Medical Genetics Commons^™

Corticobasal Syndrome With Mixed Pathology In The Absence Of Grn Mutation: A Clinico-Pathological Case Of Ftld-Tdp With Coexisting Alzheimer’S And Lewy Body Pathology, Hugo Zamarron, David Irwin, Jeffery Phillips, Edward Lee, Matthew Tisdall, Corey Mcmillan

Research Colloquium

Background: Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by often asymmetric fronto-pariteal and extra-pyramidal features that is traditionally associated with tauopathy, but pathological findings are heterogenous, including other forms of frontotemporal lobar degeneration (FTLD) and mixed pathologies of aging. We present clinical, radiographic, and histopathologic features of asymmetry in a unique patient with CBS and underlying FTLD with TDP-43 pathology (FTLD-TDP), co-occurring with other age-related pathologies.

Case Presentation: A 76-year-old man presented with progressive cognitive and motor dysfunction including asymmetric parkinsonism, left-sided dystonia and rigidity, apraxia, visuospatial impairment, and a subtle social disorder including apathy and social withdrawal. The …

Genetic Study Of Von Willebrand Factor Antigen Levels ≤ 50 Iu/Dl Identifies Variants Associated With Increased Risk Of Vwd And Bleeding, Rachel K. Friedman, Adam S. Heath, Jennifer E. Huffman, James T. Baker, Natalie R. Hasbani, Sarah A. Gagliano Taliun, Ming-Huei Chen, Tom Howard, Joanne E. Curran, John Blangero

School of Medicine Publications

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤50 IU/dL) in the general population is underexplored.

Methods: To identify genetic variants influencing VWF:Ag levels ≤50 IU/dL, we performed a genome-wide association study in 926 cases with VWF:Ag levels ≤50 IU/dL and 12,846 controls from 7 studies from the TOPMed program. We then examined whether genome-wide significant findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1,286,069 controls, and with …

Alk Drives Neuroblastoma Tumorigenesis Via Upregulation Of Postn And Activation Of Wnt And Stat3 Signaling, Miller Huang, Wanqi Fang, Alvin Farrel, Linwei Li, Tania Porras Corredor, Shahab Asgharzadeh, John Maris, William A. Weiss

Research Symposium

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. Two of the earliest known genetic drivers of NB are the oncogene MYCN and receptor tyrosine kinase ALK. While animal models show MYCN and mutationally active ALK F1174L can accelerate NB tumorigenesis, the mechanism of this cooperation is unknown. This study applied a human stem cell-based model to elucidate how ALK cooperates with MYCN to accelerate tumorigenesis of NB.

Methods: Induced pluripotent stem cells (iPSCs) were engineered with doxycycline-inducible MYCN and constitutively active ALKF1174L. These iPSCs were differentiated into trunk neural crest cells (tNCCs) and orthotopically transplanted into …

Excess Of Rare Noncoding Variants In Several Type 2 Diabetes Candidate Genes Among Asian Indian Families, Madhusmita Rout, Deepika Ramu, Mariana Mendez, Juan C. Lopez-Alvarenga, Rector Arya, Roy G. Resendez, Marcio A. Almeida, Srinivas Mummidi, Ravi Duggirala, Juan M. Peralta, John Blangero

School of Medicine Publications

Background

Type 2 diabetes (T2D) etiology is highly complex due to its multiple roots of origin. Polygenic risk scores (PRS) based on genome-wide association studies (GWAS) can partially explain T2D risk. Asian Indian people have up to six times higher risk of developing T2D than European people, and underlying causes of this disparity are unknown.

Methods

We have performed targeted sequencing of ten T2D GWAS/candidate regions using endogamous Punjabi Sikh families and replication studies using unrelated Sikh people and families from three other Indian endogamous ethnic groups (EEGs).

