Genetic Processes Commons^™

Truvari: Refined Structural Variant Comparison Preserves Allelic Diversity, Adam C English, Vipin K Menon, Richard A Gibbs, Ginger A Metcalf, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The fundamental challenge of multi-sample structural variant (SV) analysis such as merging and benchmarking is identifying when two SVs are the same. Common approaches for comparing SVs were developed alongside technologies which produce ill-defined boundaries. As SV detection becomes more exact, algorithms to preserve this refined signal are needed. Here, we present Truvari-an SV comparison, annotation, and analysis toolkit-and demonstrate the effect of SV comparison choices by building population-level VCFs from 36 haplotype-resolved long-read assemblies. We observe over-merging from other SV merging approaches which cause up to a 2.2× inflation of allele frequency, relative to Truvari.

Deciphering The Mechanism And Function Of Hsp100 Unfoldases From Protein Structure, Grace Lee, Rebecca S Kim, Sang Bum Lee, Sukyeong Lee, Francis T F Tsai

Faculty, Staff and Students Publications

Hsp100 chaperones, also known as Clp proteins, constitute a family of ring-forming ATPases that differ in 3D structure and cellular function from other stress-inducible molecular chaperones. While the vast majority of ATP-dependent molecular chaperones promote the folding of either the nascent chain or a newly imported polypeptide to reach its native conformation, Hsp100 chaperones harness metabolic energy to perform the reverse and facilitate the unfolding of a misfolded polypeptide or protein aggregate. It is now known that inside cells and organelles, different Hsp100 members are involved in rescuing stress-damaged proteins from a previously aggregated state or in recycling polypeptides marked …

Mechanisms Of Irf2bpl-Related Disorders And Identification Of A Potential Therapeutic Strategy, Shrestha Sinha Ray, Debdeep Dutta, Cassandra Dennys, Samantha Powers, Florence Roussel, Pawel Lisowski, Petar Glažar, Xiaojin Zhang, Pipasha Biswas, Joseph R Caporale, Nikolaus Rajewsky, Marc Bickle, Nicolas Wein, Hugo J Bellen, Shibi Likhite, Paul C Marcogliese, Kathrin C Meyer

Faculty, Staff and Students Publications

The recently discovered neurological disorder NEDAMSS is caused by heterozygous truncations in the transcriptional regulator IRF2BPL. Here, we reprogram patient skin fibroblasts to astrocytes and neurons to study mechanisms of this newly described disease. While full-length IRF2BPL primarily localizes to the nucleus, truncated patient variants sequester the wild-type protein to the cytoplasm and cause aggregation. Moreover, patient astrocytes fail to support neuronal survival in coculture and exhibit aberrant mitochondria and respiratory dysfunction. Treatment with the small molecule copper ATSM (CuATSM) rescues neuronal survival and restores mitochondrial function. Importantly, the in vitro findings are recapitulated in vivo, where co-expression of full-length …

Treatment Of Epilepsy Using A Targeted P38Γ Kinase Gene Therapy, Nicolle Morey, Magdalena Przybyla, Julia Van Der Hoven, Yazi D Ke, Fabien Delerue, Janet Van Eersel, Lars M Ittner

Faculty, Staff and Student Publications

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates …

Exome Sequencing Efficacy And Phenotypic Expansions Involving Esophageal Atresia/Tracheoesophageal Fistula Plus, Mary R Sy, Jaynee Chauhan, Katrina Prescott, Aliza Imam, Alison Kraus, Ana Beleza, Lee Salkeld, Saraswati Hosdurga, Michael Parker, Pradeep Vasudevan, Lily Islam, Himanshu Goel, Nicole Bain, Soo-Mi Park, Shehla Mohammed, Klaus Dieterich, Charles Coutton, Véronique Satre, Gaëlle Vieville, Alan Donaldson, Claire Beneteau, Jamal Ghoumid, Kris Van Den Bogaert, Anneleen Boogaerts, Elise Boudry, Clémence Vanlerberghe, Florence Petit, Laura Bernardini, Barbara Torres, Teresa Mattina, Diana Carli, Giorgia Mandrile, Michele Pinelli, Nicola Brunetti-Pierri, Katherine Neas, Rachel Beddow, Pernille M Tørring, Flavio Faletra, Beatrice Spedicati, Paolo Gasparini, Alessandro Mussa, Giovanni Battista Ferrero, Anne Lampe, Wayne Lam, Weimin Bi, Carlos A Bacino, Akela Kuwahara, Jeffrey O Bush, Xiaonan Zhao, Pamela N Luna, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower …

Long Read Sequencing And Expression Studies Of Ahdc1 Deletions In Xia-Gibbs Syndrome Reveal A Novel Genetic Regulatory Mechanism, Varuna Chander, Medhat Mahmoud, Jianhong Hu, Zain Dardas, Christopher M Grochowski, Moez Dawood, Michael M Khayat, He Li, Shoudong Li, Shalini Jhangiani, Viktoriya Korchina, Hua Shen, George Weissenberger, Qingchang Meng, Marie-Claude Gingras, Donna M Muzny, Harsha Doddapaneni, Jennifer E Posey, James R Lupski, Aniko Sabo, David R Murdock, Fritz J Sedlazeck, Richard A Gibbs

