Laxer, R., Lee, P., Lee, P., Lee, T., Lentini, L., Lerman, M., Levy, D., Li, S., Lieberman, S., Lim, L., Lin, C., Ling, N., Lingis, M., Lo, M., Lovell, D., Lowman, D., Luca, N., Lvovich, S., Madison, C., Madison, J., Manzoni, S. Magni, Malla, B., Maller, J., Malloy, M., Mannion, M., Manos, C., Marques, L., Martyniuk, A., Mason, T., Mathus, S., McAllister, L., McCarthy, K., McConnell, K., McCormick, E., McCurdy, D., Stokes, P. McCurdy, McGuire, S., McHale, I., McMonagle, A., McMullen‐Jackson, C., Meidan, E., Mellins, E., Mendoza, E., Mercado, R., Merritt, A., Michalowski, L., Miettunen, P., Miller, M., Milojevic, D., Mirizio, E., Misajon, E., Mitchell, M., Modica, R., Mohan, S., Moore, K., Moorthy, L., Morgan, S., Dewitt, E. Morgan, Moss, C., Moussa, T., Mruk, V., Murphy, A., Muscal, E., Nadler, R., Nahal, B., Nanda, K., Nasah, N., Nassi, L., Nativ, S., Natter, M., Neely, J., Nelson, B., Newhall, L., Ng, L., Nicholas, J., Nicolai, R., Nigrovic, P., Nocton, J., Nolan, B., Oberle, E., Obispo, B., OʼBrien, B., OʼBrien, T., Okeke, O., Oliver, M., Olson, J., OʼNeil, K., Onel, K., Orandi, A., Orlando, M., Osei‐Onomah, S., Oz, R., Pagano, E., Paller, A., Pan, N., Panupattanapong, S., Pardeo, M., Paredes, J., Parsons, A., Patel, J., Pentakota, K., Pepmueller, P., Pfeiffer, T., Phillippi, K., Phillippi, K., Marafon, D. Pires, Ponder, L., Pooni, R., Prahalad, S., Pratt, S., Protopapas, S., Puplava, B., Quach, J., Quinlan‐Waters, M., Rabinovich, C., Radhakrishna, S., Rafko, J., Raisian, J., Rakestraw, A., Ramirez, C., Ramsay, E., Ramsey, S., Randell, R., Reed, A., Reed, A., Reed, A., Reid, H., Remmel, K., Repp, A., Reyes, A., Richmond, A., Riebschleger, M., Ringold, S., Riordan, M., Riskalla, M., Ritter, M., Rivas‐Chacon, R., Robinson, A., Rodela, E., Rodriquez, M., Rojas, K., Ronis, T., Rosenkranz, M., Rosolowski, B., Rothermel, H., Rothman, D., Roth‐Wojcicki, E., Rouster‐Stevens, K., Rubinstein, T., Ruth, N., Saad, N., Sabbagh, S., Sacco, E., Sadun, R., Sandborg, C., Sanni, A., Santiago, L., Sarkissian, A., Savani, S., Scalzi, L., Schanberg, L., Scharnhorst, S., Schikler, K., Schlefman, A., Schmeling, H., Schmidt, K., Schmitt, E., Schneider, R., Schollaert‐Fitch, K., Schulert, G., Seay, T., Seper, C., Shalen, J., Sheets, R., Shelly, A., Shenoi, S., Shergill, K., Shirley, J., Shishov, M., Shivers, C., Silverman, E., Singer, N., Sivaraman, V., Sletten, J., Smith, A., Smith, C., Smith, J., Smith, J., Smitherman, E., Soep, J., Son, M., Spence, S., Spiegel, L., Spitznagle, J., Sran, R., Srinivasalu, H., Stapp, H., Steigerwald, K., Rakovchik, Y. Sterba, Stern, S., Stevens, A., Stevens, B., Stevenson, R., Stewart, K., Stingl, C., Stokes, J., Stoll, M., Stringer, E., Sule, S., Sumner, J., Sundel, R., Sutter, M., Syed, R., Syverson, G., Szymanski, A., Taber, S., Tal, R., Tambralli, A., Taneja, A., Tanner, T., Tapani, S., Tarshish, G., Tarvin, S., Tate, L., Taxter, A., Taylor, J., Terry, M., Tesher, M., Thatayatikom, A., Thomas, B., Tiffany, K., Ting, T., Tipp, A., Toib, D., Torok, K., Toruner, C., Tory, H., Toth, M., Tse, S., Tubwell, V., Twilt, M., Uriguen, S., Valcarcel, T., Van Mater, H., Vannoy, L., Varghese, C., Vasquez, N., Vazzana, K., Vehe, R., Veiga, K., Velez, J., Verbsky, J., Vilar, G., Volpe, N., von Scheven, E., Vora, S., Wagner, J., Wagner‐Weiner, L., Wahezi, D., Waite, H., Walker, J., Walters, H., Muskardin, T. Wampler, Waqar, L., Waterfield, M., Watson, M., Watts, A., Weiser, P., Weiss, J., Weiss, P., Wershba, E., White, A., Williams, C., Wise, A., Woo, J., Woolnough, L., Wright, T., Wu, E., Yalcindag, A., Yee, M., Yen, E., Yeung, R., Yomogida, K., Yu, Q., Zapata, R., Zartoshti, A., Zeft, A., Zeft, R., Zhang, Y., Zhao, Y., Zhu, A., and Zic, C.

Published
2023
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19. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, Forstner, Andreas J, O’Connell, Kevin S, Coombes, Brandon, Coleman, Jonathan RI, Qiao, Zhen, Als, Thomas D, Bigdeli, Tim B, Børte, Sigrid, Bryois, Julien, Charney, Alexander W, Drange, Ole Kristian, Gandal, Michael J, Hagenaars, Saskia P, Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M, Sloofman, Laura G, Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S, Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C, Bergen, Sarah E, Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P, Bosch, Rosa, Brum, Murielle, Brumpton, Ben M, Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M, Dale, Anders M, Dalkner, Nina, David, Friederike S, Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L, Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I Nicol, Fiorentino, Alessia, Foroud, Tatiana M, Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B, Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R, Gordon, Scott D, Gordon-Smith, Katherine, Greenwood, Tiffany A, Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A, Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S, and Kalman, Janos L

Subjects
Biological Sciences, Genetics, Biotechnology, Serious Mental Illness, Human Genome, Bipolar Disorder, Neurosciences, Brain Disorders, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Good Health and Well Being, Case-Control Studies, Chromosomes, Human, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Major Histocompatibility Complex, Multifactorial Inheritance, Phenotype, Quantitative Trait Loci, Risk Factors, HUNT All-In Psychiatry, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

20. Recovering individual-level spatial inference from aggregated binary data

Author

Walker, Nelson B., Hefley, Trevor J., Ballmann, Anne E., Russell, Robin E., and Walsh, Daniel P.

Subjects
Statistics - Methodology
Abstract

Binary regression models are commonly used in disciplines such as epidemiology and ecology to determine how spatial covariates influence individuals. In many studies, binary data are shared in a spatially aggregated form to protect privacy. For example, rather than reporting the location and result for each individual that was tested for a disease, researchers may report that a disease was detected or not detected within geopolitical units. Often, the spatial aggregation process obscures the values of response variables, spatial covariates, and locations of each individual, which makes recovering individual-level inference difficult. We show that applying a series of transformations, including a change of support, to a bivariate point process model allows researchers to recover individual-level inference for spatial covariates from spatially aggregated binary data. The series of transformations preserves the convenient interpretation of desirable binary regression models that are commonly applied to individual-level data. Using a simulation experiment, we compare the performance of our proposed method under varying types of spatial aggregation against the performance of standard approaches using the original individual-level data. We illustrate our method by modeling individual-level probability of infection using a data set that has been aggregated to protect an at-risk and endangered species of bats. Our simulation experiment and data illustration demonstrate the utility of the proposed method when access to original non-aggregated data is impractical or prohibited.