Results

We detect rare and ultra-rare variants (RVs) in KCNJ11-ABCC8 …

Accelerating Heritability, Genetic Correlation, And Genome-Wide Association Imaging Genetic Analyses In Complex Pedigrees, Brian Donohue, Si Gao, Thomas E. Nichols, Bhim M. Adhikari, Yizhou Ma, Neda Jahanshad, Francis J. Mcmahon, Elizabeth M. Humphries, William Burroughs, John Blangero

School of Medicine Publications

National and international biobanking efforts led to the collection of large and inclusive imaging genetics datasets that enable examination of the contribution of genetic and environmental factors to human brains in illness and health. High-resolution neuroimaging (~104–6 voxels) and genetic (106–8 single nucleotide polymorphic [SNP] variants) data are available in statistically powerful (N = 103–5) epidemiological and disorder-focused samples. Performing imaging genetics analyses at full resolution afforded in these datasets is a formidable computational task even under the assumption of unrelatedness among the subjects. The computational complexity rises as ~N2–3 (where N is the sample size), when …

Whole-Genome Sequencing In 333,100 Individuals Reveals Rare Non-Coding Single Variant And Aggregate Associations With Height, Gareth Hawkes, Robin N. Beaumont, Zilin Li, Ravi Mandla, Xihao Li, Christine M. Albert, Donna K. Arnett, Allison E. Ashley-Koch, Aneel A. Ashrani, Joanne E. Curran

School of Medicine Publications

The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare ( < 0.1% minor-allele-frequency) single-variant and aggregate testing of non-coding variants in regulatory regions based on proximal-regulatory, intergenic-regulatory and deep-intronic annotation. We observed 29 independent variants associated with height at P <  after conditioning on previously reported variants, with effect sizes ranging from −7cm to +4.7 cm. We also identified and replicated non-coding aggregate-based associations proximal to HMGA1 containing variants associated with a 5 cm taller height and of highly-conserved variants in MIR497HG on chromosome 17. We have developed an approach for identifying non-coding rare variants in regulatory regions with large effects from whole-genome sequencing data associated with complex traits.

Larp1 Haploinsufficiency Is Associated With An Autosomal Dominant Neurodevelopmental Disorder, James Chettle, Raymond J. Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Roberta Sierra, Lori Berry, Kent Carter

School of Medicine Publications

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1. LARP1 encodes an RNA binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and metabolic plasticity. …

Investigating The Determinants Of Frailty: The Intersection Of Genetics And Environment In Mexican Americans From South Texas, Natasha Garcia-Rodriguez, Vincent P. Diego, Marcio Almeida, Jacob Galan, Sandra Laston, Joanne E. Curran, Tom Howard, Eron Manusov, John Blangero, Sarah Williams-Blangero

Research Colloquium

Background: The projected worldwide population of people aged 65 and over is anticipated to hit 1.6 billion by 2050. Frailty, marked by increased susceptibility to adverse health outcomes, mortality, and decreased health-related quality of life (HrQoL), poses significant challenges to an aging population. The Frailty Index (FI), is the ratio of the number of accumulated health deficits to the total number of deficits considered, is used to predict frailty.

Methods: Utilizing data from the Mexican American Family Study, we investigated the heritability and gene-environment (GxE) interactions influencing frailty in 1,029 Mexican American participants. We calculated the FI using 34 variables, …

Systemic Biology Approach Linking Type 2 Diabetes And Depression In A Rio Grande Valley Family Study Population, Cameron B. Caldwell, Eron Manusov, Vincent P. Diego, Ana C. Leandro, Sandra Laston, John Blangero, Sarah Williams-Blangero, Marcio Almeida

Research Colloquium

Background: Type 2 diabetes and depression are major public health concerns that disproportionally impact Mexican Americans. Prevalence of T2D and depression have been estimated as high as 30% and 40%, respectively in Mexican American populations along the Texas-Mexico border. While the interaction between these two phenotypes is well documented, the underlying genetic basis of this interaction remains unclear. Our aims for this project were to identify genes co-expressed in type 2 diabetes and depression to dissect the interaction correlations between both conditions by means of a functional gene expression correlation network.

