Medicine and Health Sciences Commons^™

A Genome-Wide Association Study Of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants, Harold Bae, Ping An, Mary Feitosa, Et Al.

2020-Current year OA Pubs

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609,

A Whole-Genome Sequencing Study Implicates Gramd1b In Multiple Sclerosis Susceptibility, Federica Esposito, Bryan Bollman, Laura Piccio, Et Al.

2020-Current year OA Pubs

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the

Mendelian Randomization And Genetic Colocalization Infer The Effects Of The Multi-Tissue Proteome On 211 Complex Disease-Related Phenotypes, Chengran Yang, Anne M Fagan, Richard J Perrin, Herve Rhinn, Oscar Harari, Carlos Cruchaga

2020-Current year OA Pubs

BACKGROUND: Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes.

METHODS: Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several …

Genetic Diversity Fuels Gene Discovery For Tobacco And Alcohol Use, Gretchen R B Saunders, Charles C Gu, John P Rice, Nancy L Saccone, Laura J Bierut, Et Al.

2020-Current year OA Pubs

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury

Transferability Of Alzheimer Disease Polygenic Risk Score Across Populations And Its Association With Alzheimer Disease-Related Phenotypes, Sang-Hyuk Jung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry.

OBJECTIVE: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases …

Immune Phenotypes That Are Associated With Subsequent Covid-19 Severity Inferred From Post-Recovery Samples, Thomas Liechti, Yaser Iftikhar, Massimo Mangino, Margaret Beddall, Charles W Goss, Jane A O'Halloran, Philip A Mudd, Mario Roederer

2020-Current year OA Pubs

Severe COVID-19 causes profound immune perturbations, but pre-infection immune signatures contributing to severe COVID-19 remain unknown. Genome-wide association studies (GWAS) identified strong associations between severe disease and several chemokine receptors and molecules from the type I interferon pathway. Here, we define immune signatures associated with severe COVID-19 using high-dimensional flow cytometry. We measure the cells of the peripheral immune system from individuals who recovered from mild, moderate, severe or critical COVID-19 and focused only on those immune signatures returning to steady-state. Individuals that suffered from severe COVID-19 show reduced frequencies of T cell, mucosal-associated invariant T cell (MAIT) and dendritic …

Collective Genomic Segments With Differential Pleiotropic Patterns Between Cognitive Dimensions And Psychopathology, Max Lam, Chia-Yen Chen, W David Hill, Charley Xia, Ruoyu Tian, Daniel F Levey, Joel Gelernter, Murray B Stein, Alexander S Hatoum, Hailiang Huang, Anil K Malhotra, Heiko Runz, Tian Ge, Todd Lencz

2020-Current year OA Pubs

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identify collective segments of the genome, which we call "meta-loci", showing differential pleiotropic patterns for psychopathology relative to either cognitive task performance (CTP) or performance on a non-cognitive factor (NCF) derived from educational attainment. We observe that neurodevelopmental gene sets expressed during the prenatal-early childhood period predominate in CTP-relevant meta-loci, while post-natal gene sets are more involved in NCF-relevant …

Phenome-Wide Analysis Of Taiwan Biobank Reveals Novel Glycemia-Related Loci And Genetic Risks For Diabetes, Chia-Jung Lee, Ting-Huei Chen, Aylwin Ming Wee Lim, Chien-Ching Chang, Jia-Jyun Sie, Pei-Lung Chen, Su-Wei Chang, Shang-Jung Wu, Chia-Lin Hsu, Ai-Ru Hsieh, Wei-Shiung Yang, Cathy S J Fann

2020-Current year OA Pubs

To explore the complex genetic architecture of common diseases and traits, we conducted comprehensive PheWAS of ten diseases and 34 quantitative traits in the community-based Taiwan Biobank (TWB). We identified 995 significantly associated loci with 135 novel loci specific to Taiwanese population. Further analyses highlighted the genetic pleiotropy of loci related to complex disease and associated quantitative traits. Extensive analysis on glycaemic phenotypes (T2D, fasting glucose and HbA

Brain-Wide Versus Genome-Wide Vulnerability Biomarkers For Severe Mental Illnesses, Peter Kochunov, Aris Sotiras, Et Al.