Faculty, Staff and Students Publications

Xia-Gibbs syndrome (XGS; MIM# 615829) is a rare mendelian disorder characterized by Development Delay (DD), intellectual disability (ID), and hypotonia. Individuals with XGS typically harbor de novo protein-truncating mutations in the AT-Hook DNA binding motif containing 1 (AHDC1) gene, although some missense mutations can also cause XGS. Large de novo heterozygous deletions that encompass the AHDC1 gene have also been ascribed as diagnostic for the disorder, without substantial evidence to support their pathogenicity. We analyzed 19 individuals with large contiguous deletions involving AHDC1, along with other genes. One individual bore the smallest known contiguous AHDC1 deletion (∼350 Kb), encompassing eight …

A Recurrent Single-Exon Deletion In Tbck Might Be Under-Recognized In Patients With Infantile Hypotonia And Psychomotor Delay, Hongzheng Dai, Wenmiao Zhu, Bo Yuan, Nicole Walley, Kelly Schoch, Yong-Hui Jiang, John A Phillips, Melissa S Jones, Pengfei Liu, David R Murdock, Lindsay C Burrage, Brendan Lee, Jill A Rosenfeld, Rui Xiao

Faculty, Staff and Students Publications

Advanced bioinformatics algorithms allow detection of multiple-exon copy-number variations (CNVs) from exome sequencing (ES) data, while detection of single-exon CNVs remains challenging. A retrospective review of Baylor Genetics' clinical ES patient cohort identified four individuals with homozygous single-exon deletions of TBCK (exon 23, NM_001163435.2), a gene associated with an autosomal recessive neurodevelopmental phenotype. To evaluate the prevalence of this deletion and its contribution to disease, we retrospectively analyzed single nucleotide polymorphism (SNP) array data for 8194 individuals undergoing ES, followed by PCR confirmation and RT-PCR on individuals carrying homozygous or heterozygous exon 23 TBCK deletions. A fifth individual was diagnosed …

Growth Parameters In Children With Achondroplasia: A 7-Year, Prospective, Multinational, Observational Study, Ravi Savarirayan, Melita Irving, Paul Harmatz, Borja Delgado, William R Wilcox, John Philips, Natalie Owen, Carlos A Bacino, Louise Tofts, Joel Charrow, Lynda E Polgreen, Julie Hoover-Fong, Paul Arundel, Ignacio Ginebreda, Howard M Saal, Donald Basel, Rosendo Ullot Font, Keiichi Ozono, Michael B Bober, Valerie Cormier-Daire, Kim-Hanh Le Quan Sang, Genevieve Baujat, Yasemin Alanay, Frank Rutsch, Daniel Hoernschemeyer, Klaus Mohnike, Hiroshi Mochizuki, Asako Tajima, Yumiko Kotani, David D Weaver, Klane K White, Clare Army, Kevin Larrimore, Keith Gregg, George Jeha, Claire Milligan, Elena Fisheleva, Alice Huntsman-Labed, Jonathan Day

Faculty, Staff and Students Publications

Purpose: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.

Methods: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.

Results: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants < 1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants < 1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged < 1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.

Conclusion: This study represents one of the largest datasets of prospectively collected …

Spectrum Of Ddc Variants Causing Aromatic L-Amino Acid Decarboxylase (Aadc) Deficiency And Pathogenicity Interpretation Using Acmg-Amp/Acgs Recommendations, Nastassja Himmelreich, Riccardo Montioli, Sven F Garbade, Jeffrey Kopesky, Sarah H Elsea, Carla Carducci, Carla B Voltattorni, Nenad Blau

Faculty, Staff and Students Publications

Pathogenic variants in dopa decarboxylase (DDC), the gene encoding the aromatic l-amino acid decarboxylase (AADC) enzyme, lead to a severe deficiency of neurotransmitters, resulting in neurological, neuromuscular, and behavioral manifestations clinically characterized by developmental delays, oculogyric crises, dystonia, and severe neurologic dysfunction in infancy. Historically, therapy has been aimed at compensating for neurotransmitter abnormalities, but response to pharmacologic therapy varies, and in most cases, the therapy shows little or no benefit. A novel human DDC gene therapy was recently approved in the European Union that targets the underlying genetic cause of the disorder, providing a new treatment option for patients …

Privacy-Aware Estimation Of Relatedness In Admixed Populations, Su Wang, Miran Kim, Wentao Li, Xiaoqian Jiang, Han Chen, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Estimation of genetic relatedness, or kinship, is used occasionally for recreational purposes and in forensic applications. While numerous methods were developed to estimate kinship, they suffer from high computational requirements and often make an untenable assumption of homogeneous population ancestry of the samples. Moreover, genetic privacy is generally overlooked in the usage of kinship estimation methods. There can be ethical concerns about finding unknown familial relationships in third-party databases. Similar ethical concerns may arise while estimating and reporting sensitive population-level statistics such as inbreeding coefficients for the concerns around marginalization and stigmatization.

RESULTS: Here, we present SIGFRIED, which makes …

The Evolving Privacy And Security Concerns For Genomic Data Analysis And Sharing As Observed From The Idash Competition, Tsung-Ting Kuo, Xiaoqian Jiang, Haixu Tang, Xiaofeng Wang, Arif Harmanci, Miran Kim, Kai Post, Diyue Bu, Tyler Bath, Jihoon Kim, Weijie Liu, Hongbo Chen, Lucila Ohno-Machado

Faculty, Staff and Student Publications

Concerns regarding inappropriate leakage of sensitive personal information as well as unauthorized data use are increasing with the growth of genomic data repositories. Therefore, privacy and security of genomic data have become increasingly important and need to be studied. With many proposed protection techniques, their applicability in support of biomedical research should be well understood. For this purpose, we have organized a community effort in the past 8 years through the integrating data for analysis, anonymization and sharing consortium to address this practical challenge. In this article, we summarize our experience from these competitions, report lessons learned from the events …

