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.

2023

Hopiavuori BR, Masser DR, Wilkerson JL, Brush RS, Mandal NA, Anderson RE, Freeman WM. Isolation of Neuronal Synaptic Membranes by Sucrose Gradient Centrifugation. Methods Mol Biol 2625:7-15, 2023 January, PMID: 36653629

Shen Y, Khatri B, Rananaware S, Li D, Ostrov DA, Jain PK, Lessard CJ, Nguyen CQ. Ancestral origins are associated with SARS-CoV-2 susceptibility and protection in a Florida patient population. PLoS One 18:e0276700, 2023 January, PMID: 36649279, PMCID: PMC9844918

2022

Ali Mondal S, Sathiaseelan R, Mann SN, Kamal M, Luo W, Saccon TD, Isola JV, Peelor FF 3rd, Li T, Freeman WF, Miller BF, Stout MB. 17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice. Am J Physiol Endocrinol Metab, 2022 December, PMID: 36516471

Chucair-Elliott AJ, Ocañas SR, Pham K, Van Der Veldt M, Cheyney A, Stanford D, Gurley J, Elliott MH, Freeman WM. Translatomic response of retinal Müller glia to acute and chronic stress. Neurobiol Dis 175:105931, 2022 November, PMID: 36423879

Joachims ML, Khatri B, Li C, Tessneer KL, Ice JA, Stolarczyk AM, Means N, Grundahl KM, Glenn SB, Kelly JA, Lewis DM, Radfar L, Stone DU, Guthridge JM, James JA, Scofield RH, Wiley GB, Wren JD, Gaffney PM, Montgomery CG, Sivils KL, Rasmussen A, Farris AD, Adrianto I, Lessard CJ. Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses. RMD Open 8, 2022 November, PMID: 36456101, PMCID: PMC9717416

Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME, PRECISESADS Clinical Consortium., Shiboski CH, Sjögren’s International Collaborative Clinical Alliance (SICCA)., Wahren-Herlenius M, Ng WF, UK Primary Sjögren’s Syndrome Registry., Sivils KL, Adrianto I, Nordmark G, Lessard CJ. Author Correction: Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells. Nat Commun 13:6519, 2022 October, PMID: 36316359, PMCID: PMC9622850

Brown JL, Peelor FF 3rd, Georgescu C, Wren JD, Kinter M, Tyrrell VJ, O'Donnell VB, Miller BF, Van Remmen H. Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy. Redox Biol 57:102518, 2022 October, PMID: 36283174, PMCID: PMC9593840

Varshney P, Varshney GK. Expanded precision genome-editing toolbox for human disease modeling in zebrafish. Lab Anim (NY), 2022 October, PMID: 36241739

Pasula S, Gopalakrishnan J, Fu Y, Tessneer KL, Wiley MM, Pelikan RC, Kelly JA, Gaffney PM. Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3. Front Genet 13:1011965, 2022 September, PMID: 36199584, PMCID: PMC9527318

Hardin A, Dawkins B, Pezant N, Rasmussen A, Montgomery C. Genetics of neurosarcoidosis. J Neuroimmunol 372:577957, 2022 August, PMID: 36054933

Beans JA, Trinidad SB, Blacksher E, Hiratsuka VY, Spicer P, Woodahl EL, Boyer BB, Lewis CM Jr, Gaffney PM, Garrison NA, Burke W. Communicating Precision Medicine Research: Multidisciplinary Teams and Diverse Communities. Public Health Genomics:1-9, 2022 August, PMID: 35998578

Calì E, Lin SJ, Rocca C, Sahin Y, Al Shamsi A, El Chehadeh S, Chaabouni M, Mankad K, Galanaki E, Efthymiou S, Sudhakar S, Athanasiou-Fragkouli A, Çelik T, Narlı N, Bianca S, Murphy D, De Carvalho Moreira FM, SYNaPS Study Group., Andrea Accogli, Petree C, Huang K, Monastiri K, Edizadeh M, Nardello R, Ognibene M, De Marco P, Ruggieri M, Zara F, Striano P, Şahin Y, Al-Gazali L, Abi Warde MT, Gerard B, Zifarelli G, Beetz C, Fortuna S, Soler M, Valente EM, Varshney G, Maroofian R, Salpietro V, Houlden H. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genet Med, 2022 August, PMID: 36001086