Methods: A total of 528 Mexican American participants from …

Admixture Mapping Of Cognitive Function In Diverse Hispanic And Latino Adults: Results From The Hispanic Community Health Study/Study Of Latinos, Rui Xia, Xueqiu Jian, Amanda L. Rodrigue, Jan Bressler, Eric Boerwinkle, Biqi Cui, Martha L. Daviglus, Charles Decarli, Linda C. Gallo, John Blangero

School of Medicine Publications

Introduction: We conducted admixture mapping and fine-mapping analyses to identify ancestry-of-origin loci influencing cognitive abilities.

Methods: We estimated the association of local ancestry intervals across the genome with five neurocognitive measures in 7140 diverse Hispanic and Latino adults (mean age 55 years). We prioritized genetic variants in associated loci and tested them for replication in four independent cohorts.

Results: We identified nine local ancestry-associated regions for the five neurocognitive measures. There was strong biological support for the observed associations to cognitive function at all loci and there was statistical evidence of independent replication at 4q12, 9p22.1, and 13q12.13.

Discussion: Our …

Genotype-By-Environment Interactions In Nonalcoholic Fatty Liver Disease And Chronic Illness Among Mexican Americans: The Role Of Acculturation Stress, Eron Manusov, Vincent Diego, Marcio Almeida, David Ortiz, Joanne E. Curran, Jacob Galan, Ana C. Leandro, Sandra Laston, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression …

Statistical Genetic Approaches To Investigate Genotype-By-Environment Interaction: Review And Novel Extension Of Models, Vincent P. Diego, Eron G. Manusov, Marcio Almeida, Sandra Laston, David Ortiz, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

Statistical genetic models of genotype-by-environment (G×E) interaction can be divided into two general classes, one on G×E interaction in response to dichotomous environments (e.g., sex, disease-affection status, or presence/absence of an exposure) and the other in response to continuous environments (e.g., physical activity, nutritional measurements, or continuous socioeconomic measures). Here we develop a novel model to jointly account for dichotomous and continuous environments. We develop the model in terms of a joint genotype-by-sex (for the dichotomous environment) and genotype-by-social determinants of health (SDoH; for the continuous environment). Using this model, we show how a depression variable, as measured by the …

Ongoing Study Of The Association Of Apoe Gene Polymorphisms With Cognitive Impairment In The Rio Grande Valley Hispanic Population, Jaime Miguel L. Saveron, Daniela Gamez, Chun Xu

Research Symposium

Background: Alzheimer's disease (AD), a prevalent neurodegenerative disorder, exhibits a significant genetic component. In addition, mild cognitive impairment (MCI) is a key risk factor for AD. While certain demographic factors and genetic variants associated with AD and cognitive impairment have been identified in non-Hispanic populations, limited research exists on this subject within the Hispanic population, particularly in the Rio Grande Valley. This study aims to investigate the relationship between the APOE gene, specifically its ε4 allele, and cognitive impairment in the Hispanic population of the Rio Grande Valley.

Methods: A total of 269 Hispanic subjects, aged 60 and above, with …

Tyramine And Its Amtyr1 Receptor Modulate Attention In Honey Bees (Apis Mellifera), Joseph S. Latshaw, Reece E. Mazade, Mary Petersen, Julie A. Mustard, Irina Sinakevitch, Lothar Wissler, Xiaojiao Guo, Chelsea Cook, Hong Lei, Brian Smith

School of Integrative Biological & Chemical Sciences Faculty Publications

Animals must learn to ignore stimuli that are irrelevant to survival and attend to ones that enhance survival. When a stimulus regularly fails to be associated with an important consequence, subsequent excitatory learning about that stimulus can be delayed, which is a form of nonassociative conditioning called ‘latent inhibition’. Honey bees show latent inhibition toward an odor they have experienced without association with food reinforcement. Moreover, individual honey bees from the same colony differ in the degree to which they show latent inhibition, and these individual differences have a genetic basis. To investigate the mechanisms that underly individual differences in …