Modification Of The Tumor Microenvironment Enhances Anti-Pd-1 Immunotherapy In Metastatic Melanoma, Guilan Shi, Megan Scott, Cathryn G. Mangiamele, Richard Heller

Bioelectrics Publications

Resistance to checkpoint-blockade treatments is a challenge in the clinic. Both primary and acquired resistance have become major obstacles, greatly limiting the long-lasting effects and wide application of blockade therapy. Many patients with metastatic melanoma eventually require further therapy. The absence of T-cell infiltration to the tumor site is a well-accepted contributor limiting immune checkpoint inhibitor efficacy. In this study, we combined intratumoral injection of plasmid IL-12 with electrotransfer and anti-PD-1 in metastatic B16F10 melanoma tumor model to increase tumor-infiltrating lymphocytes and improve therapeutic efficacy. We showed that effective anti-tumor responses required a subset of tumor-infiltrating CD8⁺ and CD4 …

A Multi-Omics Framework Reveals Strawberry Flavor Genes And Their Regulatory Elements, Zhen Fan, Denise M Tieman, Steven J Knapp, Philipp Zerbe, Randi Famula, Christopher R Barbey, Kevin M Folta, Rodrigo R Amadeu, Manbo Lee, Youngjae Oh, Seonghee Lee, Vance M Whitaker

Faculty, Staff and Student Publications

Flavor is essential to consumer preference of foods and is an increasing focus of plant breeding programs. In fruit crops, identifying genes underlying volatile organic compounds has great promise to accelerate flavor improvement, but polyploidy and heterozygosity in many species have slowed progress. Here we use octoploid cultivated strawberry to demonstrate how genomic heterozygosity, transcriptomic intricacy and fruit metabolomic diversity can be treated as strengths and leveraged to uncover fruit flavor genes and their regulatory elements. Multi-omics datasets were generated including an expression quantitative trait loci map with 196 diverse breeding lines, haplotype-phased genomes of a highly-flavored breeding selection, a …

Clinical Exome Sequencing Uncovers A High Frequency Of Mendelian Disorders In Infants With Stroke: A Retrospective Analysis, Runjun D Kumar, Linyan Meng, Pengfei Liu, Christina Y Miyake, Kim C Worley, Weimin Bi, Seema R Lalani

Faculty, Staff and Students Publications

Background:

Stroke causes significant disability and is a common cause of death worldwide. Previous studies have estimated that 1-5% of stroke is attributable to monogenic etiologies. We set out to assess the utility of clinical exome sequencing (ES) in the evaluation of stroke.

Methods:

We retrospectively analyzed 124 individuals who received ES at the Baylor Genetics reference lab between 2012 and 2021 who had stroke as a major part of their reported phenotype.

Results:

Ages ranged from 10 days to 69 years. 8.9% of the cohort received a diagnosis, including 25% of infants less than 1 year old; an additional …

Sea-Phages Research Opportunity, Sarah Ballarin

Trick to the Treat of Internships and Research

Research opportunity targeted for freshmen and sophomores through the SEA-PHAGES program. The goal of the research is to discover new bacteriophages (viruses that infect bacteria) to help combat antibiotic resistance. Phage therapy is a promising alternative to conventional antibiotics. Phages have also been widely used in the food industry to prevent microbial growth on certain foods and are currently being explored as a method for bioremediation of oil spills and wastewater treatment.

Last year, my research team discovered two new bacteriophages: Genamy16 and NovaSharks that were able to infect the bacteria Gordonia rubripertincta. These phages can possibly be used for …

Full Issue, Winthrop Mcnair Research Bulletin

The Winthrop McNair Research Bulletin

Winthrop McNair Research Bulletin Volume 5, Full Issue

Locating Mutagen-Sensitivity Gene Mus109 In The Drosophila Melanogaster Genome Using Deficiency Mapping, Chandani Mitchell

The Winthrop McNair Research Bulletin

The complex processes involved in repairing damaged DNA are still being elucidated. Some genes that are known to have roles in the DNA repair process have been identified, such as the mutagen-sensitivity genes, or mus genes, in Drosophila melanogaster. However, the precise genomic location of some mus genes is still unknown, including mus109. It is known that mutations in mus109 cause chromosomal aberrations resulting in larval death, and previous research has mapped mus109 to a region of the X chromosome consisting of over 520,000 nucleotides and 41 genes. Therefore, this study aimed to locate mus109 using deficiency mapping. The mus109D2 …

Complement Component C4 Structural Variation And Quantitative Traits Contribute To Sex-Biased Vulnerability In Systemic Sclerosis, Martin Kerick, Marialbert Acosta-Herrera, Carmen Pilar Simeón-Aznar, José Luis Callejas, Shervin Assassi, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K De Vries-Bouwstra, Gisela Orozco, Anne Barton, Ariane L Herrick, Chikashi Terao, Yannick Allanore, Carmen Fonseca, Marta Eugenia Alarcón-Riquelme, Timothy R D J Radstake, Lorenzo Beretta, Christopher P Denton, Maureen D Mayes, Javier Martin

Faculty, Staff and Student Publications

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its …

Svat: Secure Outsourcing Of Variant Annotation And Genotype Aggregation, Miran Kim, Su Wang, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Sequencing of thousands of samples provides genetic variants with allele frequencies spanning a very large spectrum and gives invaluable insight into genetic determinants of diseases. Protecting the genetic privacy of participants is challenging as only a few rare variants can easily re-identify an individual among millions. In certain cases, there are policy barriers against sharing genetic data from indigenous populations and stigmatizing conditions.