Jang SK, Evans L, Fialkowski A, Arnett DK, Ashley-Koch AE, Barnes KC, Becker DM, Bis JC, Blangero J, Bleecker ER, Boorgula MP, Bowden DW, Brody JA, Cade BE, Jenkins BWC, Carson AP, Chavan S, Cupples LA, Custer B, Damrauer SM, David SP, de Andrade M, Dinardo CL, Fingerlin TE, Fornage M, Freedman BI, Garrett ME, Gharib SA, Glahn DC, Haessler J, Heckbert SR, Hokanson JE, Hou L, Hwang SJ, Hyman MC, Judy R, Justice AE, Kaplan RC, Kardia SLR, Kelly S, Kim W, Kooperberg C, Levy D, Lloyd-Jones DM, Loos RJF, Manichaikul AW, Gladwin MT, Martin LW, Nouraie M, Melander O, Meyers DA, Montgomery CG, North KE, Oelsner EC, Palmer ND, Payton M, Peljto AL, Peyser PA, Preuss M, Psaty BM, Qiao D, Rader DJ, Rafaels N, Redline S, Reed RM, Reiner AP, Rich SS, Rotter JI, Schwartz DA, Shadyab AH, Silverman EK, Smith NL, Smith JG, Smith AV, Smith JA, Tang W, Taylor KD, Telen MJ, Vasan RS, Gordeuk VR, Wang Z, Wiggins KL, Yanek LR, Yang IV, Young KA, Young KL, Zhang Y, Liu DJ, Keller MC, Vrieze S. Rare genetic variants explain missing heritability in smoking. Nat Hum Behav, 2022 August, PMID: 35927319

Khatri B, Tessneer KL, Rasmussen A, Aghakhanian F, Reksten TR, Adler A, Alevizos I, Anaya JM, Aqrawi LA, Baecklund E, Brun JG, Bucher SM, Eloranta ML, Engelke F, Forsblad-d'Elia H, Glenn SB, Hammenfors D, Imgenberg-Kreuz J, Jensen JL, Johnsen SJA, Jonsson MV, Kvarnström M, Kelly JA, Li H, Mandl T, Martín J, Nocturne G, Norheim KB, Palm Ø, Skarstein K, Stolarczyk AM, Taylor KE, Teruel M, Theander E, Venuturupalli S, Wallace DJ, Grundahl KM, Hefner KS, Radfar L, Lewis DM, Stone DU, Kaufman CE, Brennan MT, Guthridge JM, James JA, Scofield RH, Gaffney PM, Criswell LA, Jonsson R, Eriksson P, Bowman SJ, Omdal R, Rönnblom L, Warner B, Rischmueller M, Witte T, Farris AD, Mariette X, Alarcon-Riquelme ME, PRECISESADS Clinical Consortium., Shiboski CH, Sjögren’s International Collaborative Clinical Alliance (SICCA)., Wahren-Herlenius M, Ng WF, UK Primary Sjögren’s Syndrome Registry., Sivils KL, Adrianto I, Nordmark G, Lessard CJ. Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells. Nat Commun 13:4287, 2022 July, PMID: 35896530, PMCID: PMC9329286

Lin SJ, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon ML, Rüschendorf F, Kong IK, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim HG, Varshney GK. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Hum Mutat, 2022 July, PMID: 35815345

Bögershausen N, Krawczyk HE, Jamra RA, Lin SJ, Yigit G, Hüning I, Polo AM, Vona B, Huang K, Schmidt J, Altmüller J, Luppe J, Platzer K, Dörgeloh BB, Busche A, Biskup S, Mendes MI, Smith DEC, Salomons GS, Zibat A, Bültmann E, Nürnberg P, Spielmann M, Lemke JR, Li Y, Zenker M, Varshney GK, Hillen HS, Kratz CP, Wollnik B. WARS1 and SARS1: two tRNA synthetases implicated in autosomal recessive microcephaly. Hum Mutat, 2022 July, PMID: 35790048

Gorbsky GJ, Daum JR, Sapkota H, Summala K, Yoshida H, Georgescu C, Wren JD, Peshkin L, Horb ME. Developing immortal cell lines from Xenopus embryos, four novel cell lines derived from Xenopus tropicalis. Open Biol 12:220089, 2022 July, PMID: 35857907, PMCID: PMC9256088

Wong LL, Bruxvoort CG, Cejda NI, Delaney MR, Otero JR, Forsthoefel DJ. Intestine-enriched apolipoprotein b orthologs are required for stem cell progeny differentiation and regeneration in planarians. Nat Commun 13:3803, 2022 July, PMID: 35778403, PMCID: PMC9249923

Fu C, Wang J, Pallikkuth S, Ding Y, Chen J, Wren JD, Yang Y, Wong KK, Kameyama H, Jayaraman M, Munshi A, Tanaka T, Lidke KA, Zhang XA. EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation. Cell Mol Life Sci 79:389, 2022 June, PMID: 35773608

Trutschel D Dr rer nat, Bost P, Mariette X, Bondet V, Llibre A, Posseme C, Charbit B, Thorball CW, Jonsson R Prof, Lessard CJ, Felten R, Ng WF Prof, Chatenoud L Prof, Dumortier H, Sibilia J, Fellay J, Brokstad KA Prof, Appel S Prof Dr rer nat, Tarn Dr JR, Murci LQ Prof Dr, Mingueneau M, Meyer N, Duffy D, Schwikowski B, Gottenberg JE, Milieu Interieur, ASSESS investigators, and NECESSITY consortium.. Variability in primary Sjögren's syndrome is driven by interferon alpha, and genetically associated with the class II HLA DQ locus. Arthritis Rheumatol, 2022 June, PMID: 35726083

Meas R, Nititham J, Taylor KE, Maher S, Clairmont K, Carufe KEW, Kashgarian M, Nottoli T, Cheong A, Nagel ZD, Gaffney PM, Criswell LA, Sweasy JB. A Human MSH6 Germline Variant Associated With Systemic Lupus Erythematosus Induces Lupus-like Disease in Mice. ACR Open Rheumatol, 2022 June, PMID: 35708944, PMCID: PMC9469486

Dawkins BA, Garman L, Cejda N, Pezant N, Rasmussen A, Rybicki BA, Levin AM, Benchek P, Seshadri C, Mayanja-Kizza H, Iannuzzi MC, Stein CM, Montgomery CG. Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection. Genet Epidemiol, 2022 June, PMID: 35702824

Allani SK, Rayala R, Rivera O, Prentice HM, Chen X, Ramírez-Alcántara V, Canzoneri J, Menzie-Suderam J, Huang X, Georgescu C, Wren JD, Piazza GA, Weissbach H. A novel sulindac derivative protects against oxidative damage by a cyclooxygenase-independent mechanism. J Pharmacol Exp Ther, 2022 June, PMID: 35680377, PMCID: PMC9341458

Vanderlinden LA, Bemis EA, Seifert J, Guthridge JM, Young KA, Demoruelle MK, Feser M, DeJager W, Macwana S, Mikuls TR, O'Dell JR, Weisman MH, Buckner J, Keating RM, Gaffney PM, Kelly JA, Langefeld CD, Deane KD, James JA, Holers VM, Norris JM. Relationship Between a Vitamin D Genetic Risk Score and Autoantibodies Among First-Degree Relatives of Probands With Rheumatoid Arthritis and Systemic Lupus Erythematosus. Front Immunol 13:881332, 2022 June, PMID: 35720397, PMCID: PMC9205604

Ocañas SR, Ansere VA, Tooley KB, Hadad N, Chucair-Elliott AJ, Stanford DR, Rice S, Wronowski B, Pham KD, Hoffman JM, Austad SN, Stout MB, Freeman WM. Differential Regulation of Mouse Hippocampal Gene Expression Sex Differences by Chromosomal Content and Gonadal Sex. Mol Neurobiol, 2022 May, PMID: 35589920, PMCID: PMC9119800

Avalos PN, Forsthoefel DJ. An Emerging Frontier in Intercellular Communication: Extracellular Vesicles in Regeneration. Front Cell Dev Biol 10:849905, 2022 May, PMID: 35646926, PMCID: PMC9130466

Nair GKG, Pollalis D, Wren JD, Georgescu C, Sjoelund V, Lee SY. Proteomic Insight into the Role of Exosomes in Proliferative Vitreoretinopathy Development. J Clin Med 11, 2022 May, PMID: 35628842, PMCID: PMC9143131

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, PMCID: PMC9586602

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, PMCID: PMC9135944

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