Published
2020

21. Association of structural variation with cardiometabolic traits in Finns

Author

Chen, Lei, Abel, Haley J, Das, Indraniel, Larson, David E, Ganel, Liron, Kanchi, Krishna L, Regier, Allison A, Young, Erica P, Kang, Chul Joo, Scott, Alexandra J, Chiang, Colby, Wang, Xinxin, Lu, Shuangjia, Christ, Ryan, Service, Susan K, Chiang, Charleston WK, Havulinna, Aki S, Kuusisto, Johanna, Boehnke, Michael, Laakso, Markku, Palotie, Aarno, Ripatti, Samuli, Freimer, Nelson B, Locke, Adam E, Stitziel, Nathan O, and Hall, Ira M

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Alleles, Cardiovascular Diseases, Cholesterol, DNA Copy Number Variations, Female, Finland, Genome, Human, Genomic Structural Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Promoter Regions, Genetic, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Pyruvic Acid, Serum Albumin, Human, Finnish population, cardiometabolic traits, genome-wide association study, structural variation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47 × 10-54) and is also associated with increased levels of total cholesterol (p = 1.22 × 10-28) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81 × 10-21) and alanine (p = 6.14 × 10-12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24 × 10-10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53 × 10-35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

Published
2021

22. Measuring the Orbital Parameters of Radial Velocity Systems in Mean Motion Resonance---a Case Study of HD 200964

Author

Rosenthal, M. M., Jacobson-Galan, W., Nelson, B., Murray-Clay, R. A., Burt, J. A., Holden, B., Chang, E., Kaaz, N., Yant, J., Butler, R. P., and Vogt, S. S.

Subjects
Astrophysics - Earth and Planetary Astrophysics
Abstract

The presence of mean motion resonances (MMRs) complicates analysis and fitting of planetary systems observed through the radial velocity (RV) technique. MMR can allow planets to remain stable in regions of phase space where strong planet-planet interactions would otherwise destabilize the system. These stable orbits can occupy small phase space volumes, allowing MMRs to strongly constrain system parameters, but making searches for stable orbital parameters challenging. Furthermore, libration of the resonant angle and dynamical interaction between the planets introduces another, long period variation into the observed RV signal, complicating analysis of the periods of the planets in the system. We discuss this phenomenon using the example of HD 200964. By searching through parameter space and numerically integrating each proposed set of planetary parameters to test for long term stability, we find stable solutions in the 7:5 and 3:2 MMRs in addition to the originally identified 4:3 MMR. The 7:5 configuration provides the best match to the data, while the 3:2 configuration provides the most easily understood formation scenario. In reanalysis of the originally published shorter-baseline data, we find fits in both the 4:3 and 3:2 resonances, but not the 7:5. Because the time baseline of the data is less than the resonant libration period, the current best fit to the data may not reflect the actual resonant configuration. In the absence of a full sample of the longer libration period, we find that it is of paramount importance to incorporate long term stability when fitting for the system's orbital configuration., Comment: 26 pages, 23 figures

Published
2019
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23. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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24. Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Author

Tsetsos, Fotis, Yu, Dongmei, Sul, Jae Hoon, Huang, Alden Y, Illmann, Cornelia, Osiecki, Lisa, Darrow, Sabrina M, Hirschtritt, Matthew E, Greenberg, Erica, Muller-Vahl, Kirsten R, Stuhrmann, Manfred, Dion, Yves, Rouleau, Guy A, Aschauer, Harald, Stamenkovic, Mara, Schlögelhofer, Monika, Sandor, Paul, Barr, Cathy L, Grados, Marco A, Singer, Harvey S, Nöthen, Markus M, Hebebrand, Johannes, Hinney, Anke, King, Robert A, Fernandez, Thomas V, Barta, Csaba, Tarnok, Zsanett, Nagy, Peter, Depienne, Christel, Worbe, Yulia, Hartmann, Andreas, Budman, Cathy L, Rizzo, Renata, Lyon, Gholson J, McMahon, William M, Batterson, James R, Cath, Danielle C, Malaty, Irene A, Okun, Michael S, Berlin, Cheston, Woods, Douglas W, Lee, Paul C, Jankovic, Joseph, Robertson, Mary M, Gilbert, Donald L, Brown, Lawrence W, Coffey, Barbara J, Dietrich, Andrea, Hoekstra, Pieter J, Kuperman, Samuel, Zinner, Samuel H, Wagner, Michael, Knowles, James A, Jeremy Willsey, A, Tischfield, Jay A, Heiman, Gary A, Cox, Nancy J, Freimer, Nelson B, Neale, Benjamin M, Davis, Lea K, Coppola, Giovanni, Mathews, Carol A, Scharf, Jeremiah M, Paschou, Peristera, Tourette Association of America International Consortium for Genetics, Darrow, Sabrina, Kurlan, Roger, Leckman, James F, Smit, Jan H, and Gilles de la Tourette GWAS Replication Initiative

Subjects
Tourette Association of America International Consortium for Genetics, Gilles de la Tourette GWAS Replication Initiative, Tourette International Collaborative Genetics Study, Psychiatric Genomics Consortium Tourette Syndrome Working Group, Neurons, Humans, Tourette Syndrome, Genotype, Genome-Wide Association Study, Mental Health, Genetics, Neurosciences, Human Genome, Brain Disorders, Biotechnology, Neurodegenerative, 2.1 Biological and endogenous factors, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Published
2021

25. Diversity matters: opportunities in the study of the genetics of psychotic disorders in low- and middle-income countries in Latin America

Author

Fonseca, Lais, Sena, Brena F, Crossley, Nicolas, Lopez-Jaramillo, Carlos, Koenen, Karestan, Freimer, Nelson B, Bressan, Rodrigo A, Belangero, Sintia I, Santoro, Marcos L, and Gadelha, Ary

Subjects
Clinical and Health Psychology, Biomedical and Clinical Sciences, Clinical Sciences, Psychology, Schizophrenia, Mental Health, Prevention, Human Genome, Genetics, Brain Disorders, Serious Mental Illness, Aetiology, 2.3 Psychological, social and economic factors, Mental health, Good Health and Well Being, Reduced Inequalities, Developing Countries, Ethnicity, Genome-Wide Association Study, Humans, Latin America, Psychotic Disorders, psychotic disorders, schizophrenia, genetics, environment, Psychiatry, Clinical sciences, Clinical and health psychology
Abstract

Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America's particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies.