RESULTS: We present SVAT, a method for secure outsourcing of variant annotation and aggregation, which are two basic steps in variant interpretation and detection of causal variants. SVAT uses homomorphic encryption to encrypt the data at …

A Saturated Map Of Common Genetic Variants Associated With Human Height, Loïc Yengo, Sailaja Vedantam, Eirini Marouli, Julia Sidorenko, Eric Bartell, Saori Sakaue, Marielisa Graff, Anders U Eliasen, Yunxuan Jiang, Sridharan Raghavan, Jenkai Miao, Joshua D Arias, Sarah E Graham, Ronen E Mukamel, Cassandra N Spracklen, Xianyong Yin, Shyh-Huei Chen, Teresa Ferreira, Heather H Highland, Yingjie Ji, Tugce Karaderi, Kuang Lin, Kreete Lüll, Deborah E Malden, Carolina Medina-Gomez, Moara Machado, Amy Moore, Sina Rüeger, Xueling Sim, Scott Vrieze, Tarunveer S Ahluwalia, Masato Akiyama, Matthew A Allison, Marcus Alvarez, Mette K Andersen, Alireza Ani, Vivek Appadurai, Liubov Arbeeva, Seema Bhaskar, Lawrence F Bielak, Sailalitha Bollepalli, Lori L Bonnycastle, Jette Bork-Jensen, Jonathan P Bradfield, Yuki Bradford, Peter S Braund, Jennifer A Brody, Kristoffer S Burgdorf, Brian E Cade, Hui Cai, Qiuyin Cai, Archie Campbell, Marisa Cañadas-Garre, Eulalia Catamo, Jin-Fang Chai, Xiaoran Chai, Li-Ching Chang, Yi-Cheng Chang, Chien-Hsiun Chen, Alessandra Chesi, Seung Hoan Choi, Ren-Hua Chung, Massimiliano Cocca, Maria Pina Concas, Christian Couture, Gabriel Cuellar-Partida, Rebecca Danning, E Warwick Daw, Frauke Degenhard, Graciela E Delgado, Alessandro Delitala, Ayse Demirkan, Xuan Deng, Poornima Devineni, Alexander Dietl, Maria Dimitriou, Latchezar Dimitrov, Rajkumar Dorajoo, Arif B Ekici, Jorgen E Engmann, Zammy Fairhurst-Hunter, Aliki-Eleni Farmaki, Jessica D Faul, Juan-Carlos Fernandez-Lopez, Lukas Forer, Margherita Francescatto, Sandra Freitag-Wolf, Christian Fuchsberger, Tessel E Galesloot, Yan Gao, Zishan Gao, Frank Geller, Olga Giannakopoulou, Franco Giulianini, Anette P Gjesing, Anuj Goel, Scott D Gordon, Mathias Gorski, Jakob Grove, Xiuqing Guo, Stefan Gustafsson, Jeffrey Haessler, Thomas F Hansen, Aki S Havulinna, Simon J Haworth, Jing He, Nancy Heard-Costa, Prashantha Hebbar, George Hindy, Yuk-Lam A Ho, Edith Hofer, Elizabeth Holliday, Katrin Horn, Whitney E Hornsby, Jouke-Jan Hottenga, Hongyan Huang, Jie Huang, Alicia Huerta-Chagoya, Jennifer E Huffman, Yi-Jen Hung, Shaofeng Huo, Mi Yeong Hwang, Hiroyuki Iha, Daisuke D Ikeda, Masato Isono, Anne U Jackson, Susanne Jäger, Iris E Jansen, Ingegerd Johansson, Jost B Jonas, Anna Jonsson, Torben Jørgensen, Ioanna-Panagiota Kalafati, Masahiro Kanai, Stavroula Kanoni, Line L Kårhus, Anuradhani Kasturiratne, Tomohiro Katsuya, Takahisa Kawaguchi, Rachel L Kember, Katherine A Kentistou, Han-Na Kim, Young Jin Kim, Marcus E Kleber, Maria J Knol, Azra Kurbasic, Marie Lauzon, Phuong Le, Rodney Lea, Jong-Young Lee, Hampton L Leonard, Shengchao A Li, Xiaohui Li, Xiaoyin Li, Jingjing Liang, Honghuang Lin, Shih-Yi Lin, Jun Liu, Xueping Liu, Ken Sin Lo, Jirong Long, Laura Lores-Motta, Jian'an Luan, Valeriya Lyssenko, Leo-Pekka Lyytikäinen, Anubha Mahajan, Vasiliki Mamakou, Massimo Mangino, Ani Manichaikul, Jonathan Marten, Manuel Mattheisen, Laven Mavarani, Aaron F Mcdaid, Karina Meidtner, Tori L Melendez, Josep M Mercader, Yuri Milaneschi, Jason E Miller, Iona Y Millwood, Pashupati P Mishra, Ruth E Mitchell, Line T Møllehave, Anna Morgan, Soeren Mucha, Matthias Munz, Masahiro Nakatochi, Christopher P Nelson, Maria Nethander, Chu Won Nho, Aneta A Nielsen, Ilja M Nolte, Suraj S Nongmaithem, Raymond Noordam, Ioanna Ntalla, Teresa Nutile, Anita Pandit, Paraskevi Christofidou, Katri