Functional Characterization Of The Ipsc Generated Hepatocytes Using Genome-Wide Transcriptomic Analysis, Ashley Ikwuezunma, Erica De Leon, Ana C. Leandro, Joanne E. Curran, John Blangero, Satish Kumar

Research Colloquium

Advances in iPSC technologies now allow us to consider non-invasive large-scale in-vitro disease modeling experiments on disease appropriate cell types in human subjects to better understand human disease pathophysiology, disease genetics and to develop better diagnostic and therapeutic technologies. We performed differential gene expression and functional annotation analysis using genome wide mRNA sequencing data to evaluate the functional and disease modeling potential of iPSC generated hepatocytes. Following the criteria moderated t statistics FDR corrected p-value ≤ 0.05 and fold change-absolute ≥ 2.0, 7,246 genes/transcripts were significantly differentially expressed iPSCs and hepatocytes. The 3,791 of these DE genes/transcripts were significantly …

Gene By Environment Interaction And Metabolic-Associated Fatty Liver Disease In Mexican American Patients With Depression, Khalid Sheikh, Vincent P. Diego, Sandra L. Laston, Eron G. Manusov, Sarah Williams-Blangero, John Blangero

Research Colloquium

Knowledge of genetic and environmental (G x E) interaction effects on metabolic-associated fatty liver disease (MAFLD) is limited. The purpose of this study was to examine the impact of G x E interaction effects on MAFLD in Mexican Americans in the Rio Grande Valley (RGV). The environment examined was depression as measured by the Beck Depression Inventory-II (BDI-II). We examined potential G x E interaction in the phenotypic expression of MAFLD, including hepatic steatosis and hepatic fibrosis, using variance component models and likelihood-based statistical inference. Significant G x E interactions were identified for hepatic fibrosis x BDI-II. These findings provide …

Variant Of Fii Gene Plays A Critical Role In Coagulation Potential In Mexican-Americans, Hoang Anh T. Nguyen, Shuchita Vijay Jhaveri, Marcio A. Almeida, Vincent P. Diego, Satish Kumar, Juan M. Peralta, Joanne E. Curran, Bernadette W. Luu, Donna M. Lehman, Ralph A. Defronzo, Laura Almasy, Sarah Williams-Blangero, Ravi Duggirala, John Blangero, Tom Howard

Research Symposium

Background: Disruption in the balance between coagulation and bleeding can result in varying phenotypes such as hypercoagulability and can lead to the development of cardiovascular disease. In our study utilizing extended families of Mexican-Americans from South Texas, we performed a search for protein-altering variants influencing coagulation potential.

Methods: Mexican-Americans in the study were genotyped using Illumina-(human)-exome-24 chip to screen for protein-altering variants. Variants were analyzed for their association with FII activity, aPTT, and PT. Linear-mixed-model analysis was performed to estimate trait heritabilities and to interrogate single nucleotide variations (SNV) for evidence of genetic association. To control for multiple testing, associations …

Dpyd Pathogenic Variants Associated With Fluoropyrimidines Toxicity, Diana Cristina Pérez-Ibave, Noé Israel Oliva-García, Irasema Ramos-Martínez, Francisco Javier Villarreal Alvarado, Valeria Jimena Gómez Ordaz, Jonatán Isaí Cortes Alfaro, Carlos Horacio Burciaga-Flores, Juan Francisco González-Guerrero, Oscar Vidal-Gutiérrez, Maria De Lourdes Garza-Rodriguez

Research Symposium

Background: Genetic variants in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism. DPYD contributes to the development of severe FPs-related toxicity, and pathogenic DPYD variants detection reduces side effects and complications associated with FP-toxicity. The allelic frequency of these variants in the Mexican population is currently unknown.

Methods: The study was carried out at the Centro Universitario Contra el Cáncer (CUCC) of the Universidad Autónoma de Nuevo León (UANL) in Monterrey México. Genomic DNA was isolated from 154 subjects using the QIAamp DNA Blood Midi kit (QIAGEN) following the manufacturer's recommendations. We …

Genotype-By-Socioeconomic Status Interaction Influences Heart Disease Risk Scores And Carotid Artery Thickness In Mexican Americans: The Predominant Role Of Education In Comparison To Household Income And Socioeconomic Index, Vincent P. Diego, Eron G. Manusov, Xi Mao, Joanne E. Curran, Harald H. H. Goring, Marcio A. Almeida, Michael Mahaney, Juan M. Peralta, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

Background: Socioeconomic status (SES) is a potent environmental determinant of health. To our knowledge, no assessment of genotype-environment interaction has been conducted to consider the joint effects of socioeconomic status and genetics on risk for cardiovascular disease (CVD). We analyzed Mexican American Family Studies (MAFS) data to evaluate the hypothesis that genotype-by-environment interaction (GxE) is an important determinant of variation in CVD risk factors.

Methods: We employed a linear mixed model to investigate GxE in Mexican American extended families. We studied two proxies for CVD [Pooled Cohort Equation Risk Scores/Framingham Risk Scores (FRS/PCRS) and carotid artery intima-media thickness (CA-IMT)] in …

Potential Mirna Biomarkers And Therapeutic Targets For Early Atherosclerotic Lesions, Genesio M. Karere, Jeremy P. Glenn, Ge Li, Ayati Konar, John L. Vandeberg, Laura A. Cox

School of Medicine Publications

Identification of potential therapeutic targets and biomarkers indicative of burden of early atherosclerosis that occur prior to advancement to life-threatening unstable plaques is the key to eradication of CAD prevalence and incidences. We challenged 16 baboons with a high cholesterol, high fat diet for 2 years and evaluated early-stage atherosclerotic lesions (fatty streaks, FS, and fibrous plaques, FP) in formalin-fixed common iliac arteries (CIA). We used small RNA sequencing to identify expressed miRNAs in CIA and in baseline blood samples of the same animals. We found 412 expressed miRNAs in CIA and 356 in blood samples. Eight miRNAs (miR-7975, -486-5p, …

Multi-Ancestry Transcriptome-Wide Association Analyses Yield Insights Into Tobacco Use Biology And Drug Repurposing, Fang Cheng, Xingyan Wang, Seon-Kyeong Jang, Bryan C. Quach, J. Dylan Weissenkampen, Chachrit Khunsriraksakul, Lina Yang, John Blangero, Joanne E. Curran, Ravindranath Duggirala, Juan M. Peralta

School of Medicine Publications

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with …

Powerful, Scalable And Resource-Efficient Meta-Analysis Of Rare Variant Associations In Large Whole Genome Sequencing Studies, Xihao Li, Corbin Quick, Hufeng Zhou, Sheila M. Gaynor, John Blangero, Joanne E. Curran, Ravindranath Duggirala, Harald H. H. Goring, Michael Mahaney, Juan M. Peralta

School of Medicine Publications

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of …

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

School of Medicine Publications

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 …

The Genetic Contribution To Solving The Cocktail-Party Problem, Samuel R. Mathias, Emma Knowles, Josephine Mollon, Amanda Rodrigue, Mary K. Woolsey, Rene L. Olvera, Juan M. Peralta, Satish Kumar, Harald H. H. Goring, Ravi Duggirala, Joanne E. Curran, John Blangero, David C. Glahn

