%0 Journal Article %J JAMA Netw Open %D 2020 %T Epidemiology of Functional Seizures Among Adults Treated at a University Hospital. %A Goleva, Slavina B %A Lake, Allison M %A Torstenson, Eric S %A Haas, Kevin F %A Davis, Lea K %K Adult %K Anxiety %K Case-Control Studies %K Comorbidity %K Delayed Diagnosis %K Depression %K Female %K Hospitals, University %K Humans %K Male %K Mental Disorders %K Middle Aged %K Odds Ratio %K Risk Factors %K Seizures %K Stress Disorders, Post-Traumatic %X

Importance: Functional seizures (formerly psychogenic nonepileptic seizures), paroxysmal episodes that are often similar to epileptic seizures in their clinical presentation and display no aberrant brain electrical patterns, are understudied. Patients experience a long diagnostic delay, few treatment modalities, a high rate of comorbidities, and significant stigma due to the lack of knowledge about functional seizures.

Objective: To characterize the clinical epidemiology of a population of patients with functional seizures observed at Vanderbilt University Medical Center (VUMC).

Design, Setting, and Participants: This case-control study included patients with functional seizures identified in the VUMC electronic health record (VUMC-EHR) system from October 1989 to October 2018. Patients with epilepsy were excluded from the study and all remaining patients in the VUMC medical center system were used as controls. In total, the study included 1431 patients diagnosed with functional seizures, 2251 with epilepsy and functional seizures, 4715 with epilepsy without functional seizures, and 502 200 control patients who received treatment at VUMC for a minimum of a 3 years. Data were analyzed from November 2018 to March 2020.

Exposure: Diagnosis of functional seizures, as identified from the VUMC-EHR system by an automated phenotyping algorithm that incorporated International Classification of Diseases, Ninth Revision (ICD-9) codes, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, Current Procedural Terminology codes, and natural language processing.

Main Outcomes and Measures: Associations of functional seizures with comorbidities and risk factors, measured in odds ratios (ORs).

Results: Of 2 346 808 total patients in the VUMC-EHR aged 18 years or older, 3341 patients with functional seizures were identified (period prevalence, 0.14%), 1062 (74.2%) of whom were women and for which the median (interquartile range) age was 49.3 (39.4-59.9) years. This assessment replicated previously reported associations with psychiatric disorders including posttraumatic stress disorder (PTSD) (OR, 1.22; 95% CI, 1.21-1.24; P < 3.02 × 10-5), anxiety (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 × 10-5), and depression (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 × 10-5), and identified novel associations with cerebrovascular disease (OR, 1.08; 95% CI, 1.06-1.09; P < 3.02 × 10-5). An association was found between functional seizures and the known risk factor sexual assault trauma (OR, 10.26; 95% CI, 10.09-10.44; P < 3.02 × 10-5), and sexual assault trauma was found to mediate nearly a quarter of the association between female sex and functional seizures in the VUMC-EHR.

Conclusions and Relevance: This case-control study found evidence to support previously reported associations, discovered new associations between functional seizures and PTSD, anxiety, and depression. An association between cerebrovascular disease and functional seizures was also found. Results suggested that sexual trauma may be a mediating factor in the association between female sex and functional seizures.

%B JAMA Netw Open %V 3 %P e2027920 %8 2020 12 01 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33372972?dopt=Abstract %R 10.1001/jamanetworkopen.2020.27920 %0 Journal Article %J Int J Equity Health %D 2020 %T Race, socioeconomic deprivation, and hospitalization for COVID-19 in English participants of a national biobank. %A Patel, Aniruddh P %A Paranjpe, Manish D %A Kathiresan, Nina P %A Rivas, Manuel A %A Khera, Amit V %K Adult %K Aged %K Biological Specimen Banks %K Continental Population Groups %K Coronavirus Infections %K COVID-19 %K Female %K Health Status Disparities %K Hospitalization %K Humans %K Male %K Middle Aged %K Pandemics %K Pneumonia, Viral %K Prospective Studies %K Socioeconomic Factors %K United Kingdom %X

Preliminary reports suggest that the Coronavirus Disease 2019 (COVID- 19) pandemic has led to disproportionate morbidity and mortality among historically disadvantaged populations. We investigate the racial and socioeconomic associations of COVID- 19 hospitalization among 418,794 participants of the UK Biobank, of whom 549 (0.13%) had been hospitalized. Both Black participants (odds ratio 3.7; 95%CI 2.5-5.3) and Asian participants (odds ratio 2.2; 95%CI 1.5-3.2) were at substantially increased risk as compared to White participants. We further observed a striking gradient in COVID- 19 hospitalization rates according to the Townsend Deprivation Index - a composite measure of socioeconomic deprivation - and household income. Adjusting for socioeconomic factors and cardiorespiratory comorbidities led to only modest attenuation of the increased risk in Black participants, adjusted odds ratio 2.4 (95%CI 1.5-3.7). These observations confirm and extend earlier preliminary and lay press reports of higher morbidity in non-White individuals in the context of a large population of participants in a national biobank. The extent to which this increased risk relates to variation in pre-existing comorbidities, differences in testing or hospitalization patterns, or additional disparities in social determinants of health warrants further study.