Pärna, Marc Pauper, Eva R B Petersen, Liselotte V Petersen, Niina Pitkänen, Ozren Polašek, Alaitz Poveda, Michael H Preuss, Saiju Pyarajan, Laura M Raffield, Hiromi Rakugi, Julia Ramirez, Asif Rasheed, Dennis Raven, Nigel W Rayner, Carlos Riveros, Rebecca Rohde, Daniela Ruggiero, Sanni E Ruotsalainen, Kathleen A Ryan, Maria Sabater-Lleal, Richa Saxena, Markus Scholz, Anoop Sendamarai, Botong Shen, Jingchunzi Shi, Jae Hun Shin, Carlo Sidore, Colleen M Sitlani, Roderick C Slieker, Roelof A J Smit, Albert V Smith, Jennifer A Smith, Laura J Smyth, Lorraine Southam, Valgerdur Steinthorsdottir, Liang Sun, Fumihiko Takeuchi, Divya Sri Priyanka Tallapragada, Kent D Taylor, Bamidele O Tayo, Catherine Tcheandjieu, Natalie Terzikhan, Paola Tesolin, Alexander Teumer, Elizabeth Theusch, Deborah J Thompson, Gudmar Thorleifsson, Paul R H J Timmers, Stella Trompet, Constance Turman, Simona Vaccargiu, Sander W Van Der Laan, Peter J Van Der Most, Jan B Van Klinken, Jessica Van Setten, Shefali S Verma, Niek Verweij, Yogasudha Veturi, Carol A Wang, Chaolong Wang, Lihua Wang, Zhe Wang, Helen R Warren, Wen Bin Wei, Ananda R Wickremasinghe, Matthias Wielscher, Kerri L Wiggins, Bendik S Winsvold, Andrew Wong, Yang Wu, Matthias Wuttke, Rui Xia, Tian Xie, Ken Yamamoto, Jingyun Yang, Jie Yao, Hannah Young, Noha A Yousri, Lei Yu, Lingyao Zeng, Weihua Zhang, Xinyuan Zhang, Jing-Hua Zhao, Wei Zhao, Wei Zhou, Martina E Zimmermann, Magdalena Zoledziewska, Linda S Adair, Hieab H H Adams, Carlos A Aguilar-Salinas, Fahd Al-Mulla, Donna K Arnett, Folkert W Asselbergs, Bjørn Olav Åsvold, John Attia, Bernhard Banas, Stefania Bandinelli, David A Bennett, Tobias Bergler, Dwaipayan Bharadwaj, Ginevra Biino, Hans Bisgaard, Eric Boerwinkle, Carsten A Böger, Klaus Bønnelykke, Dorret I Boomsma, Anders D Børglum, Judith B Borja, Claude Bouchard, Donald W Bowden, Ivan Brandslund, Ben Brumpton, Julie E Buring, Mark J Caulfield, John C Chambers, Giriraj R Chandak, Stephen J Chanock, Nish Chaturvedi, Yii-Der Ida Chen, Zhengming Chen, Ching-Yu Cheng, Ingrid E Christophersen, Marina Ciullo, John W Cole, Francis S Collins, Richard S Cooper, Miguel Cruz, Francesco Cucca, L Adrienne Cupples, Michael J Cutler, Scott M Damrauer, Thomas M Dantoft, Gert J De Borst, Lisette C P G M De Groot, Philip L De Jager, Dominique P V De Kleijn, H Janaka De Silva, George V Dedoussis, Anneke I Den Hollander, Shufa Du, Douglas F Easton, Petra J M Elders, A Heather Eliassen, Patrick T Ellinor, Sölve Elmståhl, Jeanette Erdmann, Michele K Evans, Diane Fatkin, Bjarke Feenstra, Mary F Feitosa, Luigi Ferrucci, Ian Ford, Myriam Fornage, Andre Franke, Paul W Franks, Barry I Freedman, Paolo Gasparini, Christian Gieger, Giorgia Girotto, Michael E Goddard, Yvonne M Golightly, Clicerio Gonzalez-Villalpando, Penny Gordon-Larsen, Harald Grallert, Struan F A Grant, Niels Grarup, Lyn Griffiths, Vilmundur Gudnason, Christopher Haiman, Hakon Hakonarson, Torben Hansen, Catharina A Hartman, Andrew T Hattersley, Caroline Hayward, Susan R Heckbert, Chew-Kiat Heng, Christian Hengstenberg, Alex W Hewitt, Haretsugu Hishigaki, Carel B Hoyng, Paul L Huang, Wei Huang, Steven C Hunt, Kristian Hveem, Elina Hyppönen, William G Iacono, Sahoko Ichihara, M Arfan Ikram, Carmen R Isasi, Rebecca D Jackson, Marjo-Riitta Jarvelin, Zi-Bing Jin, Karl-Heinz Jöckel, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Mika Kähönen, Yoichiro Kamatani, Kui Dong Kang, Jaakko Kaprio, Sharon L R Kardia, Fredrik Karpe, Norihiro Kato, Frank Kee, Thorsten Kessler, Amit V Khera, Chiea Chuen Khor, Lambertus A L M Kiemeney, Bong-Jo Kim, Eung Kweon