School of Medicine Publications

Communicating in everyday situations requires solving the cocktail-party problem, or segregating the acoustic mixture into its constituent sounds and attending to those of most interest. Humans show dramatic variation in this ability, leading some to experience real-world problems irrespective of whether they meet criteria for clinical hearing loss. Here, we estimated the genetic contribution to cocktail-party listening by measuring speech-reception thresholds (SRTs) in 425 people from large families and ranging in age from 18 to 91 years. Roughly half the variance of SRTs was explained by genes (h 2 = 0.567). The genetic correlation between SRTs and hearing thresholds …

Identification Of Healthspan-Promoting Genes In Caenorhabditis Elegans Based On A Human Gwas Study, Nadine Saul, Ineke Dhondt, Mikko Kuokkanen, Markus Perola, Clara Verschuuren, Brecht Wouters, Henrik Von Chrzanowski, Winnok H. De Vos, Liesbet Temmerman, Walter Luyten

School of Medicine Publications

To find drivers of healthy ageing, a genome-wide association study (GWAS) was performed in healthy and unhealthy older individuals. Healthy individuals were defined as free from cardiovascular disease, stroke, heart failure, major adverse cardiovascular event, diabetes, dementia, cancer, chronic obstructive pulmonary disease (COPD), asthma, rheumatism, Crohn’s disease, malabsorption or kidney disease. Six single nucleotide polymorphisms (SNPs) with unknown function associated with ten human genes were identified as candidate healthspan markers. Thirteen homologous or closely related genes were selected in the model organism C. elegans for evaluating healthspan after targeted RNAi-mediated knockdown using pathogen resistance, muscle integrity, chemotaxis index and the …

Comparing Empirical Kinship Derived Heritability For Imaging Genetics Traits In The Uk Biobank And Human Connectome Project, Si Gao, Brian Donohue, Kathryn S. Hatch, Shuo Chen, Tianzhou Ma, Yizhou Ma, Mark D. Kvarta, Bhim M. Adhikari, Neda Jahanshad, John Blangero

School of Medicine Publications

Imaging genetics analyses use neuroimaging traits as intermediate phenotypes to infer the degree of genetic contribution to brain structure and function in health and/or illness. Coefficients of relatedness (CR) summarize the degree of genetic similarity among subjects and are used to estimate the heritability – the proportion of phenotypic variance explained by genetic factors. The CR can be inferred directly from genome-wide genotype data to explain the degree of shared variation in common genetic polymorphisms (SNP-heritability) among related or unrelated subjects. We developed a central processing and graphics processing unit (CPU and GPU) accelerated Fast and Powerful Heritability Inference …

Multi-Phenotype Genome-Wide Association Studies Of The Norfolk Island Isolate Implicate Pleiotropic Loci Involved In Chronic Kidney Disease, Ngan K. Tran, Rodney A. Lea, Samuel Holland, Quan Nguyen, Arti M. Raghubar, Heidi G. Sutherland, Miles C. Benton, Nicholas B. Blackburn, Joanne E. Curran, John Blangero

School of Medicine Publications

Chronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple …

Determinants Of Penetrance And Variable Expressivity In Monogenic Metabolic Conditions Across 77,184 Exomes, Julia K. Goodrich, Moriel Singer-Berk, Rachel Son, Abigail Sveden, Jordan Wood, Eleina England, Joanne B. Cole, John Blangero, Ben Weisburd, Ravi Duggirala

School of Medicine Publications

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than …

Robust, Flexible, And Scalable Tests For Hardy-Weinberg Equilibrium Across Diverse Ancestries, Alan M. Kwong, Thomas W. Blackwell, Jonathon Lefaive, Mariza De Andrade, John Barnard, Kathleen C. Barnes, John Blangero

School of Medicine Publications

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype …

Sequencing Of 53,831 Diverse Genomes From The Nhlbi Topmed Program, Daniel Taliun, Daniel N. Harris, Michael D. Kessler, Jedidiah Carlson, John Blangero, Joanne E. Curran, Michael C. Mahaney, Harald H. H. Goring, Ravindranath Duggirala, Juan M. Peralta

School of Medicine Publications

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and …