Published
2021

26. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T.R., Farh, Kai-How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Jr., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberley D., Chan, Raymond C.K., Chan, Ronald Y.L., Chen, Eric Y.H., Cheng, Wei, Cheung, Eric FC., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Lee, Jimmy, Lee, S. Hong, Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K.E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Spencer, Chris C.A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H.M., Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H.R., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Nöthen, Markus M., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P., Rujescu, Dan, Sham, Pak C., Sklar, Pamela, St Clair, David, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Sullivan, Patrick F., O'Donovan, Michael C., Qin, Shengying, Sawa, Akira, Kahn, Rene, Hong, Kyung Sue, Shi, Wenzhao, Tsuang, Ming, Itokawa, Masanari, Feng, Gang, Glatt, Stephen J., Ma, Xiancang, Tang, Jinsong, Ruan, Yunfeng, Liu, Ruize, Zhu, Feng, Horiuchi, Yasue, Lee, Byung Dae, Joo, Eun-Jeong, Myung, Woojae, Ha, Kyooseob, Won, Hong-Hee, Baek, Ji Hyung, Chung, Young Chul, Kim, Sung-Wan, Kusumawardhani, Agung, Chen, Wei J., Hwu, Hai-Gwo, Hishimoto, Akitoyo, Otsuka, Ikuo, Sora, Ichiro, Toyota, Tomoko, Yoshikawa, Takeo, Kunugi, Hiroshi, Hattori, Kotaro, Ishiwata, Sayuri, Numata, Shusuke, Ohmori, Tetsuro, Arai, Makoto, Ozeki, Yuji, Fujii, Kumiko, Kim, Se Joo, Lee, Heon-Jeong, Ahn, Yong Min, Kim, Se Hyun, Akiyama, Kazufumi, Shimoda, Kazutaka, Kinoshita, Makoto, Hsu, Yu-Han H., Pintacuda, Greta, Nacu, Eugeniu, Kim, April, Tsafou, Kalliopi, Petrossian, Natalie, Crotty, William, Suh, Jung Min, Riseman, Jackson, Martin, Jacqueline M., Biagini, Julia C., Mena, Daya, Ching, Joshua K.T., Malolepsza, Edyta, Li, Taibo, Singh, Tarjinder, Ge, Tian, Egri, Shawn B., Tanenbaum, Benjamin, Stanclift, Caroline R., Apffel, Annie M., Carr, Steven A., Schenone, Monica, Jaffe, Jake, Fornelos, Nadine, Eggan, Kevin C., and Lage, Kasper

Published
2023
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27. Extensions of Multiple-Group Item Response Theory Alignment: Application to Psychiatric Phenotypes in an International Genomics Consortium

Author

Mansolf, Maxwell, Vreeker, Annabel, Reise, Steven P, Freimer, Nelson B, Glahn, David C, Gur, Raquel E, Moore, Tyler M, Pato, Carlos N, Pato, Michele T, Palotie, Aarno, Holm, Minna, Suvisaari, Jaana, Partonen, Timo, Kieseppä, Tuula, Paunio, Tiina, Boks, Marco, Kahn, René, Ophoff, Roel A, Bearden, Carrie E, Loohuis, Loes Olde, Teshiba, Terri, deGeorge, Daniella, Bilder, Robert M, Investigators, and Consortium, the WGSPD

Subjects
Applied and Developmental Psychology, Education, Specialist Studies In Education, Social and Personality Psychology, Psychology, Human Genome, Genetics, Mental health, Good Health and Well Being, test equating, differential item functioning, mega-analysis, harmonization, data integration, GROUP Investigators, WGSPD Consortium, Specialist Studies in Education, Social Sciences Methods, Specialist studies in education, Applied and developmental psychology, Social and personality psychology
Abstract

Large-scale studies spanning diverse project sites, populations, languages, and measurements are increasingly important to relate psychological to biological variables. National and international consortia already are collecting and executing mega-analyses on aggregated data from individuals, with different measures on each person. In this research, we show that Asparouhov and Muthén's alignment method can be adapted to align data from disparate item sets and response formats. We argue that with these adaptations, the alignment method is well suited for combining data across multiple sites even when they use different measurement instruments. The approach is illustrated using data from the Whole Genome Sequencing in Psychiatric Disorders consortium and a real-data-based simulation is used to verify accurate parameter recovery. Factor alignment appears to increase precision of measurement and validity of scores with respect to external criteria. The resulting parameter estimates may further inform development of more effective and efficient methods to assess the same constructs in prospectively designed studies.

Published
2020

28. Stroke in mitral valve prolapse: risk factors and left atrial function in cryptogenic versus non-cryptogenic ischemic subtypes

Author

Francesca Calicchio, Lisa J. Lim, Danielle Cross, Dwight Bibby, Qizhi Fang, Karl Meisel, Nelson B. Schiller, and Francesca N. Delling

Subjects
stroke, mitral valve prolapse (MVP), left atrial function, left atrial function index, echocardiography, cryptogenic stroke, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background and purposeMitral valve prolapse (MVP) has been associated with an increased risk of ischemic stroke. Older age, thicker mitral leaflets, and significant mitral regurgitation (MR) leading to atrial fibrillation have been traditionally considered risk factors for ischemic stroke in MVP. However, specific risk factors for MVP-stroke subtypes are not well defined. The aim of this study is to evaluate clinical and echocardiographic parameters, including left atrial (LA) function, in MVP with cryptogenic (C) vs. non-cryptogenic (NC) stroke.MethodsIn this case-control matched study, MVPs were identified in consecutive echocardiograms obtained after a stroke from January 2013 to December2016 at the University of California, San Francisco. MVP was defined as leaflet displacement ≥2 mm in the parasternal long-axis view at end-systole. Age/gender matched MVPs without stroke and healthy controls without MVP were also identified. We analyzed LA end-systolic/diastolic volume index, emptying fraction (LAEF), function index (LAFI), and global longitudinal strain in all MVPs and controls. We also measured left ventricular (LV) volume indexes, mass index, ejection fraction (EF), degree of MR and leaflet thickness.ResultsWe identified a total of 30 MVPs (age 70 ± 12, 50% females) with stroke (11 with C- and 19 with NC-stroke), 20 age/gender matched MVPs without a stroke and 16 controls. MVPs without stroke had lower BMI, less hypertension but more MR (≥moderate in 45% vs. 17%), more abnormal LA function (lower LAEF, LAFI) and larger LV volumes/mass (all p < 0.05) when compared to MVPs with stroke. Leaflet thickness was overall mild (

Published
2023
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29. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author

Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Jr., Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F. Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, and Makoto Kinoshita

Subjects
Molecular interaction, Developmental neuroscience, Cellular neuroscience, Proteomics, Science
Abstract

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Published
2023
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30. Distinct and shared contributions of diagnosis and symptom domains to cognitive performance in severe mental illness in the Paisa population: a case-control study

Author

Service, Susan K, Upegui, Cristian Vargas, Ramírez, Mauricio Castaño, Port, Allison M, Moore, Tyler M, Umanes, Marfred Munoz, Arango, Luis Guillermo Agudelo, Díaz-Zuluaga, Ana M, Espejo, Juanita Melo, López, María Cecilia, Palacio, Juan David, Sánchez, Sergio Ruiz, Valencia, Johanna, Teshiba, Terri M, Espinoza, Alesandra, Loohuis, Loes Olde, De la Hoz Gomez, Juan, Brodey, Benjamin B, Sabatti, Chiara, Escobar, Javier I, Reus, Victor I, Jaramillo, Carlos Lopez, Gur, Ruben C, Bearden, Carrie E, and Freimer, Nelson B