Kim, Hyung-Lae Kim, Paulus Kirchhof, Mika Kivimaki, Woon-Puay Koh, Heikki A Koistinen, Genovefa D Kolovou, Jaspal S Kooner, Charles Kooperberg, Anna Köttgen, Peter Kovacs, Adriaan Kraaijeveld, Peter Kraft, Ronald M Krauss, Meena Kumari, Zoltan Kutalik, Markku Laakso, Leslie A Lange, Claudia Langenberg, Lenore J Launer, Loic Le Marchand, Hyejin Lee, Nanette R Lee, Terho Lehtimäki, Huaixing Li, Liming Li, Wolfgang Lieb, Xu Lin, Lars Lind, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Markus Loeffler, Barry London, Steven A Lubitz, Stephen J Lye, David A Mackey, Reedik Mägi, Patrik K E Magnusson, Gregory M Marcus, Pedro Marques Vidal, Nicholas G Martin, Winfried März, Fumihiko Matsuda, Robert W Mcgarrah, Matt Mcgue, Amy Jayne Mcknight, Sarah E Medland, Dan Mellström, Andres Metspalu, Braxton D Mitchell, Paul Mitchell, Dennis O Mook-Kanamori, Andrew D Morris, Lorelei A Mucci, Patricia B Munroe, Mike A Nalls, Saman Nazarian, Amanda E Nelson, Matt J Neville, Christopher Newton-Cheh, Christopher S Nielsen, Markus M Nöthen, Claes Ohlsson, Albertine J Oldehinkel, Lorena Orozco, Katja Pahkala, Päivi Pajukanta, Colin N A Palmer, Esteban J Parra, Cristian Pattaro, Oluf Pedersen, Craig E Pennell, Brenda W J H Penninx, Louis Perusse, Annette Peters, Patricia A Peyser, David J Porteous, Danielle Posthuma, Chris Power, Peter P Pramstaller, Michael A Province, Qibin Qi, Jia Qu, Daniel J Rader, Olli T Raitakari, Sarju Ralhan, Loukianos S Rallidis, Dabeeru C Rao, Susan Redline, Dermot F Reilly, Alexander P Reiner, Sang Youl Rhee, Paul M Ridker, Michiel Rienstra, Samuli Ripatti, Marylyn D Ritchie, Dan M Roden, Frits R Rosendaal, Jerome I Rotter, Igor Rudan, Femke Rutters, Charumathi Sabanayagam, Danish Saleheen, Veikko Salomaa, Nilesh J Samani, Dharambir K Sanghera, Naveed Sattar, Börge Schmidt, Helena Schmidt, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Laura J Scott, Rodney J Scott, Peter Sever, Eric J Shiroma, M Benjamin Shoemaker, Xiao-Ou Shu, Eleanor M Simonsick, Mario Sims, Jai Rup Singh, Andrew B Singleton, Moritz F Sinner, J Gustav Smith, Harold Snieder, Tim D Spector, Meir J Stampfer, Klaus J Stark, David P Strachan, Leen M 'T Hart, Yasuharu Tabara, Hua Tang, Jean-Claude Tardif, Thangavel A Thanaraj, Nicholas J Timpson, Anke Tönjes, Angelo Tremblay, Tiinamaija Tuomi, Jaakko Tuomilehto, Maria-Teresa Tusié-Luna, Andre G Uitterlinden, Rob M Van Dam, Pim Van Der Harst, Nathalie Van Der Velde, Cornelia M Van Duijn, Natasja M Van Schoor, Veronique Vitart, Uwe Völker, Peter Vollenweider, Henry Völzke, Niels H Wacher-Rodarte, Mark Walker, Ya Xing Wang, Nicholas J Wareham, Richard M Watanabe, Hugh Watkins, David R Weir, Thomas M Werge, Elisabeth Widen, Lynne R Wilkens, Gonneke Willemsen, Walter C Willett, James F Wilson, Tien-Yin Wong, Jeong-Taek Woo, Alan F Wright, Jer-Yuarn Wu, Huichun Xu, Chittaranjan S Yajnik, Mitsuhiro Yokota, Jian-Min Yuan, Eleftheria Zeggini, Babette S Zemel, Wei Zheng, Xiaofeng Zhu, Joseph M Zmuda, Alan B Zonderman, John-Anker Zwart, Daniel I Chasman, Yoon Shin Cho, Iris M Heid, Mark I Mccarthy, Maggie C Y Ng, Christopher J O'Donnell, Fernando Rivadeneira, Unnur Thorsteinsdottir, Yan V Sun, E Shyong Tai, Michael Boehnke, Panos Deloukas, Anne E Justice, Cecilia M Lindgren, Ruth J F Loos, Karen L Mohlke, Kari E North, Kari Stefansson, Robin G Walters, Thomas W Winkler, Kristin L Young, Po-Ru Loh, Jian Yang, Tõnu Esko, Themistocles L Assimes, Adam Auton, Goncalo R Abecasis, Cristen J Willer, Adam E Locke, Sonja I Berndt, Guillaume Lettre, Timothy M Frayling, Yukinori Okada, Andrew R Wood, Peter M Visscher, Joel N Hirschhorn

