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.

2021

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

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

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

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

2020

Ansere VA, Ali-Mondal S, Sathiaseelan R, Garcia DN, Isola JVV, Henseb JD, Saccon TD, Ocañas SR, Tooley KB, Stout MB, Schneider A, Freeman WM. Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion. Mech Ageing Dev 194:111425, 2020 December, PMID: 33383072

Qaisar R, Pharaoh G, Bhaskaran S, Xu H, Ranjit R, Bian J, Ahn B, Georgescu C, Wren JD, Van Remmen H. Restoration of Sarcoplasmic Reticulum Ca2 ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice. Int J Mol Sci 22, 2020 December, PMID: 33375170, PMCID: PMC7792969

Nielsen JB, Rom O, Surakka I, Graham SE, Zhou W, Roychowdhury T, Fritsche LG, Gagliano Taliun SA, Sidore C, Liu Y, Gabrielsen ME, Skogholt AH, Wolford B, Overton W, Zhao Y, Chen J, Zhang H, Hornsby WE, Acheampong A, Grooms A, Schaefer A, Zajac GJM, Villacorta L, Zhang J, Brumpton B, Løset M, Rai V, Lundegaard PR, Olesen MS, Taylor KD, Palmer ND, Chen YD, Choi SH, Lubitz SA, Ellinor PT, Barnes KC, Daya M, Rafaels N, Weiss ST, Lasky-Su J, Tracy RP, Vasan RS, Cupples LA, Mathias RA, Yanek LR, Becker LC, Peyser PA, Bielak LF, Smith JA, Aslibekyan S, Hidalgo BA, Arnett DK, Irvin MR, Wilson JG, Musani SK, Correa A, Rich SS, Guo X, Rotter JI, Konkle BA, Johnsen JM, Ashley-Koch AE, Telen MJ, Sheehan VA, Blangero J, Curran JE, Peralta JM, Montgomery C, Sheu WH, Chung RH, Schwander K, Nouraie SM, Gordeuk VR, Zhang Y, Kooperberg C, Reiner AP, Jackson RD, Bleecker ER, Meyers DA, Li X, Das S, Yu K, LeFaive J, Smith A, Blackwell T, Taliun D, Zollner S, Forer L, Schoenherr S, Fuchsberger C, Pandit A, Zawistowski M, Kheterpal S, Brummett CM, Natarajan P, Schlessinger D, Lee S, Kang HM, Cucca F, Holmen OL, Åsvold BO, Boehnke M, Kathiresan S, Abecasis GR, Chen YE, Willer CJ, Hveem K. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nat Commun 11:6417, 2020 December, PMID: 33339817, PMCID: PMC7749177

Bajana S, Thomas K, Georgescu C, Zhao Y, Wren JD, Kovats S, Sun XH. Augmenting E Protein Activity Impairs cDC2 Differentiation at the Pre-cDC Stage. Front Immunol 11:577718, 2020 December, PMID: 33391258, PMCID: PMC7775562

Mann SN, Hadad N, Nelson Holte M, Rothman AR, Sathiaseelan R, Ali Mondal S, Agbaga MP, Unnikrishnan A, Subramaniam M, Hawse J, Huffman DM, Freeman WM, Stout MB. Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α. Elife 9, 2020 December, PMID: 33289482, PMCID: PMC7744101

Garman L, Pelikan RC, Rasmussen A, Lareau CA, Savoy KA, Deshmukh US, Bagavant H, Levin AM, Daouk S, Drake WP, Montgomery CG. Single Cell Transcriptomics Implicate Novel Monocyte and T Cell Immune Dysregulation in Sarcoidosis. Front Immunol 11:567342, 2020 December, PMID: 33363531, PMCID: PMC7753017