2020-Current year OA Pubs

Severe mental illnesses (SMI), including major depressive (MDD), bipolar (BD), and schizophrenia spectrum (SSD) disorders have multifactorial risk factors and capturing their complex etiopathophysiology in an individual remains challenging. Regional vulnerability index (RVI) was used to measure individual's brain-wide similarity to the expected SMI patterns derived from meta-analytical studies. It is analogous to polygenic risk scores (PRS) that measure individual's similarity to genome-wide patterns in SMI. We hypothesized that RVI is an intermediary phenotype between genome and symptoms and is sensitive to both genetic and environmental risks for SMI. UK Biobank sample of N = 17,053/19,265 M/F (age = 64.8 …

Multi-Trait Genome-Wide Association Study Of Opioid Addiction: Oprm1 And Beyond, Nathan Gaddis, Arpana Agrawal, Paul W Jeffries, Kathleen Bucholz, Elliot C Nelson, Laura Bierut, Et Al.

2020-Current year OA Pubs

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r

Integrating Transcriptomics, Metabolomics, And Gwas Helps Reveal Molecular Mechanisms For Metabolite Levels And Disease Risk, Xianyong Yin, Adam E Locke, Nathan O Stitziel, Et Al.

2020-Current year OA Pubs

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 …

Shared Brain And Genetic Architectures Between Mental Health And Physical Activity, Wei Zhang, Sarah E Paul, Anderson Winkler, Ryan Bogdan, Janine D Bijsterbosch

2020-Current year OA Pubs

Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N = 6389), we applied canonical correlation analysis to estimate associations between the amplitude and connectivity strength of subnetworks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health measures (primarily of depression, anxiety disorders, …

Altered Methylation Pattern In Exoc4 Is Associated With Stroke Outcome: An Epigenome-Wide Association Study, Natalia Cullell, Carolina Soriano-Tárraga, Et Al.

2020-Current year OA Pubs

BACKGROUND AND PURPOSE: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke.

METHODS: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (ΔNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites …

Stroke Genetics Informs Drug Discovery And Risk Prediction Across Ancestries, Aniket Mishra, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry

Genome Scanning Of Behavioral Selection In A Canine Olfactory Detection Breeding Cohort, Alexander W Eyre, Isain Zapata, Elizabeth Hare, Katharine M N Lee, Claire Bellis, Jennifer L Essler, Cynthia M Otto, James A Serpell, Carlos E Alvarez

2020-Current year OA Pubs

Research on working dogs is growing rapidly due to increasing global demand. Here we report genome scanning of the risk of puppies being eliminated for behavioral reasons prior to entering the training phase of the US Transportation Security Administration's (TSA) canine olfactory detection breeding and training program through 2013. Elimination of dogs for behavioral rather than medical reasons was based on evaluations at three, six, nine and twelve months after birth. Throughout that period, the fostered dogs underwent standardized behavioral tests at TSA facilities, and, for a subset of tests, dogs were tested in four different environments. Using methods developed …

Does Social Intolerance Vary According To Cognitive Styles, Genetic Cognitive Capacity, Or Education?, Aino Saarinen, Liisa Keltikangas-Järvinen, Henrik Dobewall, C Robert Cloninger, Ari Ahola-Olli, Terho Lehtimäki, Nina Hutri-Kähönen, Olli Raitakari, Suvi Rovio, Niklas Ravaja

2020-Current year OA Pubs

BACKGROUND: Low education, low cognitive abilities, and certain cognitive styles are suggested to predispose to social intolerance and prejudices. Evidence is, however, restricted by comparatively small samples, neglect of confounding variables and genetic factors, and a narrow focus on a single sort of prejudice. We investigated the relationships of education, polygenic cognitive potential, cognitive performance, and cognitive styles with social intolerance in adulthood over a 15-year follow-up.

