Genes & Human Disease Research Program

The human genome is composed of more than 3 billion nucleotides that essentially functions as a molecular hard drive that stores all the information needed for how the cells in our body function. Of the 3 billion nucleotides, roughly 2% encodes for the different proteins that perform the various cellular functions needed for life. The remaining 98% of the human genome regulates what, when, and how each gene is expressed during the life of a cell. The random inheritance of different variations of the DNA sequences of encoded genes and non-protein coding regulatory regions from a person’s parents provides, in many ways, the characteristics that make each individual unique. Unfortunately, inheritance of genetic variations also increases a person’s risk of developing different human diseases.

The Genes and Human Disease Research Program focuses on identifying and understanding how genetic variations cause human diseases. While our investigators share this focus, each has their own specific interests including determining the function of non-coding RNA, and understanding how the complex 3D organization of the genome, disease-associated non-coding variants, and the epigenome regulate gene expression in health and disease. In addition, our faculty are developing and applying new machine and deep-learning approaches to identify new disease-associated genetic variations and define disease-associated gene networks.

The Genes and Human Disease Research Program works closely with the OMRF CLIA certified Clinical Genomics Center, the OMRF CAP-accredited Biorepository and the OMRF Quantitative Analysis Core. These Cores were established using funding from various grants through the NIH Institutional Development Award (IDeA) program, and continue to be supported by the OMRF. Our investigators benefit from the state-of-the-art sequencing technologies, sample procurement, processing and storage, and data analysis expertise afforded by these Cores.

2022

Bagavant H, Cizio K, Araszkiewicz AM, Papinska JA, Garman L, Li C, Pezant N, Drake WP, Montgomery CG, Deshmukh US. Systemic immune response to vimentin and granuloma formation in a model of pulmonary sarcoidosis. J Transl Autoimmun 5:100153, 2022 April, PMID: 35434591, PMCID: PMC9006845

Wang J, Wren JD, Ding Y, Chen J, Mittal N, Xu C, Li X, Zeng C, Wang M, Shi J, Zhang YH, Han SJ, Zhang XA. EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer. Cancer Lett:215641, 2022 March, PMID: 35339615, PMCID: PMC9036562

Ocañas SR, Pham KD, Blankenship HE, Machalinski AH, Chucair-Elliott AJ, Freeman WM. Minimizing the ex vivo confounds of cell-isolation techniques on transcriptomic and translatomic profiles of purified microglia. eNeuro, 2022 February, PMID: 35228310, PMCID: PMC8970438

Ahn B, Ranjit R, Kneis P, Xu H, Piekarz KM, Freeman WM, Kinter M, Richardson A, Ran Q, Brooks SV, Van Remmen H. Scavenging mitochondrial hydrogen peroxide by peroxiredoxin 3 overexpression attenuates contractile dysfunction and muscle atrophy in a murine model of accelerated sarcopenia. Aging Cell:e13569, 2022 February, PMID: 35199907, PMCID: PMC8920438

Habicher J, Varshney GK, Waldmann L, Snitting D, Allalou A, Zhang H, Ghanem A, Öhman Mägi C, Dierker T, Kjellén L, Burgess SM, Ledin J. Chondroitin/dermatan sulfate glycosyltransferase genes are essential for craniofacial development. PLoS Genet 18:e1010067, 2022 February, PMID: 35192612, PMCID: PMC8896900

Roopnarinesingh XR, Porter H, Giles C, Brown C, Georgescu C, Wren J. Multi-tissue DNA methylation microarray signature is predictive of gene function. Epigenetics:1-15, 2022 February, PMID: 35152835

Kiss T, Nyúl-Tóth Á, Gulej R, Tarantini S, Csipo T, Mukli P, Ungvari A, Balasubramanian P, Yabluchanskiy A, Benyo Z, Conley SM, Wren JD, Garman L, Huffman DM, Csiszar A, Ungvari Z. Old blood from heterochronic parabionts accelerates vascular aging in young mice: transcriptomic signature of pathologic smooth muscle remodeling. Geroscience, 2022 February, PMID: 35124764

Song CJ, Li Z, Ahmed UKB, Bland SJ, Yashchenko A, Liu S, Aloria EJ, Lever JM, Gonzalez NM, Bickel MA, Giles CB, Georgescu C, Wren JD, Lang ML, Benveniste EN, Harrington LE, Tsiokas L, George JF, Jones KL, Crossman DK, Agarwal A, Mrug M, Yoder BK, Hopp K, Zimmerman KA. A Comprehensive Immune Cell Atlas of Cystic Kidney Disease Reveals the Involvement of Adaptive Immune Cells in Injury-Mediated Cyst Progression in Mice. J Am Soc Nephrol, 2022 February, PMID: 35110364, PMCID: PMC8970461

Taub MA, Conomos MP, Keener R, Iyer KR, Weinstock JS, Yanek LR, Lane J, Miller-Fleming TW, Brody JA, Raffield LM, McHugh CP, Jain D, Gogarten SM, Laurie CA, Keramati A, Arvanitis M, Smith AV, Heavner B, Barwick L, Becker LC, Bis JC, Blangero J, Bleecker ER, Burchard EG, Celedón JC, Chang YPC, Custer B, Darbar D, de Las Fuentes L, DeMeo DL, Freedman BI, Garrett ME, Gladwin MT, Heckbert SR, Hidalgo BA, Irvin MR, Islam T, Johnson WC, Kaab S, Launer L, Lee J, Liu S, Moscati A, North KE, Peyser PA, Rafaels N, Seidman C, Weeks DE, Wen F, Wheeler MM, Williams LK, Yang IV, Zhao W, Aslibekyan S, Auer PL, Bowden DW, Cade BE, Chen Z, Cho MH, Cupples LA, Curran JE, Daya M, Deka R, Eng C, Fingerlin TE, Guo X, Hou L, Hwang SJ, Johnsen JM, Kenny EE, Levin AM, Liu C, Minster RL, Naseri T, Nouraie M, Reupena MS, Sabino EC, Smith JA, Smith NL, Su JL, Taylor JG, Telen MJ, Tiwari HK, Tracy RP, White MJ, Zhang Y, Wiggins KL, Weiss ST, Vasan RS, Taylor KD, Sinner MF, Silverman EK, Shoemaker MB, Sheu WH, Sciurba F, Schwartz DA, Rotter JI, Roden D, Redline S, Raby BA, Psaty BM, Peralta JM, Palmer ND, Nekhai S, Montgomery CG, Mitchell BD, Meyers DA, McGarvey ST, NHLBI CARE Network., Mak AC, Loos RJ, Kumar R, Kooperberg C, Konkle BA, Kelly S, Kardia SL, Kaplan R, He J, Gui H, Gilliland FD, Gelb BD, Fornage M, Ellinor PT, de Andrade M, Correa A, Chen YI, Boerwinkle E, Barnes KC, Ashley-Koch AE, Arnett DK, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium., TOPMed Hematology and Hemostasis Working Group., TOPMed Structural Variation Working Group., Laurie CC, Abecasis G, Nickerson DA, Wilson JG, Rich SS, Levy D, Ruczinski I, Aviv A, Blackwell TW, Thornton T, O'Connell J, Cox NJ, Perry JA, Armanios M, Battle A, Pankratz N, Reiner AP, Mathias RA. Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom 2, 2022 January, PMID: 35530816, PMCID: PMC9075703

Piekarz KM, Georgescu C, Wren JD, Towner RA, Van Remmen H. Pharmacologic treatment with OKN-007 reduces alpha-motor neuron loss in spinal cord of aging mice. Geroscience, 2022 January, PMID: 34984634, PMCID: PMC8811061

2021

Norheim KB, Imgenberg-Kreuz J, Alexsson A, Johnsen SJA, Bårdsen K, Brun JG, Dehkordi RK, Theander E, Mandl T, Jonsson R, Ng WF, Lessard CJ, Rasmussen A, Sivilis K, Ronnblom L, Omdal R. Genetic variants at the RTP4/MASP1 locus are associated with fatigue in Scandinavian patients with primary Sjögren's syndrome. RMD Open 7, 2021 December, PMID: 34907023, PMCID: PMC8671987

Sharpe AL, Trzeciak M, Eliason NL, Blankenship HE, Byrd BAM, Douglas PD, Freeman WM, Beckstead MJ. Repeated cocaine or methamphetamine treatment alters astrocytic CRF2 and GLAST expression in the ventral midbrain. Addict Biol:e13120, 2021 November, PMID: 34825430

Bodas M, Subramaniyan B, Moore AR, Metcalf JP, Ocañas SR, Freeman WM, Georgescu C, Wren JD, Walters MS. The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation. Cells 10, 2021 November, PMID: 34831437, PMCID: PMC8620267

Garton J, Shankar M, Chapman B, Rose K, Gaffney PM, Webb CF. Deficiencies in the DNA Binding Protein ARID3a Alter Chromatin Structures Important for Early Human Erythropoiesis. Immunohorizons 5:802-817, 2021 October, PMID: 34663594, PMCID: PMC8900713

Porter HL, Brown CA, Roopnarinesingh X, Giles CB, Georgescu C, Freeman WM, Wren JD. Many chronological aging clocks can be found throughout the epigenome: Implications for quantifying biological aging. Aging Cell:e13492, 2021 October, PMID: 34655509, PMCID: PMC8590098

Van Remmen H, Freeman WM, Miller BF, Kinter M, Wren JD, Chiao A, Towner RA, Snider TA, Sonntag WE, Richardson A. Oklahoma Nathan Shock Aging Center - assessing the basic biology of aging from genetics to protein and function. Geroscience, 2021 October, PMID: 34606039, PMCID: PMC8599778

Rodrigues ACZ, Messi ML, Wang ZM, Bonilla HJ, Freeman WM, Delbono O. Long-term, induced expression of Hand2 in peripheral sympathetic neurons ameliorates sarcopenia in geriatric mice. J Cachexia Sarcopenia Muscle, 2021 September, PMID: 34546662, PMCID: PMC8718059

Witas R, Rasmussen A, Scofield RH, Radfar L, Stone DU, Grundahl K, Lewis D, Sivils KL, Lessard CJ, Farris AD, Nguyen CQ. Defective Efferocytosis in a Murine Model of Sjögren's Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor. Int J Mol Sci 22, 2021 September, PMID: 34575873, PMCID: PMC8466327

Edwards SL, Erdenebat P, Morphis AC, Kumar L, Wang L, Chamera T, Georgescu C, Wren JD, Li J. Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development. Cell Rep 36:109623, 2021 August, PMID: 34469721, PMCID: PMC8442575

Subramaniyan B, Larabee JL, Bodas M, Moore AR, Burgett AWG, Myers DA, Georgescu C, Wren JD, Papin JF, Walters MS. Characterization of the SARS-CoV-2 Host Response in Primary Human Airway Epithelial Cells from Aged Individuals. Viruses 13, 2021 August, PMID: 34452468, PMCID: PMC8402710

Gopalakrishnan J, Tessneer KL, Fu Y, Pasula S, Pelikan RC, Kelly JA, Wiley GB, Gaffney PM. Variants on the UBE2L3-YDJC autoimmune disease risk haplotype increase UBE2L3 gene expression by modulating CTCF and YY1 binding. Arthritis Rheumatol, 2021 July, PMID: 34279042, PMCID: PMC8712360

Shin U, Nakhro K, Oh CK, Carrington B, Song H, Varshney GK, Kim Y, Song H, Jeon S, Robbins G, Kim S, Yoon S, Choi YJ, Kim YJ, Burgess S, Kang S, Sood R, Lee Y, Myung K. Large-scale generation and phenotypic characterization of zebrafish CRISPR mutants of DNA repair genes. DNA Repair (Amst) 107:103173, 2021 July, PMID: 34390914

Lin SJ, Vona B, Barbalho PG, Kaiyrzhanov R, Maroofian R, Petree C, Severino M, Stanley V, Varshney P, Bahena P, Alzahrani F, Alhashem A, Pagnamenta AT, Aubertin G, Estrada-Veras JI, Hernández HAD, Mazaheri N, Oza A, Thies J, Renaud DL, Dugad S, McEvoy J, Sultan T, Pais LS, Tabarki B, Villalobos-Ramirez D, Rad A, Genomics England Research Consortium., Galehdari H, Ashrafzadeh F, Sahebzamani A, Saeidi K, Torti E, Elloumi HZ, Mora S, Palculict TB, Yang H, Wren JD, Ben Fowler, Joshi M, Behra M, Burgess SM, Nath SK, Hanna MG, Kenna M, Merritt JL 2nd, Houlden H, Karimiani EG, Zaki MS, Haaf T, Alkuraya FS, Gleeson JG, Varshney GK. Biallelic variants in KARS1 are associated with neurodevelopmental disorders and hearing loss recapitulated by the knockout zebrafish. Genet Med, 2021 June, PMID: 34172899, PMCID: PMC8956360