Faculty, Staff and Student Publications

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the …

Usp7 Substrates Identified By Proteomics Analysis Reveal The Specificity Of Usp7, Litong Nie, Chao Wang, Xiaoguang Liu, Hongqi Teng, Siting Li, Min Huang, Xu Feng, Guangsheng Pei, Qinglei Hang, Zhongming Zhao, Boyi Gan, Li Ma, Junjie Chen

Faculty, Staff and Student Publications

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells of

Quality Of Life, Illness Perceptions, And Parental Lived Experiences In Tango2-Related Metabolic Encephalopathy And Arrhythmias, Chaya N Murali, Seema R Lalani, Mahshid S Azamian, Christina Y Miyake, Hadley Stevens Smith

Faculty, Staff and Students Publications

TANGO2 disorder is a rare genetic disease with multi-system effects that causes episodic crises. Quality of life and psychosocial effects of this rare disease have not previously been studied. To examine health-related quality of life (HRQoL), illness perceptions, and lived experience, we surveyed 16 children and 31 parents of children with TANGO2 disorder identified via a disease-specific social media group and research foundation email distribution list. We assessed HRQoL by parent proxy-report and child self-report using the Pediatric Quality of Life Inventory (PedsQL™). Parental perceptions of their child's condition were assessed using the revised illness perceptions questionnaire adapted for TANGO2 …

Genome-Wide Association Analyses Of Physical Activity And Sedentary Behavior Provide Insights Into Underlying Mechanisms And Roles In Disease Prevention, Zhe Wang, Andrew Emmerich, Nicolas J Pillon, Tim Moore, Daiane Hemerich, Marilyn C Cornelis, Eugenia Mazzaferro, Siacia Broos, Tarunveer S Ahluwalia, Traci M Bartz, Amy R Bentley, Lawrence F Bielak, Mike Chong, Audrey Y Chu, Diane Berry, Rajkumar Dorajoo, Nicole D Dueker, Elisa Kasbohm, Bjarke Feenstra, Mary F Feitosa, Christian Gieger, Mariaelisa Graff, Leanne M Hall, Toomas Haller, Fernando P Hartwig, David A Hillis, Ville Huikari, Nancy Heard-Costa, Christina Holzapfel, Anne U Jackson, Åsa Johansson, Anja Moltke Jørgensen, Marika A Kaakinen, Robert Karlsson, Kathleen F Kerr, Boram Kim, Chantal M Koolhaas, Zoltan Kutalik, Vasiliki Lagou, Penelope A Lind, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Massimo Mangino, Christoph Metzendorf, Kristine R Monroe, Alexander Pacolet, Louis Pérusse, Rene Pool, Rebecca C Richmond, Natalia V Rivera, Sebastien Robiou-Du-Pont, Katharina E Schraut, Christina-Alexandra Schulz, Heather M Stringham, Toshiko Tanaka, Alexander Teumer, Constance Turman, Peter J Van Der Most, Mathias Vanmunster, Frank J A Van Rooij, Jana V Van Vliet-Ostaptchouk, Xiaoshuai Zhang, Jing-Hua Zhao, Wei Zhao, Zhanna Balkhiyarova, Marie N Balslev-Harder, Sebastian E Baumeister, John Beilby, John Blangero, Dorret I Boomsma, Soren Brage, Peter S Braund, Jennifer A Brody, Marcel Bruinenberg, Ulf Ekelund, Ching-Ti Liu, John W Cole, Francis S Collins, L Adrienne Cupples, Tõnu Esko, Stefan Enroth, Jessica D Faul, Lindsay Fernandez-Rhodes, Alison E Fohner, Oscar H Franco, Tessel E Galesloot, Scott D Gordon, Niels Grarup, Catharina A Hartman, Gerardo Heiss, Jennie Hui, Thomas Illig, Russell Jago, Alan James, Peter K Joshi, Taeyeong Jung, Mika Kähönen, Tuomas O Kilpeläinen, Woon-Puay Koh, Ivana Kolcic, Peter P Kraft, Johanna Kuusisto, Lenore J Launer, Aihua Li, Allan Linneberg, Jian'an Luan, Pedro Marques Vidal, Sarah E Medland, Yuri Milaneschi, Arden Moscati, Bill Musk, Christopher P Nelson, Ilja M Nolte, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Christine Power, Olli T Raitakari, Mägi Reedik, Alex P Reiner, Paul M Ridker, Igor Rudan, Kathy Ryan, Mark A Sarzynski, Laura J Scott, Robert A Scott, Stephen Sidney, Kristin Siggeirsdottir, Albert V Smith, Jennifer A Smith, Emily Sonestedt, Marin Strøm, E Shyong Tai, Koon K Teo, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Andre G Uitterlinden, Jagadish Vangipurapu, Natasja Van Schoor, Uwe Völker, Gonneke Willemsen, Kayleen Williams, Quenna Wong, Huichun Xu, Kristin L Young, Jian Min Yuan, M Carola Zillikens, Alan B Zonderman, Adam Ameur, Stefania Bandinelli, Joshua C Bis, Michael Boehnke, Claude Bouchard, Daniel I Chasman, George Davey Smith, Eco J C De Geus, Louise Deldicque, Marcus Dörr, Michele K Evans, Luigi Ferrucci, Myriam Fornage, Caroline Fox, Theodore Garland, Vilmundur Gudnason, Ulf Gyllensten, Torben Hansen, Caroline Hayward, Bernardo L Horta, Elina Hyppönen, Marjo-Riitta Jarvelin, W Craig Johnson, Sharon L R Kardia, Lambertus A Kiemeney, Markku Laakso, Claudia Langenberg, Terho Lehtimäki, Loic Le Marchand, Patrik K E Magnusson, Nicholas G Martin, Mads Melbye, Andres Metspalu, David Meyre, Kari E North, Claes Ohlsson, Albertine J Oldehinkel, Marju Orho-Melander, Guillaume Pare, Taesung Park, Oluf Pedersen, Brenda W J H Penninx, Tune H Pers, Ozren Polasek, Inga Prokopenko, Charles N Rotimi, Nilesh J Samani, Xueling Sim, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Nicholas J Timpson, Rob M Van Dam, Nathalie Van Der Velde, Cornelia M Van Duijn, Peter Vollenweider, Henry Völzke, Trudy Voortman, Gérard Waeber, Nicholas J Wareham, David R Weir, Heinz-Erich Wichmann, James F Wilson, Andrea L Hevener, Anna Krook, Juleen R Zierath, Martine A I Thomis, Ruth J F Loos, Marcel Den Hoed