Subjects
Biological Psychology, Psychology, Applied and Developmental Psychology, Depression, Behavioral and Social Science, Bipolar Disorder, Neurosciences, Mental Health, Clinical Research, Brain Disorders, Schizophrenia, Serious Mental Illness, 2.1 Biological and endogenous factors, Aetiology, 2.3 Psychological, social and economic factors, 2.4 Surveillance and distribution, Mental health, Good Health and Well Being, Adult, Case-Control Studies, Cognition, Cognition Disorders, Colombia, Depressive Disorder, Major, Female, Humans, Linear Models, Male, Middle Aged, Schizophrenic Psychology, Young Adult, Clinical Sciences, Public Health and Health Services, Clinical sciences, Applied and developmental psychology, Clinical and health psychology
Abstract

BackgroundSevere mental illness diagnoses have overlapping symptomatology and shared genetic risk, motivating cross-diagnostic investigations of disease-relevant quantitative measures. We analysed relationships between neurocognitive performance, symptom domains, and diagnoses in a large sample of people with severe mental illness not ascertained for a specific diagnosis (cases), and people without mental illness (controls) from a single, homogeneous population.MethodsIn this case-control study, cases with severe mental illness were ascertained through electronic medical records at Clínica San Juan de Dios de Manizales (Manizales, Caldas, Colombia) and the Hospital Universitario San Vicente Fundación (Medellín, Antioquía, Colombia). Participants were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (CNB). Cases had structured interview-based diagnoses of schizophrenia, bipolar 1, bipolar 2, or major depressive disorder. Linear mixed models, using CNB tests as repeated measures, modelled neurocognition as a function of diagnosis, sex, and all interactions. Follow-up analyses in cases included symptom factor scores obtained from exploratory factor analysis of symptom data as main effects.FindingsBetween Oct 1, 2017, and Nov 1, 2019, 2406 participants (1689 cases [schizophrenia n=160; bipolar 1 disorder n=519; bipolar 2 disorder n=204; and major depressive disorder n=806] and 717 controls; mean age 39 years (SD 14); and 1533 female) were assessed. Participants with bipolar 1 disorder and schizophrenia had similar impairments in accuracy and speed across cognitive domains. Participants with bipolar 2 disorder and major depressive disorder performed similarly to controls, with subtle deficits in executive and social cognition. A three-factor model (psychosis, mania, and depression) best represented symptom data. Controlling for diagnosis, premorbid IQ, and disease severity, high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, whereas high depression scores were associated with increased social cognition accuracy.InterpretationCross-diagnostic investigations showed that neurocognitive function in severe mental illness is characterised by two distinct profiles (bipolar 1 disorder and schizophrenia, and bipolar 2 disorder and major depressive disorder), and is associated with specific symptom domains. These results suggest the utility of this design for elucidating severe mental illness causes and trajectories.FundingUS National Institute of Mental Health.

Published
2020

31. History of etidronate

Author

Watts, Nelson B, Chesnut, Charles H, Genant, Harry K, Harris, Steven T, Jackson, Rebecca D, Licata, Angelo A, Miller, Paul D, Mysiw, W Jerry, Richmond, Bradford, and Valent, David

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Dentistry, Rare Diseases, Dental/Oral and Craniofacial Disease, Aging, Osteoporosis, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Musculoskeletal, Bone Density, Bone Density Conservation Agents, Diphosphonates, Etidronic Acid, Female, History, 20th Century, History, 21st Century, Humans, Male, Osteitis Deformans, Osteoporosis, Postmenopausal, Bisphosphonates, Etidronate, Paget's disease, Fracture, Biological Sciences, Engineering, Medical and Health Sciences, Endocrinology & Metabolism, Clinical sciences
Abstract

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Published
2020

32. Left Atrial End-Diastolic Volume Index as a Predictor of Cardiovascular Outcomes

Author

Thadani, Samir R, Shaw, Richard E, Fang, Qizhi, Whooley, Mary A, and Schiller, Nelson B

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Cardiovascular, Heart Disease, Clinical Research, Heart Disease - Coronary Heart Disease, Good Health and Well Being, Aged, Cohort Studies, Diastole, Echocardiography, Female, Follow-Up Studies, Heart Atria, Heart Diseases, Heart Failure, Hospitalization, Humans, Male, Middle Aged, Myocardial Infarction, Organ Size, Outcome Assessment, Health Care, Predictive Value of Tests, Prospective Studies, Survival Analysis, cardiovascular diseases, echocardiography, heart failure, left atrium, myocardial infarction, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundThe left atrial end-systolic volume index (LAESVI) is a predictor of cardiovascular outcomes and is the recommended measurement of left atrial size. The left atrial end-diastolic volume index (LAEDVI), representing the minimum or residual left atrial volume, has not been fully evaluated as a predictor of cardiovascular events. This study evaluated the predictive power of LAEDVI compared with LAESVI for heart failure (HF) hospitalizations, a composite of HF hospitalizations, myocardial infarction, stroke, and heart disease death, and all-cause mortality.MethodsWe measured LAESVI and LAEDVI in subjects without atrial fibrillation or flutter or significant mitral valve disease. Using Cox proportional-hazard models, the association of LAESVI and LAEDVI with the stated outcomes was examined.ResultsAfter a mean of 7.3±2.6 years of follow-up, there were 147 HF hospitalizations, 118 myocardial infarctions, 45 strokes, 96 heart disease deaths, and 351 deaths from all causes in 938 subjects. When comparing the highest and the lowest quartiles of LAEDVI, there was a near 6-fold increase in the hazard ratio (HR) for HF hospitalization (HR, 5.96; P

Published
2020

33. Association of Machine Learning-Derived Phenogroupings of Echocardiographic Variables with Heart Failure in Stable Coronary Artery Disease: The Heart and Soul Study.

Author

Mishra, Rakesh K, Tison, Geoffrey H, Fang, Qizhi, Scherzer, Rebecca, Whooley, Mary A, and Schiller, Nelson B

Subjects
Humans, Echocardiography, Prognosis, Hospitalization, Risk Factors, Prospective Studies, Coronary Artery Disease, Heart Failure, Machine Learning, Heart failure, Machine learning, Stable coronary artery disease, Patient Safety, Heart Disease, Cardiovascular, Clinical Research, Atherosclerosis, Heart Disease - Coronary Heart Disease, 2.1 Biological and endogenous factors, Aetiology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
Abstract

BackgroundMany individual echocardiographic variables have been associated with heart failure (HF) in patients with stable coronary artery disease (CAD), but their combined utility for prediction has not been well studied.MethodsUnsupervised model-based cluster analysis was performed by researchers blinded to the study outcome in 1,000 patients with stable CAD on 15 transthoracic echocardiographic variables. We evaluated associations of cluster membership with HF hospitalization using Cox proportional hazards regression analysis.ResultsThe echo-derived clusters partitioned subjects into four phenogroupings: phenogroup 1 (n = 85) had the highest levels, phenogroups 2 (n = 314) and 3 (n = 205) displayed intermediate levels, and phenogroup 4 (n = 396) had the lowest levels of cardiopulmonary structural and functional abnormalities. Over 7.1 ± 3.2 years of follow-up, there were 198 HF hospitalizations. After multivariable adjustment for traditional cardiovascular risk factors, phenogroup 1 was associated with a nearly fivefold increased risk (hazard ratio [HR] = 4.8; 95% CI, 2.4-9.5), phenogroup 2 was associated with a nearly threefold increased risk (HR = 2.7; 95% CI, 1.4-5.0), and phenogroup 3 was associated with a nearly twofold increased risk (HR = 1.9; 95% CI, 1.0-3.8) of HF hospitalization, relative to phenogroup 4.ConclusionsTransthoracic echocardiographic variables can be used to classify stable CAD patients into separate phenogroupings that differentiate cardiopulmonary structural and functional abnormalities and can predict HF hospitalization, independent of traditional cardiovascular risk factors.

