Genetic Processes 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 …

Pulmonary Fibrosis As A Presentation Of Short Telomere Syndrome: Case Report, Roy Kondapavuluru, Jian Garcia Cruz, Sreejith Pillai, Andres Suarez Parraga

Research Colloquium

Introduction: Short telomere syndrome (STS), also known as accelerated aging syndrome, is an inheritable gene mutation resulting in decreased telomere length causing high cell turnover of organ systems such as skin, bone marrow, liver, hair, lungs, and immune system. Due to diverse clinical manifestations, STS poses a diagnostic challenge, with bone marrow failure and idiopathic pulmonary fibrosis being frequent manifestations. The inherited form of STS demonstrates genetic anticipation occurring at an earlier age with more severe manifestations in the affected progeny. We present a rare case of inherited STS in a young patient with severe pulmonary fibrosis.

Case Presentation: A …

The Genetic Determinants Of Recurrent Somatic Mutations In 43,693 Blood Genomes, Joshua S. Weinstock, Cecelia A. Laurie, Jai G. Broome, Kent D. Taylor, Xiuqing Guo, Alan R. Shuldiner, Jeffrey R. O'Connell, Ravi Duggirala, Joanne E. Curran, John Blangero

School of Medicine Publications

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid …

Whole Genome Sequence Association Analysis Of Fasting Glucose And Fasting Insulin Levels In Diverse Cohorts From The Nhlbi Topmed Program, Daniel Dicorpo, Sheila M. Gaynor, Emily M. Russell, Kenneth E. Westerman, Laura M. Raffield, Marcio Almeida, Juan M. Peralta, John Blangero, Joanne E. Curran, Ravindranath Duggirala

School of Medicine Publications

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well …

Non-Alcoholic Fatty Liver Disease And Depression: Evidence For Genotype × Environment Interaction In Mexican Americans, Eron G. Manusov, Vincent P. Diego, Khalid Sheikh, Sandra Laston, John Blangero, Sarah Williams-Blangero

School of Medicine Publications

This study examines the impact of G × E interaction effects on non-alcoholic fatty liver disease (NAFLD) among Mexican Americans in the Rio Grande Valley (RGV) of South Texas. We examined potential G × E interaction using variance components models and likelihood-based statistical inference in the phenotypic expression of NAFLD, including hepatic steatosis and hepatic fibrosis (identified using vibration controlled transient elastography and controlled attenuation parameter measured by the FibroScan Device). We screened for depression using the Beck Depression Inventory-II (BDI-II). We identified significant G × E interactions for hepatic fibrosis × BDI-II. These findings provide evidence that genetic factors …

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 …

Mendelian Randomization Supports Bidirectional Causality Between Telomere Length And Clonal Hematopoiesis Of Indeterminate Potential, Tetsushi Nakao, Alexander G. Bick, Margaret A. Taub, Seyedeh M. Zekavat, Md M. Uddin, Abhishek Niroula, Juan M. Peralta, Joanne E. Curran, John Blangero

School of Medicine Publications

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies …

The Seventh International Rasopathies Symposium: Pathways To A Cure—Expanding Knowledge, Enhancing Research, And Therapeutic Discovery, Maria I. Kontaridis, Amy E. Roberts, Lisa Schill, Lisa Schoyer, Beth Stronach, Gregor Andelfinger, Yoko Aoki, Marni E. Axelrad, Annette Bakker, Alejandro Lopez-Juarez

Health & Biomedical Sciences Faculty Publications

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use …

Whole Genome Sequence Analysis Of Platelet Traits In The Nhlbi Trans-Omics For Precision Medicine Initiative, Amarise Little, Yao Hu, Quan Sun, Deepti Jain, Jai G. Broome, Ming-Huei Chen, Florian Thibord, Caitlin Mchugh, John Blangero, Joanne E. Curran

School of Medicine Publications

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet …

Genome Sequencing Unveils A Regulatory Landscape Of Platelet Reactivity, Ali R. Keramati, Ming-Huei Chen, Lisa R. Yanek, Arunoday Bhan, John Blangero, Benjamin A. T. Rodriguez, Joanne E. Curran, Michael Mahaney, Harald Hh Goring, Ravi Duggirala

School of Medicine Publications

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are …

The Genetic Architecture Of The Human Cerebral Cortex, Katrina L. Grasby, Neda Jahanshad, Jodie N. Painter, Lucia Colodro-Conde, Janita Bralten, Derrek P. Hibar, Penelope A. Lind, Fabrizio Pizzagalli, Marcio A. Almeida, Joanne E. Curran, John Blangero

School of Medicine Publications

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area …

Fine Mapping And Identification Of Serum Urate Loci In American Indians: The Strong Heart Family Study, Geetha Chittoor, Karin Haack, Poojitha Balakrishnan, Christopher Bizon, Sandra Laston, Lyle G. Best, Jean W. Maccluer, Kari E. North, Jason G. Umans

School of Medicine Publications

While studies have reported genetic loci affecting serum urate (SU) concentrations, few studies have been conducted in minority populations. Our objective for this study was to identify genetic loci regulating SU in a multigenerational family-based cohort of American Indians, the Strong Heart Family Study (SHFS). We genotyped 162,718 single nucleotide polymorphisms (SNPs) in 2000 SHFS participants using an Illumina MetaboChip array. A genome-wide association analysis of SU was conducted using measured genotype analysis approach accounting for kinships in SOLAR, and meta-analysis in METAL. Our results showed strong association of SU with rs4481233, rs9998811, rs7696092 and rs13145758 (minor allele frequency (MAF) …

Genetic And Environmental (Physical Fitness And Sedentary Activity) Interaction Effects On Cardiometabolic Risk Factors In Mexican American Children And Adolescents, Rector Arya, Vidya S. Farook, Roy G. Resendez, Srinivas Mummidi, Laura Almasy, Joanne E. Curran, Christopher P. Jenkinson, John Blangero, Ravindranath Duggirala, Vincent P. Diego

School of Medicine Publications

Knowledge on genetic and environmental (G × E) interaction effects on cardiometabolic risk factors (CMRFs) in children is limited. The purpose of this study was to examine the impact of G × E interaction effects on CMRFs in Mexican American (MA) children (n = 617, ages 6–17 years). The environments examined were sedentary activity (SA), assessed by recalls from “yesterday” (SAy) and “usually” (SAu) and physical fitness (PF) assessed by Harvard PF scores (HPFS). CMRF data included body mass index (BMI), waist circumference (WC), fat mass (FM), fasting insulin (FI), homeostasis model of assessment—insulin resistance (HOMA‐IR), high‐density lipoprotein cholesterol …

Fast Genome-Wide Qtl Association Mapping On Pedigree And Population Data, Hua Zhou, John Blangero, Thomas D. Dyer, Kei-Hang K. Chan, Kenneth Lange, Eric M. Sobel

School of Medicine Publications

Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. …

Multiethnic Genome-Wide Meta-Analysis Of Ectopic Fat Depots Identifies Loci Associated With Adipocyte Development And Differentiation, Audrey Y. Chu, Xuan Deng, Virginia A. Fisher, Alexander Drong, Yang Zhang, Mary F. Feitosa, Ching-Ti Liu, Olivia Weeks, Audrey C. Choh, Qing Duan, Thomas D. Dyer

School of Medicine Publications

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men for six ectopic fat traits in European, African, Hispanic, and Chinese ancestry populations, with and without sex stratification. In total, 7 new loci were identified in association with ectopic fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; PATXN1 and UBE2E2 …