Ortiz-Fernández L, Saruhan-Direskeneli G, Alibaz-Oner F, Kaymaz-Tahra S, Coit P, Kong X, Kiprianos AP, Maughan RT, Aydin SZ, Aksu K, Keser G, Kamali S, Inanc M, Springer J, Akar S, Onen F, Akkoc N, Khalidi NA, Koening C, Karadag O, Kiraz S, Forbess L, Langford CA, McAlear CA, Ozbalkan Z, Yavuz S, Çetin GY, Alpay-Kanitez N, Chung S, Ates A, Karaaslan Y, McKinnon-Maksimowicz K, Monach PA, Ozer HTE, Seyahi E, Fresko I, Cefle A, Seo P, Warrington KJ, Ozturk MA, Ytterberg SR, Cobankara V, Onat AM, Duzgun N, Bıcakcıgil M, Yentür SP, Lally L, Manfredi AA, Baldissera E, Erken E, Yazici A, Kısacık B, Kaşifoğlu T, Dalkilic E, Cuthbertson D, Pagnoux C, Sreih A, Reales G, Wallace C, Wren JD, Cunninghame-Graham DS, Vyse TJ, Sun Y, Chen H, Grayson PC, Tombetti E, Jiang L, Mason JC, Merkel PA, Direskeneli H, Sawalha AH. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet, 2020 December, PMID: 33308445, PMCID: PMC7820633

Raj P, Song R, Zhu H, Riediger L, Jun DJ, Liang C, Arana C, Zhang B, Gao Y, Wakeland BE, Dozmorov I, Zhou J, Kelly JA, Lauwerys BR, Guthridge JM, Olsen NJ, Nath SK, Pasare C, van Oers N, Gilkeson G, Tsao BP, Gaffney PM, Gregersen PK, James JA, Zuo X, Karp DR, Li QZ, Wakeland EK. Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus. Genome Biol 21:281, 2020 November, PMID: 33213505, PMCID: PMC7677828

Chucair-Elliott AJ, Ocañas SR, Stanford DR, Ansere VA, Buettner KB, Porter H, Eliason NL, Reid JJ, Sharpe AL, Stout MB, Beckstead MJ, Miller BF, Richardson A, Freeman WM. Inducible cell-specific mouse models for paired epigenetic and transcriptomic studies of microglia and astroglia. Commun Biol 3:693, 2020 November, PMID: 33214681, PMCID: PMC7678837

Chai G, Webb A, Li C, Antaki D, Lee S, Breuss MW, Lang N, Stanley V, Anzenberg P, Yang X, Marshall T, Gaffney P, Wierenga KJ, Chung BH, Tsang MH, Pais LS, Lovgren AK, VanNoy GE, Rehm HL, Mirzaa G, Leon E, Diaz J, Neumann A, Kalverda AP, Manfield IW, Parry DA, Logan CV, Johnson CA, Bonthron DT, Valleley EMA, Issa MY, Abdel-Ghafar SF, Abdel-Hamid MS, Jennings P, Zaki MS, Sheridan E, Gleeson JG. Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly. Neuron, 2020 November, PMID: 33220177

Gurley JM, Gmyrek GB, McClellan ME, Hargis EA, Hauck SM, Dozmorov MG, Wren JD, Carr DJJ, Elliott MH. Neuroretinal-Derived Caveolin-1 Promotes Endotoxin-Induced Inflammation in the Murine Retina. Invest Ophthalmol Vis Sci 61:19, 2020 October, PMID: 33079993, PMCID: PMC7585394

Wolfstetter G, Pfeifer K, Backman M, Masudi TA, Mendoza-García P, Chen S, Sonnenberg H, Sukumar SK, Uçkun E, Varshney GK, Uv A, Palmer RH. Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells. Sci Rep 10:14954, 2020 September, PMID: 32917927, PMCID: PMC7486895

Rao G, Dwivedi SKD, Zhang Y, Dey A, Shameer K, Karthik R, Srikantan S, Hossen MN, Wren JD, Madesh M, Dudley JT, Bhattacharya R, Mukherjee P. MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer. EMBO Rep:e48483, 2020 August, PMID: 32851774, PMCID: PMC7534609

Peng V, Georgescu C, Bakowska A, Pankow A, Qian L, Wren JD, Sun XH. E proteins orchestrate dynamic transcriptional cascades implicated in the suppression of the differentiation of group 2 innate lymphoid cells. J Biol Chem, 2020 August, PMID: 32817168, PMCID: PMC7606671

Pharaoh G, Brown JL, Sataranatarajan K, Kneis P, Bian J, Ranjit R, Hadad N, Georgescu C, Rabinovitch P, Ran Q, Wren JD, Freeman W, Kinter M, Richardson A, Van Remmen H. Targeting cPLA2 derived lipid hydroperoxides as a potential intervention for sarcopenia. Sci Rep 10:13968, 2020 August, PMID: 32811851, PMCID: PMC7435184

Ichino N, Serres MR, Urban RM, Urban MD, Treichel AJ, Schaefbauer KJ, Greif LE, Varshney GK, Skuster KJ, McNulty MS, Daby CL, Wang Y, Liao HK, El-Rass S, Ding Y, Liu W, Anderson JL, Wishman MD, Sabharwal A, Schimmenti LA, Sivasubbu S, Balciunas D, Hammerschmidt M, Farber SA, Wen XY, Xu X, McGrail M, Essner JJ, Burgess SM, Clark KJ, Ekker SC. Building the vertebrate codex using the gene breaking protein trap library. Elife 9, 2020 August, PMID: 32779569, PMCID: PMC7486118

Wolff CA, Lawrence MM, Porter H, Zhang Q, Reid JJ, Laurin JL, Musci RV, Linden MA, Peelor FF 3rd, Wren JD, Creery JS, Cutler KJ, Carson RH, Price JC, Hamilton KL, Miller BF. Sex differences in changes of protein synthesis with rapamycin treatment are minimized when metformin is added to rapamycin. Geroscience, 2020 August, PMID: 32761290

Howell RD, Dominguez-Lopez S, Ocañas SR, Freeman WM, Beckstead MJ. Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters. Neurobiol Aging 95:195-204, 2020 August, PMID: 32846275, PMCID: PMC7606778

Arabnejad M, Montgomery CG, Gaffney PM, McKinney BA. Nearest-Neighbor Projected Distance Regression for Epistasis Detection in GWAS With Population Structure Correction. Front Genet 11:784, 2020 July, PMID: 32774345, PMCID: PMC7387719

Garman L, Montgomery CG, Rivera NV. Recent advances in sarcoidosis genomics: epigenetics, gene expression, and gene by environment (G × E) interaction studies. Curr Opin Pulm Med, 2020 July, PMID: 32701681, PMCID: PMC7735660

Rodríguez-Morales R, Vélez-Negrón V, Torrado-Tapias A, Varshney G, Behra M. Expression patterns of activating transcription factor 5 (atf5a and atf5b) in zebrafish. Gene Expr Patterns:119126, 2020 July, PMID: 32663618

Ansere VA, Freeman WM. Exercising your mind. Science 369:144-145, 2020 July, PMID: 32646988

Joachims ML, Leehan KM, Dozmorov MG, Georgescu C, Pan Z, Lawrence C, Marlin MC, Macwana S, Rasmussen A, Radfar L, Lewis DM, Stone DU, Grundahl K, Scofield RH, Lessard CJ, Wren JD, Thompson LF, Guthridge JM, Sivils KL, Moore JS, Farris AD. Sjögren's Syndrome Minor Salivary Gland CD4 Memory T Cells Associate with Glandular Disease Features and have a Germinal Center T Follicular Helper Transcriptional Profile. J Clin Med 9, 2020 July, PMID: 32650575, PMCID: PMC7408878

Wren JD, Bai Y, Qin ZS, Yan D, Homayouni R. Proceedings of the 2019 MidSouth Computational Biology and Bioinformatics Society (MCBIOS) Conference. BMC Bioinformatics 21:254, 2020 July, PMID: 32631224, PMCID: PMC7336605

Banote RK, Chebli J, Şatır TM, Varshney GK, Camacho R, Ledin J, Burgess SM, Abramsson A, Zetterberg H. Amyloid precursor protein-b facilitates cell adhesion during early development in zebrafish. Sci Rep 10:10127, 2020 June, PMID: 32576936, PMCID: PMC7311384

Agasing AM, Wu Q, Khatri B, Borisow N, Ruprecht K, Brandt AU, Gawde S, Kumar G, Quinn JL, Ko RM, Mao-Draayer Y, Lessard CJ, Paul F, Axtell RC. Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica. Nat Commun 11:2856, 2020 June, PMID: 32503977, PMCID: PMC7275086

Sui Y, Li X, Oh S, Zhang B, Freeman WM, Shin S, Janknecht R. Opposite Roles of the JMJD1A Interaction Partners MDFI and MDFIC in Colorectal Cancer. Sci Rep 10:8710, 2020 May, PMID: 32457453, PMCID: PMC7250871

Sataranatarajan K, Pharaoh G, Brown JL, Ranjit R, Piekarz KM, Street K, Wren JD, Georgescu C, Kinter C, Kinter M, Freeman WM, Richardson A, Van Remmen H. Molecular changes in transcription and metabolic pathways underlying muscle atrophy in the CuZnSOD null mouse model of sarcopenia. Geroscience, 2020 May, PMID: 32394347, PMCID: PMC7394980

Ray-Jones H, Duffus K, McGovern A, Martin P, Shi C, Hankinson J, Gough O, Yarwood A, Morris AP, Adamson A, Taylor C, Ding J, Gaddi VP, Fu Y, Gaffney P, Orozco G, Warren RB, Eyre S. Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31. BMC Biol 18:47, 2020 May, PMID: 32366252, PMCID: PMC7199343

Verstappen GM, Ice JA, Bootsma H, Pringle S, Haacke EA, de Lange K, van der Vries GB, Hickey P, Vissink A, Spijkervet FKL, Lessard CJ, Kroese FGM. Gene expression profiling of epithelium-associated FcRL4 B cells in primary Sjögren's syndrome reveals a pathogenic signature. J Autoimmun 109:102439, 2020 May, PMID: 32201227

Sapkota H, Wren JD, Gorbsky GJ. Chondrosarcoma-associated gene 1 (CSAG1) maintains the integrity of the mitotic centrosome in cells with defective p53. J Cell Sci, 2020 April, PMID: 32295846, PMCID: PMC7272337

Forsthoefel DJ, Cejda NI, Khan UW, Newmark PA. Cell-type diversity and regionalized gene expression in the planarian intestine. Elife 9, 2020 April, PMID: 32240093, PMCID: PMC7117911

Medley SC, Rathnakar BH, Georgescu C, Wren JD, Olson LE. Fibroblast-specific Stat1 deletion enhances the myofibroblast phenotype during tissue repair. Wound Repair Regen, 2020 March, PMID: 32175700, PMCID: PMC7321860

Kiss T, Tarantini S, Csipo T, Balasubramanian P, Nyúl-Tóth Á, Yabluchanskiy A, Wren JD, Garman L, Huffman DM, Csiszar A, Ungvari Z. Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood. Geroscience, 2020 March, PMID: 32172434, PMCID: PMC7205954

Garman L, Pezant N, Pastori A, Savoy KA, Li C, Levin AM, Iannuzzi MC, Rybicki BA, Adrianto I, Montgomery CG. Genome-Wide Association Study of Ocular Sarcoidosis Confirms HLA Associations and Implicates Barrier Function and Autoimmunity in African Americans. Ocul Immunol Inflamm:1-6, 2020 March, PMID: 32141793, PMCID: PMC7483204

Petree C, Varshney GK. MultiFRAGing: Rapid and Simultaneous Genotyping of Multiple Alleles in a Single Reaction. Sci Rep 10:3172, 2020 February, PMID: 32081936, PMCID: PMC7035419

Kiss T, Nyúl-Tóth Á, Balasubramanian P, Tarantini S, Ahire C, Yabluchanskiy A, Csipo T, Farkas E, Wren JD, Garman L, Csiszar A, Ungvari Z. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. Geroscience, 2020 February, PMID: 32056076, PMCID: PMC7206476

Vona B, Doll J, Hofrichter MAH, Haaf T, Varshney GK. Small fish, big prospects: using zebrafish to unravel the mechanisms of hereditary hearing loss. Hear Res:107906, 2020 February, PMID: 32063424, PMCID: PMC7415493