Faculty, Staff and Student Publications

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle …

The Microrna Processor Drosha Is A Candidate Gene For A Severe Progressive Neurological Disorder, Scott Barish, Mumine Senturk, Kelly Schoch, Amanda L Minogue, Diego Lopergolo, Chiara Fallerini, Jake Harland, Jacob H Seemann, Nicholas Stong, Peter G Kranz, Sujay Kansagra, Mohamad A Mikati, Joan Jasien, Mays El-Dairi, Paolo Galluzzi, Francesca Ariani, Alessandra Renieri, Francesca Mari, Michael F Wangler, Swathi Arur, Yong-Hui Jiang, Shinya Yamamoto, Vandana Shashi, Hugo J Bellen

Faculty, Staff and Students Publications

DROSHA encodes a ribonuclease that is a subunit of the Microprocessor complex and is involved in the first step of microRNA (miRNA) biogenesis. To date, DROSHA has not yet been associated with a Mendelian disease. Here, we describe two individuals with profound intellectual disability, epilepsy, white matter atrophy, microcephaly and dysmorphic features, who carry damaging de novo heterozygous variants in DROSHA. DROSHA is constrained for missense variants and moderately intolerant to loss-of-function (o/e = 0.24). The loss of the fruit fly ortholog drosha causes developmental arrest and death in third instar larvae, a severe reduction in brain size and loss …

Dual Mechanisms Implemented By Lin-28 For Positive Regulation Of Hbl-1 Are Necessary For Proper Development Of Distinct Tissues In Caenorhabditis Elegans, Madeleine Minutillo

Graduate School of Biomedical Sciences Theses and Dissertations

In Caenorhabditis elegans, the heterochronic pathway is comprised of a hierarchy of genes that control the proper timing of developmental events. hbl-1 (Hunchback Like-1) encodes an Ikaros family zinc-finger transcription factor that promotes the L2 stage cell fate events of the hypodermis. The downregulation ofhbl-1 is a crucial step for the transition from the L2 to the L3 stage. There are two known processes through which negative regulation of hbl-1 occurs: suppression of hbl-1 expression by 3 let-7 miRNAs through the hbl-1 3’UTR and inhibition of HBL-1 activity by LIN-46. The mechanisms by which hbl-1 is positively regulated have not …

Infection And Transmission Determinants Of Flea-Borne Rickettsioses, Hanna J. Laukaitis

Graduate Theses and Dissertations (2019 - present)

The genus Rickettsia is comprised of Gram-negative, obligate intracellular bacteria that are spread by hematophagous arthropods. Elucidating the factors conferring rickettsial virulence has perplexed investigators for decades, complicated by the lack of efficient genetic tools necessary to uncover rickettsial- and vector-specific factors contributing to persistence. The advent of transposon mutagenesis has enabled the field to make vast developments in uncovering novel rickettsial mechanisms utilized in various host backgrounds. Thus, the aim of this study was to generate Rickettsia felis transposon mutants and characterize novel phenotypes associated with genetic disruption in an arthropod background. Distribution of rickettsiae is reliant on the …

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 …

Structural Basis For The Simultaneous Recognition Of Nemo And Acceptor Ubiquitin By The Hoip Nzf1 Domain, Simin Rahighi, Mamta Iyer, Hamid Oveisi, Sammy Nasser, Vincent Duong

Pharmacy Faculty Articles and Research

Ubiquitination of NEMO by the linear ubiquitin chain assembly complex (LUBAC) is essential for activating the canonical NF-κB signaling pathway. While the NZF1 domain of the HOIP subunit of LUBAC recognizes the NEMO substrate, it is unclear how it cooperates with the catalytic domains in the ubiquitination process. Here, we report a crystal structure of NEMO in complex with HOIP NZF1 and linear diubiquitin chains, in which the two proteins bind to distinct sites on NEMO. Moreover, the NZF1 domain simultaneously interacts with NEMO and Ile44 surface of a proximal ubiquitin from a linear diubiquitin chain, where the C-term tail …

Synthesis And Evaluation Of Anti-Hiv Activity Of Mono- And Di-Substituted Phosphonamidate Conjugates Of Tenofovir, Aaminat Qureshi, Louise A. Ouattara, Naglaa Salem El-Sayed, Amita Verma, Gustavo F. Doncel, Muhammad Iqbal Choudhary, Hina Siddiqui, Keykavous Parang

Pharmacy Faculty Articles and Research

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several …

Genetic Risk, Midlife Life's Simple 7, And Incident Dementia In The Atherosclerosis Risk In Communities Study, Adrienne Tin, Jan Bressler, Jeannette Simino, Kevin J Sullivan, Hao Mei, B Gwen Windham, Michael Griswold, Rebecca F Gottesman, Eric Boerwinkle, Myriam Fornage, Thomas H Mosley

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Higher scores in Life's Simple 7 (LS7), a metric for cardiovascular and brain health, have been associated with lower risk of dementia. It is uncertain whether this association holds among those with high genetic risk of dementia. Our objective is to evaluate the extent that LS7 may offset dementia risk across the range of genetic risk.

METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) Study were followed from 1987-1989 to 2019. We derived midlife LS7 scores and generated genetic risk scores (GRS) using genome-wide summary statistics of Alzheimer disease, which have been used to study the …