Singh B, Maiti GP, Zhou X, Fazel-Najafabadi M, Bae SC, Sun C, Terao C, Okada Y, Chua KH, Kochi Y, Guthridge JM, Zhang H, Weirauch M, James JA, Harley JB, Varshney GK, Looger LL, Nath SK. Lupus susceptibility region containing CDKN1B rs34330 mechanistically influences expression and function of multiple target genes, also linked to proliferation and apoptosis. Arthritis Rheumatol, 2021 May, PMID: 33982894, PMCID: PMC8589926

Colón-Cruz L, Rodriguez-Morales R, Santana-Cruz A, Cantres-Velez J, Torrado-Tapias A, Lin SJ, Yudowski G, Kensler R, Marie B, Burgess SM, Renaud O, Varshney GK, Behra M. Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors. Front Mol Neurosci 14:624265, 2021 April, PMID: 33958989, PMCID: PMC8093779

Sun G, Chen J, Ding Y, Wren JD, Xu F, Lu L, Wang Y, Wang DW, Zhang XA. A Bioinformatics Perspective on the Links Between Tetraspanin-Enriched Microdomains and Cardiovascular Pathophysiology. Front Cardiovasc Med 8:630471, 2021 March, PMID: 33860000, PMCID: PMC8042132

Kwong AM, Blackwell TW, LeFaive J, de Andrade M, Barnard J, Barnes KC, Blangero J, Boerwinkle E, Burchard EG, Cade BE, Chasman DI, Chen H, Conomos MP, Cupples LA, Ellinor PT, Eng C, Gao Y, Guo X, Ryan Irvin M, Kelly TN, Kim W, Kooperberg C, Lubitz SA, Mak ACY, Manichaikul AW, Mathias RA, Montasser ME, Montgomery CG, Musani S, Palmer ND, Peloso GM, Qiao D, Reiner AP, Roden DM, Shoemaker MB, Smith JA, Smith NL, Lasky Su J, Tiwari HK, Weeks DE, Weiss ST, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Analysis Working Group., Scott LJ, Smith AV, Abecasis GR, Boehnke M, Min Kang H. Robust, flexible, and scalable tests for Hardy-Weinberg Equilibrium across diverse ancestries. Genetics, 2021 March, PMID: 33720349, PMCID: PMC8128395

Kurup K, Matyi S, Giles CB, Wren JD, Jones K, Ericsson A, Raftery D, Wang L, Promislow D, Richardson A, Unnikrishnan A. Calorie restriction prevents age-related changes in the intestinal microbiota. Aging (Albany NY) 13:6298-6329, 2021 March, PMID: 33744869, PMCID: PMC7993711

Corbin JM, Georgescu C, Wren JD, Xu C, Asch AS, Ruiz-Echevarría MJ. Seed-mediated RNA interference of androgen signaling and survival networks induces cell death in prostate cancer cells. Mol Ther Nucleic Acids 24:337-351, 2021 March, PMID: 33850637, PMCID: PMC8022159

Dwivedi SKD, Rao G, Dey A, Mukherjee P, Wren JD, Bhattacharya R. Small Non-Coding-RNA in Gynecological Malignancies. Cancers (Basel) 13, 2021 March, PMID: 33802524, PMCID: PMC7961667

Tarbell E, Jiang K, Hennon TR, Holmes L, Williams S, Fu Y, Gaffney PM, Liu T, Jarvis JN. CD4  T cells from children with active juvenile idiopathic arthritis show altered chromatin features associated with transcriptional abnormalities. Sci Rep 11:4011, 2021 February, PMID: 33597588, PMCID: PMC7889855

Shi C, Ray-Jones H, Ding J, Duffus K, Fu Y, Gaddi VP, Gough O, Hankinson J, Martin P, McGovern A, Yarwood A, Gaffney P, Eyre S, Rattray M, Warren RB, Orozco G. Chromatin looping links target genes with genetic risk loci for dermatological traits. J Invest Dermatol, 2021 February, PMID: 33607115, PMCID: PMC8315765

Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, Taliun SAG, Corvelo A, Gogarten SM, Kang HM, Pitsillides AN, LeFaive J, Lee SB, Tian X, Browning BL, Das S, Emde AK, Clarke WE, Loesch DP, Shetty AC, Blackwell TW, Smith AV, Wong Q, Liu X, Conomos MP, Bobo DM, Aguet F, Albert C, Alonso A, Ardlie KG, Arking DE, Aslibekyan S, Auer PL, Barnard J, Barr RG, Barwick L, Becker LC, Beer RL, Benjamin EJ, Bielak LF, Blangero J, Boehnke M, Bowden DW, Brody JA, Burchard EG, Cade BE, Casella JF, Chalazan B, Chasman DI, Chen YI, Cho MH, Choi SH, Chung MK, Clish CB, Correa A, Curran JE, Custer B, Darbar D, Daya M, de Andrade M, DeMeo DL, Dutcher SK, Ellinor PT, Emery LS, Eng C, Fatkin D, Fingerlin T, Forer L, Fornage M, Franceschini N, Fuchsberger C, Fullerton SM, Germer S, Gladwin MT, Gottlieb DJ, Guo X, Hall ME, He J, Heard-Costa NL, Heckbert SR, Irvin MR, Johnsen JM, Johnson AD, Kaplan R, Kardia SLR, Kelly T, Kelly S, Kenny EE, Kiel DP, Klemmer R, Konkle BA, Kooperberg C, Köttgen A, Lange LA, Lasky-Su J, Levy D, Lin X, Lin KH, Liu C, Loos RJF, Garman L, Gerszten R, Lubitz SA, Lunetta KL, Mak ACY, Manichaikul A, Manning AK, Mathias RA, McManus DD, McGarvey ST, Meigs JB, Meyers DA, Mikulla JL, Minear MA, Mitchell BD, Mohanty S, Montasser ME, Montgomery C, Morrison AC, Murabito JM, Natale A, Natarajan P, Nelson SC, North KE, O'Connell JR, Palmer ND, Pankratz N, Peloso GM, Peyser PA, Pleiness J, Post WS, Psaty BM, Rao DC, Redline S, Reiner AP, Roden D, Rotter JI, Ruczinski I, Sarnowski C, Schoenherr S, Schwartz DA, Seo JS, Seshadri S, Sheehan VA, Sheu WH, Shoemaker MB, Smith NL, Smith JA, Sotoodehnia N, Stilp AM, Tang W, Taylor KD, Telen M, Thornton TA, Tracy RP, Van Den Berg DJ, Vasan RS, Viaud-Martinez KA, Vrieze S, Weeks DE, Weir BS, Weiss ST, Weng LC, Willer CJ, Zhang Y, Zhao X, Arnett DK, Ashley-Koch AE, Barnes KC, Boerwinkle E, Gabriel S, Gibbs R, Rice KM, Rich SS, Silverman EK, Qasba P, Gan W, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium., Papanicolaou GJ, Nickerson DA, Browning SR, Zody MC, Zöllner S, Wilson JG, Cupples LA, Laurie CC, Jaquish CE, Hernandez RD, O'Connor TD, Abecasis GR. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590:290-299, 2021 February, PMID: 33568819, PMCID: PMC7875770

Vona B, Mazaheri N, Lin SJ, Dunbar LA, Maroofian R, Azaiez H, Booth KT, Vitry S, Rad A, Rüschendorf F, Varshney P, Fowler B, Beetz C, Alagramam KN, Murphy D, Shariati G, Sedaghat A, Houlden H, Petree C, VijayKumar S, Smith RJH, Haaf T, El-Amraoui A, Bowl MR, Varshney GK, Galehdari H. A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans. Hum Genet, 2021 January, PMID: 33496845, PMCID: PMC8099798

Bodas M, Moore AR, Subramaniyan B, Georgescu C, Wren JD, Freeman WM, Brown BR, Metcalf JP, Walters MS. Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells. Am J Respir Cell Mol Biol, 2021 January, PMID: 33444514, PMCID: PMC8008804

Oyelakin A, Horeth E, Song EC, Min S, Che M, Marzullo B, Lessard CJ, Rasmussen A, Radfar L, Scofield RH, Lewis DM, Stone DU, Grundahl K, De Rossi SS, Kurago Z, Farris AD, Sivils KL, Sinha S, Kramer JM, Romano RA. Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren's Syndrome. Front Immunol 11:606268, 2021 January, PMID: 33488608, PMCID: PMC7821166