%B Int J Equity Health %V 19 %P 114 %8 2020 07 06 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32631328?dopt=Abstract %R 10.1186/s12939-020-01227-y %0 Journal Article %J PLoS Genet %D 2020 %T Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma. %A Tanigawa, Yosuke %A Wainberg, Michael %A Karjalainen, Juha %A Kiiskinen, Tuomo %A Venkataraman, Guhan %A Lemmelä, Susanna %A Turunen, Joni A %A Graham, Robert R %A Havulinna, Aki S %A Perola, Markus %A Palotie, Aarno %A Daly, Mark J %A Rivas, Manuel A %K Adult %K Aged %K Aged, 80 and over %K Angiopoietin-like Proteins %K Biological Specimen Banks %K Case-Control Studies %K Cohort Studies %K Female %K Finland %K Gene Frequency %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Glaucoma %K Humans %K Intraocular Pressure %K Loss of Function Mutation %K Male %K Middle Aged %K Mutation, Missense %K Polymorphism, Single Nucleotide %K United Kingdom %X

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10-9 and 1.07 x 10-13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10-12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.

%B PLoS Genet %V 16 %P e1008682 %8 2020 05 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/32369491?dopt=Abstract %R 10.1371/journal.pgen.1008682 %0 Journal Article %J Am J Hum Genet %D 2020 %T A Robust Method Uncovers Significant Context-Specific Heritability in Diverse Complex Traits. %A Dahl, Andy %A Nguyen, Khiem %A Cai, Na %A Gandal, Michael J %A Flint, Jonathan %A Zaitlen, Noah %K Adult %K Animals %K Computer Simulation %K Female %K Gene-Environment Interaction %K Genetic Markers %K Genome-Wide Association Study %K Humans %K Male %K Mental Disorders %K Middle Aged %K Models, Genetic %K Multifactorial Inheritance %K Phenomics %K Phenotype %K Rats %X

Gene-environment interactions (GxE) can be fundamental in applications ranging from functional genomics to precision medicine and is a conjectured source of substantial heritability. However, unbiased methods to profile GxE genome-wide are nascent and, as we show, cannot accommodate general environment variables, modest sample sizes, heterogeneous noise, and binary traits. To address this gap, we propose a simple, unifying mixed model for gene-environment interaction (GxEMM). In simulations and theory, we show that GxEMM can dramatically improve estimates and eliminate false positives when the assumptions of existing methods fail. We apply GxEMM to a range of human and model organism datasets and find broad evidence of context-specific genetic effects, including GxSex, GxAdversity, and GxDisease interactions across thousands of clinical and molecular phenotypes. Overall, GxEMM is broadly applicable for testing and quantifying polygenic interactions, which can be useful for explaining heritability and invaluable for determining biologically relevant environments.

%B Am J Hum Genet %V 106 %P 71-91 %8 2020 01 02 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31901249?dopt=Abstract %R 10.1016/j.ajhg.2019.11.015 %0 Journal Article %J Nat Commun %D 2020 %T Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. %A Sajuthi, Satria P %A DeFord, Peter %A Li, Yingchun %A Jackson, Nathan D %A Montgomery, Michael T %A Everman, Jamie L %A Rios, Cydney L %A Pruesse, Elmar %A Nolin, James D %A Plender, Elizabeth G %A Wechsler, Michael E %A Mak, Angel C Y %A Eng, Celeste %A Salazar, Sandra %A Medina, Vivian %A Wohlford, Eric M %A Huntsman, Scott %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Abecasis, Goncalo %A Kang, Hyun Min %A Rice, Kenneth M %A Kumar, Rajesh %A Oh, Sam %A Rodriguez-Santana, Jose %A Burchard, Esteban G %A Seibold, Max A %K Angiotensin-Converting Enzyme 2 %K Betacoronavirus %K Child %K Coronavirus Infections %K COVID-19 %K Epithelial Cells %K Gene Expression Profiling %K Gene Expression Regulation %K Genetic Variation %K Host-Pathogen Interactions %K Humans %K Inflammation %K Interferons %K Interleukin-13 %K Middle Aged %K Nasal Mucosa %K Pandemics %K Peptidyl-Dipeptidase A %K Pneumonia, Viral %K SARS-CoV-2 %K Serine Endopeptidases %K Virus Internalization %X

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

%B Nat Commun %V 11 %P 5139 %8 2020 10 12 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33046696?dopt=Abstract %R 10.1038/s41467-020-18781-2 %0 Journal Article %J Elife %D 2017 %T Genetic identification of a common collagen disease in puerto ricans via identity-by-descent mapping in a health system. %A Belbin, Gillian Morven %A Odgis, Jacqueline %A Sorokin, Elena P %A Yee, Muh-Ching %A Kohli, Sumita %A Glicksberg, Benjamin S %A Gignoux, Christopher R %A Wojcik, Genevieve L %A Van Vleck, Tielman %A Jeff, Janina M %A Linderman, Michael %A Schurmann, Claudia %A Ruderfer, Douglas %A Cai, Xiaoqiang %A Merkelson, Amanda %A Justice, Anne E %A Young, Kristin L %A Graff, Misa %A North, Kari E %A Peters, Ulrike %A James, Regina %A Hindorff, Lucia %A Kornreich, Ruth %A Edelmann, Lisa %A Gottesman, Omri %A Stahl, Eli Ea %A Cho, Judy H %A Loos, Ruth Jf %A Bottinger, Erwin P %A Nadkarni, Girish N %A Abul-Husn, Noura S %A Kenny, Eimear E %K Adolescent %K Adult %K Aged %K Child %K Collagen Diseases %K Female %K Fibrillar Collagens %K Genotype %K Heterozygote %K Hispanic Americans %K Homozygote %K Humans %K Male %K Middle Aged %K Molecular Epidemiology %K Multigene Family %K Musculoskeletal Diseases %K New York City %K Pedigree %K Whole Genome Sequencing %K Young Adult %X

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, , with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

%B Elife %V 6 %8 2017 09 12 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28895531?dopt=Abstract %R 10.7554/eLife.25060