Published
2020

34. Immunosuppressive effect and global dysregulation of blood transcriptome in response to psychosocial stress in vervet monkeys (Chlorocebus sabaeus).

Author

Jasinska, Anna J, Pandrea, Ivona, He, Tianyu, Benjamin, Cassandra, Newton, Maurice, Lee, Jen Chieh, Freimer, Nelson B, Coppola, Giovanni, and Jentsch, James D

Abstract

Psychosocial stressors - life events that challenge social support and relationships - represent powerful risk factors for human disease; included amongst these events are relocation, isolation and displacement. To evaluate the impact of a controlled psychosocial stressor on physiology and underlying molecular pathways, we longitudinally studied the influence of a 28-day period of quarantine on biomarkers of immune signalling, microbial translocation, glycaemic health and blood transcriptome in the wild-born vervet monkey. This event caused a coordinated, mostly transient, reduction of circulating levels of nine immune signalling molecules. These were paralleled by a massive dysregulation of blood transcriptome, including genes implicated in chronic pathologies and immune functions. Immune and inflammatory functions were enriched among the genes downregulated in response to stress. An upregulation of genes involved in blood coagulation, platelet activation was characteristic of the rapid response to stress induction. Stress also decreased neutrophils and increased CD4 + T cell proportions in blood. This model of psychosocial stress, characterised by an immune dysregulation at the transcriptomic, molecular and cellular levels, creates opportunities to uncover the underlying mechanisms of stress-related diseases with an immune component, including cardiovascular diseases and susceptibility to infections.

Published
2020

35. Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Author

Sul, Jae Hoon, Service, Susan K, Huang, Alden Y, Ramensky, Vasily, Hwang, Sun-Goo, Teshiba, Terri M, Park, YoungJun, Ori, Anil PS, Zhang, Zhongyang, Mullins, Niamh, Olde Loohuis, Loes M, Fears, Scott C, Araya, Carmen, Araya, Xinia, Spesny, Mitzi, Bejarano, Julio, Ramirez, Margarita, Castrillón, Gabriel, Gomez-Makhinson, Juliana, Lopez, Maria C, Montoya, Gabriel, Montoya, Claudia P, Aldana, Ileana, Escobar, Javier I, Ospina-Duque, Jorge, Kremeyer, Barbara, Bedoya, Gabriel, Ruiz-Linares, Andres, Cantor, Rita M, Molina, Julio, Coppola, Giovanni, Ophoff, Roel A, Macaya, Gabriel, Lopez-Jaramillo, Carlos, Reus, Victor, Bearden, Carrie E, Sabatti, Chiara, and Freimer, Nelson B

Subjects
Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

Published
2020

36. Short Sleep Is Associated With Low Bone Mineral Density and Osteoporosis in the Women's Health Initiative

Author

Ochs‐Balcom, Heather M, Hovey, Kathleen M, Andrews, Christopher, Cauley, Jane A, Hale, Lauren, Li, Wenjun, Bea, Jennifer W, Sarto, Gloria E, Stefanick, Marcia L, Stone, Katie L, Watts, Nelson B, Zaslavsky, Oleg, and Wactawski‐Wende, Jean

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Clinical Sciences, Osteoporosis, Clinical Research, Aging, Sleep Research, Prevention, Musculoskeletal, Good Health and Well Being, Absorptiometry, Photon, Bone Density, Cross-Sectional Studies, Female, Humans, Middle Aged, Osteoporosis, Postmenopausal, Sleep, Time Factors, Women's Health, SLEEP, SLEEP DURATION, BONE, DUAL-ENERGY X-RAY ABSORPTIOMETRY, BONE DENSITY, OSTEOPOROSIS, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences
Abstract

Short sleep duration, recognized as a public health epidemic, is associated with adverse health conditions, yet little is known about the association between sleep and bone health. We tested the associations of usual sleep behavior and bone mineral density (BMD) and osteoporosis. In a sample of 11,084 postmenopausal women from the Women's Health Initiative (WHI; mean age 63.3 years, SD = 7.4), we performed a cross-sectional study of the association of self-reported usual hours of sleep and sleep quality (WHI Insomnia Rating Score) with whole body, total hip, femoral neck, and spine BMD using linear regression models. We also studied the association of sleep duration and quality with dual-energy X-ray absorptiometry (DXA)-defined low bone mass (T-score

Published
2020

37. ACE2 and TMPRSS2 variation in savanna monkeys (Chlorocebus spp.): Potential risk for zoonotic/anthroponotic transmission of SARS-CoV-2 and a potential model for functional studies.

Author

Schmitt, Christopher A, Bergey, Christina M, Jasinska, Anna J, Ramensky, Vasily, Burt, Felicity, Svardal, Hannes, Jorgensen, Matthew J, Freimer, Nelson B, Grobler, J Paul, and Turner, Trudy R

Subjects
Animals, Zoonoses, Pneumonia, Viral, Coronavirus Infections, Primate Diseases, Disease Susceptibility, Serine Endopeptidases, Peptidyl-Dipeptidase A, Pandemics, Spike Glycoprotein, Coronavirus, Whole Genome Sequencing, Betacoronavirus, Chlorocebus aethiops, Pneumonia, Viral, Spike Glycoprotein, Coronavirus, General Science & Technology
Abstract

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has devastated health infrastructure around the world. Both ACE2 (an entry receptor) and TMPRSS2 (used by the virus for spike protein priming) are key proteins to SARS-CoV-2 cell entry, enabling progression to COVID-19 in humans. Comparative genomic research into critical ACE2 binding sites, associated with the spike receptor binding domain, has suggested that African and Asian primates may also be susceptible to disease from SARS-CoV-2 infection. Savanna monkeys (Chlorocebus spp.) are a widespread non-human primate with well-established potential as a bi-directional zoonotic/anthroponotic agent due to high levels of human interaction throughout their range in sub-Saharan Africa and the Caribbean. To characterize potential functional variation in savanna monkey ACE2 and TMPRSS2, we inspected recently published genomic data from 245 savanna monkeys, including 163 wild monkeys from Africa and the Caribbean and 82 captive monkeys from the Vervet Research Colony (VRC). We found several missense variants. One missense variant in ACE2 (X:14,077,550; Asp30Gly), common in Ch. sabaeus, causes a change in amino acid residue that has been inferred to reduce binding efficiency of SARS-CoV-2, suggesting potentially reduced susceptibility. The remaining populations appear as susceptible as humans, based on these criteria for receptor usage. All missense variants observed in wild Ch. sabaeus populations are also present in the VRC, along with two splice acceptor variants (at X:14,065,076) not observed in the wild sample that are potentially disruptive to ACE2 function. The presence of these variants in the VRC suggests a promising model for SARS-CoV-2 infection and vaccine and therapy development. In keeping with a One Health approach, characterizing actual susceptibility and potential for bi-directional zoonotic/anthroponotic transfer in savanna monkey populations may be an important consideration for controlling COVID-19 epidemics in communities with frequent human/non-human primate interactions that, in many cases, may have limited health infrastructure.

Published
2020

38. ForestQC: Quality control on genetic variants from next-generation sequencing data using random forest.

Author

Li, Jiajin, Jew, Brandon, Zhan, Lingyu, Hwang, Sungoo, Coppola, Giovanni, Freimer, Nelson B, and Sul, Jae Hoon

Subjects
Humans, Computational Biology, Polymorphism, Single Nucleotide, Algorithms, Quality Control, Software, Databases, Genetic, Genetic Variation, High-Throughput Nucleotide Sequencing, Machine Learning, Whole Genome Sequencing, Polymorphism, Single Nucleotide, Databases, Genetic, Mathematical Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract

Next-generation sequencing technology (NGS) enables the discovery of nearly all genetic variants present in a genome. A subset of these variants, however, may have poor sequencing quality due to limitations in NGS or variant callers. In genetic studies that analyze a large number of sequenced individuals, it is critical to detect and remove those variants with poor quality as they may cause spurious findings. In this paper, we present ForestQC, a statistical tool for performing quality control on variants identified from NGS data by combining a traditional filtering approach and a machine learning approach. Our software uses the information on sequencing quality, such as sequencing depth, genotyping quality, and GC contents, to predict whether a particular variant is likely to be false-positive. To evaluate ForestQC, we applied it to two whole-genome sequencing datasets where one dataset consists of related individuals from families while the other consists of unrelated individuals. Results indicate that ForestQC outperforms widely used methods for performing quality control on variants such as VQSR of GATK by considerably improving the quality of variants to be included in the analysis. ForestQC is also very efficient, and hence can be applied to large sequencing datasets. We conclude that combining a machine learning algorithm trained with sequencing quality information and the filtering approach is a practical approach to perform quality control on genetic variants from sequencing data.

Published
2019

39. Genetic architecture of human plasma lipidome and its link to cardiovascular disease.

Author

Tabassum, Rubina, Rämö, Joel T, Ripatti, Pietari, Koskela, Jukka T, Kurki, Mitja, Karjalainen, Juha, Palta, Priit, Hassan, Shabbeer, Nunez-Fontarnau, Javier, Kiiskinen, Tuomo TJ, Söderlund, Sanni, Matikainen, Niina, Gerl, Mathias J, Surma, Michal A, Klose, Christian, Stitziel, Nathan O, Laivuori, Hannele, Havulinna, Aki S, Service, Susan K, Salomaa, Veikko, Pirinen, Matti, FinnGen Project, Jauhiainen, Matti, Daly, Mark J, Freimer, Nelson B, Palotie, Aarno, Taskinen, Marja-Riitta, Simons, Kai, and Ripatti, Samuli

Subjects
FinnGen Project, Plasma, Humans, Cardiovascular Diseases, Lipids, Genome-Wide Association Study, Lipidomics
Abstract

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P

Published
2019

40. Echocardiographic determination of pulmonary arterial capacitance.

Author

Papolos, Alexander, Fan, Eugene, Wagle, Rohan R, Foster, Elyse, Boyle, Andrew J, Yeghiazarians, Yerem, MacGregor, John S, Grossman, William, Schiller, Nelson B, Ganz, Peter, and Tison, Geoffrey H

Subjects
Pulmonary Artery, Humans, Hypertension, Pulmonary, Echocardiography, Doppler, Stroke Volume, Prognosis, Prospective Studies, Predictive Value of Tests, Vascular Capacitance, Pulmonary Circulation, Ventricular Function, Right, Adult, Aged, Middle Aged, Female, Male, Cardiac Catheterization, Arterial Pressure, Echocardiography, Heart failure, Imaging and diagnostics, Pulmonary hypertension, Clinical Research, Cardiovascular, Heart Disease, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Cardiorespiratory Medicine and Haematology, Nuclear Medicine & Medical Imaging
Abstract

A growing body of evidence has demonstrated that pulmonary arterial capacitance (PAC) is the strongest hemodynamic predictor of clinical outcomes across a wide spectrum of cardiovascular disease, including pulmonary hypertension and heart failure. We hypothesized that a ratio of right ventricular stroke volume (RVOT VTI) to the associated peak arterial systolic pressure (PASP) could function as a reliable non-invasive surrogate for PAC. We performed a prospective study of patients undergoing simultaneous transthoracic echocardiography and right heart catheterization (RHC) for various clinical indications. Measurements of the RVOT VTI/PASP ratio from echocardiographic measurements were compared against PAC calculated from RHC measurements. Correlation coefficients and Bland-Altman analysis compared the RVOT VTI/PASP ratio with PAC. Forty-five subjects were enrolled, 38% were female and mean age was 54 years (SD 13 years). The reason for referral to RHC was most commonly post-heart transplant surveillance (40%), followed by heart failure (22%), and pulmonary hypertension (18%). Pre-capillary pulmonary hypertension was present in 18%, isolated post-capillary pulmonary hypertension was present in 13%, and combined pre-and post-capillary pulmonary hypertension was present in 29%. The RVOT VTI/PASP ratio was obtainable in the majority of patients (78%), and Pearson's correlation demonstrated moderately-strong association between PAC and the RVOT VTI/PASP ratio, r = 0.75 (P

Published
2019

41. Exome sequencing of Finnish isolates enhances rare-variant association power

Author

Locke, Adam E, Steinberg, Karyn Meltz, Chiang, Charleston WK, Service, Susan K, Havulinna, Aki S, Stell, Laurel, Pirinen, Matti, Abel, Haley J, Chiang, Colby C, Fulton, Robert S, Jackson, Anne U, Kang, Chul Joo, Kanchi, Krishna L, Koboldt, Daniel C, Larson, David E, Nelson, Joanne, Nicholas, Thomas J, Pietilä, Arto, Ramensky, Vasily, Ray, Debashree, Scott, Laura J, Stringham, Heather M, Vangipurapu, Jagadish, Welch, Ryan, Yajnik, Pranav, Yin, Xianyong, Eriksson, Johan G, Ala-Korpela, Mika, Järvelin, Marjo-Riitta, Männikkö, Minna, Laivuori, Hannele, Dutcher, Susan K, Stitziel, Nathan O, Wilson, Richard K, Hall, Ira M, Sabatti, Chiara, Palotie, Aarno, Salomaa, Veikko, Laakso, Markku, Ripatti, Samuli, Boehnke, Michael, and Freimer, Nelson B

Subjects
Medical Biochemistry and Metabolomics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Alleles, Cholesterol, HDL, Cluster Analysis, Endpoint Determination, Finland, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Geographic Mapping, Humans, Multifactorial Inheritance, Quantitative Trait Loci, Reproducibility of Results, Exome Sequencing, FinnGen Project, General Science & Technology
Abstract

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

Published
2019

42. Correlations between processing technology, microstructure and properties of a Ni-rich Ti–Ni shape memory alloy

Author

Eduardo M. Sashihara, Pedro N. Inoue, Odair D. Rigo, Nelson B. Lima, and Jorge Otubo

Subjects
Ni–Ti Forming, Microstructure and properties, Martensitic transformation, Mining engineering. Metallurgy, TN1-997
Abstract

A Ti-50.8Ni (at.%)/Ti-55.9Ni (wt.%) VIM processed ingot was rotary swaged and rolled in parallel, obtaining bars with a total Area Reduction above 90% (from forged/rolled raw state one). Throughout the successive stages, the microstructural evolution, thermal and mechanical properties were compared. Deformation bands, grain morphology, precipitates and oxidation were evaluated (by OM and SEM/EDS). An essentially (∼100%) austenitic phase was detected at room temperature (via XRD/Rietveld method), while the Martensitic Transformation temperatures occurred at negative temperatures (via DSC). The rolled bar got through the process more regularly, with homogeneous and refined structure. Typical defects such as superficial microcracks and creases were relevant in the last stages of the two-dies rotary swaging with inductive heating. The work hardening level (via Hardness Test) was similar in both metal forming processes, being 5–7% more pronounced at the edge area of the bars due to redundant work.

Published
2022
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43. Childhood‐Onset Lupus Nephritis in the Childhood Arthritis and Rheumatology Research Alliance Registry: Short‐Term Kidney Status and Variation in Care

Author

Smitherman, Emily A., Chahine, Rouba A., Beukelman, Timothy, Lewandowski, Laura B., Rahman, A. K. M. Fazlur, Wenderfer, Scott E., Curtis, Jeffrey R., Hersh, Aimee O., Abel, N., Abulaban, K., Adams, A., Adams, M., Agbayani, R., Aiello, J., Akoghlanian, S., Alejandro, C., Allenspach, E., Alperin, R., Alpizar, M., Amarilyo, G., Ambler, W., Anderson, E., Ardoin, S., Armendariz, S., Baker, E., Balboni, I., Balevic, S., Ballenger, L., Ballinger, S., Balmuri, N., Barbar‐Smiley, F., Barillas‐Arias, L., Basiaga, M., Baszis, K., Becker, M., Bell‐Brunson, H., Beltz, E., Benham, H., Benseler, S., Bernal, W., Beukelman, T., Bigley, T., Binstadt, B., Black, C., Blakley, M., Bohnsack, J., Boland, J., Boneparth, A., Bowman, S., Bracaglia, C., Brooks, E., Brothers, M., Brown, A., Brunner, H., Buckley, M., Buckley, M., Bukulmez, H., Bullock, D., Cameron, B., Canna, S., Cannon, L., Carper, P., Cartwright, V., Cassidy, E., Cerracchio, L., Chalom, E., Chang, J., Chang‐Hoftman, A., Chauhan, V., Chira, P., Chinn, T., Chundru, K., Clairman, H., Co, D., Confair, A., Conlon, H., Connor, R., Cooper, A., Cooper, J., Cooper, S., Correll, C., Corvalan, R., Costanzo, D., Cron, R., Curiel‐Duran, L., Curington, T., Curry, M., Dalrymple, A., Davis, A., Davis, C., Davis, C., Davis, T., De Benedetti, F., De Ranieri, D., Dean, J., Dedeoglu, F., DeGuzman, M., Delnay, N., Dempsey, V., DeSantis, E., Dickson, T., Dingle, J., Donaldson, B., Dorsey, E., Dover, S., Dowling, J., Drew, J., Driest, K., Du, Q., Duarte, K., Durkee, D., Duverger, E., Dvergsten, J., Eberhard, A., Eckert, M., Ede, K., Edelheit, B., Edens, C., Edens, C., Edgerly, Y., Elder, M., Ervin, B., Fadrhonc, S., Failing, C., Fair, D., Falcon, M., Favier, L., Federici, S., Feldman, B., Fennell, J., Ferguson, I., Ferguson, P., Ferreira, B., Ferrucho, R., Fields, K., Finkel, T., Fitzgerald, M., Fleming, C., Flynn, O., Fogel, L., Fox, E., Fox, M., Franco, L., Freeman, M., Fritz, K., Froese, S., Fuhlbrigge, R., Fuller, J., George, N., Gerhold, K., Gerstbacher, D., Gilbert, M., Gillispie‐Taylor, M., Giverc, E., Godiwala, C., Goh, I., Goheer, H., Goldsmith, D., Gotschlich, E., Gotte, A., Gottlieb, B., Gracia, C., Graham, T., Grevich, S., Griffin, T., Griswold, J., Grom, A., Guevara, M., Guittar, P., Guzman, M., Hager, M., Hahn, T., Halyabar, O., Hammelev, E., Hance, M., Hanson, A., Harel, L., Haro, S., Harris, J., Harry, O., Hartigan, E., Hausmann, J., Hay, A., Hayward, K., Heiart, J., Hekl, K., Henderson, L., Henrickson, M., Hersh, A., Hickey, K., Hill, P., Hillyer, S., Hiraki, L., Hiskey, M., Hobday, P., Hoffart, C., Holland, M., Hollander, M., Hong, S., Horwitz, M., Hsu, J., Huber, A., Huggins, J., Hui‐Yuen, J., Hung, C., Huntington, J., Huttenlocher, A., Ibarra, M., Imundo, L., Inman, C., Insalaco, A., Jackson, A., Jackson, S., James, K., Janow, G., Jaquith, J., Jared, S., Johnson, N., Jones, J., Jones, J., Jones, J., Jones, K., Jones, S., Joshi, S., Jung, L., Justice, C., Justiniano, A., Karan, N., Kaufman, K., Kemp, A., Kessler, E., Khalsa, U., Kienzle, B., Kim, S., Kimura, Y., Kingsbury, D., Kitcharoensakkul, M., Klausmeier, T., Klein, K., Klein‐Gitelman, M., Kompelien, B., Kosikowski, A., Kovalick, L., Kracker, J., Kramer, S., Kremer, C., Lai, J., Lam, J., Lang, B., Lapidus, S., Lapin, B., Lasky, A., Latham, D., Lawson, E., Laxer, R., Lee, P., Lee, P., Lee, T., Lentini, L., Lerman, M., Levy, D., Li, S., Lieberman, S., Lim, L., Lin, C., Ling, N., Lingis, M., Lo, M., Lovell, D., Lowman, D., Luca, N., Lvovich, S., Madison, C., Madison, J., Manzoni, S. Magni, Malla, B., Maller, J., Malloy, M., Mannion, M., Manos, C., Marques, L., Martyniuk, A., Mason, T., Mathus, S., McAllister, L., McCarthy, K., McConnell, K., McCormick, E., McCurdy, D., Stokes, P. McCurdy, McGuire, S., McHale, I., McMonagle, A., McMullen‐Jackson, C., Meidan, E., Mellins, E., Mendoza, E., Mercado, R., Merritt, A., Michalowski, L., Miettunen, P., Miller, M., Milojevic, D., Mirizio, E., Misajon, E., Mitchell, M., Modica, R., Mohan, S., Moore, K., Moorthy, L., Morgan, S., Dewitt, E. Morgan, Moss, C., Moussa, T., Mruk, V., Murphy, A., Muscal, E., Nadler, R., Nahal, B., Nanda, K., Nasah, N., Nassi, L., Nativ, S., Natter, M., Neely, J., Nelson, B., Newhall, L., Ng, L., Nicholas, J., Nicolai, R., Nigrovic, P., Nocton, J., Nolan, B., Oberle, E., Obispo, B., OʼBrien, B., OʼBrien, T., Okeke, O., Oliver, M., Olson, J., OʼNeil, K., Onel, K., Orandi, A., Orlando, M., Osei‐Onomah, S., Oz, R., Pagano, E., Paller, A., Pan, N., Panupattanapong, S., Pardeo, M., Paredes, J., Parsons, A., Patel, J., Pentakota, K., Pepmueller, P., Pfeiffer, T., Phillippi, K., Marafon, D. Pires, Phillippi, K., Ponder, L., Pooni, R., Prahalad, S., Pratt, S., Protopapas, S., Puplava, B., Quach, J., Quinlan‐Waters, M., Rabinovich, C., Radhakrishna, S., Rafko, J., Raisian, J., Rakestraw, A., Ramirez, C., Ramsay, E., Ramsey, S., Randell, R., Reed, A., Reed, A., Reed, A., Reid, H., Remmel, K., Repp, A., Reyes, A., Richmond, A., Riebschleger, M., Ringold, S., Riordan, M., Riskalla, M., Ritter, M., Rivas‐Chacon, R., Robinson, A., Rodela, E., Rodriquez, M., Rojas, K., Ronis, T., Rosenkranz, M., Rosolowski, B., Rothermel, H., Rothman, D., Roth‐Wojcicki, E., Rouster – Stevens, K., Rubinstein, T., Ruth, N., Saad, N., Sabbagh, S., Sacco, E., Sadun, R., Sandborg, C., Sanni, A., Santiago, L., Sarkissian, A., Savani, S., Scalzi, L., Schanberg, L., Scharnhorst, S., Schikler, K., Schlefman, A., Schmeling, H., Schmidt, K., Schmitt, E., Schneider, R., Schollaert‐Fitch, K., Schulert, G., Seay, T., Seper, C., Shalen, J., Sheets, R., Shelly, A., Shenoi, S., Shergill, K., Shirley, J., Shishov, M., Shivers, C., Silverman, E., Singer, N., Sivaraman, V., Sletten, J., Smith, A., Smith, C., Smith, J., Smith, J., Smitherman, E., Soep, J., Son, M., Spence, S., Spiegel, L., Spitznagle, J., Sran, R., Srinivasalu, H., Stapp, H., Steigerwald, K., Rakovchik, Y. Sterba, Stern, S., Stevens, A., Stevens, B., Stevenson, R., Stewart, K., Stingl, C., Stokes, J., Stoll, M., Stringer, E., Sule, S., Sumner, J., Sundel, R., Sutter, M., Syed, R., Syverson, G., Szymanski, A., Taber, S., Tal, R., Tambralli, A., Taneja, A., Tanner, T., Tapani, S., Tarshish, G., Tarvin, S., Tate, L., Taxter, A., Taylor, J., Terry, M., Tesher, M., Thatayatikom, A., Thomas, B., Tiffany, K., Ting, T., Tipp, A., Toib, D., Torok, K., Toruner, C., Tory, H., Toth, M., Tse, S., Tubwell, V., Twilt, M., Uriguen, S., Valcarcel, T., Van Mater, H., Vannoy, L., Varghese, C., Vasquez, N., Vazzana, K., Vehe, R., Veiga, K., Velez, J., Verbsky, J., Vilar, G., Volpe, N., von Scheven, E., Vora, S., Wagner, J., Wagner‐Weiner, L., Wahezi, D., Waite, H., Walker, J., Walters, H., Muskardin, T. Wampler, Waqar, L., Waterfield, M., Watson, M., Watts, A., Weiser, P., Weiss, J., Weiss, P., Wershba, E., White, A., Williams, C., Wise, A., Woo, J., Woolnough, L., Wright, T., Wu, E., Yalcindag, A., Yee, M., Yen, E., Yeung, R., Yomogida, K., Yu, Q., Zapata, R., Zartoshti, A., Zeft, A., Zeft, R., Zhang, Y., Zhao, Y., Zhu, A., and Zic, C.

Published
2023
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45. Geospatial investigations in Colombia reveal variations in the distribution of mood and psychotic disorders

Author

Song, Janet, primary, Ramírez, Mauricio Castaño, additional, Okano, Justin T., additional, Service, Susan K., additional, de la Hoz, Juan, additional, Díaz-Zuluaga, Ana M., additional, Upegui, Cristian Vargas, additional, Gallago, Cristian, additional, Arias, Alejandro, additional, Sánchez, Alexandra Valderrama, additional, Teshiba, Terri, additional, Sabatti, Chiara, additional, Gur, Ruben C., additional, Bearden, Carrie E., additional, Escobar, Javier I., additional, Reus, Victor I., additional, Jaramillo, Carlos Lopez, additional, Freimer, Nelson B., additional, Olde Loohuis, Loes M., additional, and Blower, Sally, additional

Published
2024
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47. Self-organization of solar magnetic fields

Author

Jarboe, T. R., Benedett, T. E., Everson, C. J., Hansen, C. J., Hossack, A. C., Morgan, K. D., Nelson, B. A., Penna, J. M., and Sutherland, D. A.

Subjects
Astrophysics - Solar and Stellar Astrophysics
Abstract

Self-organization properties of sustained magnetized plasma are applied to selected solar data to understand solar magnetic fields. Torsional oscillations are speed-up and slow-down bands of the azimuthal flow that correlate with the solar cycle, and they imply the existence of a symmetric solar dynamo with a measured polar flux of 3x10^14 Wb. It is shown that the solar dynamo is thin (~0.1 Mm gradient scale size) and powerful (~10^23 W). These properties are found from the amplitude of the torsional oscillations and the relationship of their velocity contours to solar magnetograms supports the result. The dynamo has enough power to heat the chromosphere and to power the corona and the solar wind. The dynamo also causes a rigid rotation of the heliosphere out to at least the corona and the relationship of the rotation of the corona to solar magnetograms supports this result as well. The thin solar dynamo sustains a thin stable minimum energy state that seems to be covering most of the solar surface just below the photosphere. The magnetic field lines of the minimum energy state should be parallel to the solar surface and rotate with distance from the surface with 2{\pi} radians of rotation in ~1 Mm Resistive diffusion helps to push the magnetic fields to the surface and the global magnetic structure (GMS) seems to lose {\pi} radians every 11 years, causing the observed 180 degree flipping of the solar magnetic field. The thin sheets of magnetized plasma in solar prominences may be the lost thin sheets of the GMS. For completeness, the formation of sunspots, CMEs and flares is discussed., Comment: arXiv admin note: substantial text overlap with arXiv:1712.01247

Published
2018

48. Sustained neutron production from a sheared-flow stabilized Z-pinch

Author

Zhang, Y., Shumlak, U., Nelson, B. A., Golingo, R. P., Weber, T. R., Stepanov, A. D., Claveau, E. L., Forbes, E. G., Draper, Z. T., Mitrani, J. M., McLean, H. S., Tummel, K. K., Higginson, D. P., and Cooper, C. M.

Subjects
Physics - Plasma Physics
Abstract

The sheared-flow stabilized $Z$-pinch has demonstrated long-lived plasmas with fusion-relevant parameters. This Letter presents the first experimental results demonstrating sustained, quasi-steady-state neutron production from the Fusion $Z$-pinch Experiment (FuZE), operated with a mixture of 20% deuterium/80% hydrogen by volume. Neutron emissions lasting approximately $5~\mu$s are reproducibly observed with pinch currents of approximately $200$ kA during an approximately $16~\mu$s period of plasma quiescence. The average neutron yield is estimated to be $\left ( 1.25\pm 0.45 \right )\times 10^{5}$ neutrons/pulse and scales with the square of the deuterium concentration. Coincident with the neutron signal, plasma temperatures of $1-2$ keV, and densities of approximately $10^{17}$ cm$^{-3}$ with $0.3$ cm pinch radii are measured with fully-integrated diagnostics., Comment: 5 pages and 6 figures

Published
2018
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