METHODS: We used data from the prospective population-based Young Finns Study (n = 960-1679). Social intolerance was evaluated with the Social Intolerance Scale in 1997, 2001, and 2011; cognitive performance with the Cambridge …

A Multitrait Locus Regulates Sarbecovirus Pathogenesis, Alexandra Schäfer, Emma S Winkler, Michael S Diamond, Et Al

2020-Current year OA Pubs

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential …

Gawmerge Expands Gwas Sample Size And Diversity By Combining Array-Based Genotyping And Whole-Genome Sequencing, Ravi Mathur, Fang Fang, Nathan Gaddis, Dana B Hancock, Michael H Cho, John E Hokanson, Laura J Bierut, Sharon M Lutz, Kendra Young, Albert V Smith, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Edwin K Silverman, Grier P Page, Eric O Johnson

2020-Current year OA Pubs

Genome-wide association studies (GWAS) have made impactful discoveries for complex diseases, often by amassing very large sample sizes. Yet, GWAS of many diseases remain underpowered, especially for non-European ancestries. One cost-effective approach to increase sample size is to combine existing cohorts, which may have limited sample size or be case-only, with public controls, but this approach is limited by the need for a large overlap in variants across genotyping arrays and the scarcity of non-European controls. We developed and validated a protocol, Genotyping Array-WGS Merge (GAWMerge), for combining genotypes from arrays and whole-genome sequencing, ensuring complete variant overlap, and allowing …

Sex Differences In The Genetic Architecture Of Cognitive Resilience To Alzheimer's Disease, Jaclyn M Eissman, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts …

Gene-Based Polygenic Risk Scores Analysis Of Alcohol Use Disorder In African Americans, Dongbing Lai, Arpana Agrawal, Et Al

2020-Current year OA Pubs

Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRS

Blocking Cell Cycle Progression Through Cdk4/6 Protects Against Chronic Kidney Disease, Yosuke Osaki, Marika Manolopoulou, Alla V Ivanova, Nicholas Vartanian, Melanie Phillips Mignemi, Justin Kern, Jianchun Chen, Haichun Yang, Agnes B Fogo, Mingzhi Zhang, Cassianne Robinson-Cohen, Leslie S. Gewin

2020-Current year OA Pubs

Acute and chronic kidney injuries induce increased cell cycle progression in renal tubules. While increased cell cycle progression promotes repair after acute injury, the role of ongoing tubular cell cycle progression in chronic kidney disease is unknown. Two weeks after initiation of chronic kidney disease, we blocked cell cycle progression at G1/S phase by using an FDA-approved, selective inhibitor of CDK4/6. Blocking CDK4/6 improved renal function and reduced tubular injury and fibrosis in 2 murine models of chronic kidney disease. However, selective deletion of cyclin D1, which complexes with CDK4/6 to promote cell cycle progression, paradoxically increased tubular injury. Expression …

Whole-Exome Sequencing Reveals Damaging Gene Variants Associated With Hypoalphalipoproteinemia, Weilai Dong, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those …

Gene-Lifestyle Interactions In The Genomics Of Human Complex Traits, Vincent Laville, Yun J Sung, Karen Schwander, Mary F Feitosa, Aldi T Kraja, Mike Province, C Charles Gu, D C Rao, Et Al

2020-Current year OA Pubs

The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that …

Enhancing Discovery Of Genetic Variants For Posttraumatic Stress Disorder Through Integration Of Quantitative Phenotypes And Trauma Exposure Information, Adam X. Maihofer, Andrew C. Heath, Et Al.

2020-Current year OA Pubs

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).

METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. …

Genome-Wide Analysis Of Mitochondrial Dna Copy Number Reveals Loci Implicated In Nucleotide Metabolism, Platelet Activation, And Megakaryocyte Proliferation, R J Longchamps, Mary Feitosa, Mary Wojczynski, Aldi Kraja, Michael Province, Et Al.

2020-Current year OA Pubs

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes …