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.

2025

Tsaliki M, Cavett J, Kurien BT, Bruxvoort C, Lewis VM, Ice JA, Dave D, Khosravani S, Grundahl K, Lessard CJ, Rasmussen A, Sivils KL, Farris AD, Koelsch KA, Scofield RH. A cross-sectional observational study of patients with sicca with salivary autoantibodies defines a potential new phenotype of Sjögren's disease. Ann Rheum Dis, 2025 May, PMID: 40320334

Kurien BT, Ice JA, Wood RA, Pharaoh G, Cavett J, Lewis V, Bhaskaran S, Rasmussen A, Lessard CJ, Farris AD, Sivilis K, Koelsch KA, Van Remmen H, Scofield RH. Mitochondrial dysfunction and fatigue in Sjögren's disease. RMD Open 11, 2025 April, PMID: 40274303, PMCID: PMC12020762

Efthymiou S, Leo CP, Deng C, Lin SJ, Maroofian R, Lin R, Karagoz I, Zhang K, Kaiyrzhanov R, Scardamaglia A, Owrang D, Turchetti V, Jahnke F, Huang K, Petree C, Derrick AV, Rees MI, Alvi JR, Sultan T, Li C, Jacquemont ML, Tran-Mau-Them F, Valenzuela-Palafoll M, Sidlow R, Yoon G, Morrow MM, Carere DA, O'Connor M, Fleischer J, Gerkes EH, Phornphutkul C, Isidor B, Rivier-Ringenbach C, Philippe C, Kurul SH, Soydemir D, Kara B, Sunnetci-Akkoyunlu D, Bothe V, Platzer K, Wieczorek D, Koch-Hogrebe M, Rahner N, Thuresson AC, Matsson H, Frykholm C, Bozdoğan ST, Bisgin A, Chatron N, Lesca G, Cabet S, Tümer Z, Hjortshøj TD, Rønde G, Marquardt T, Reunert J, Afzal E, Zamani M, Azizimalamiri R, Galehdari H, Nourbakhsh P, Chamanrou N, Chung SK, Suri M, Benke PJ, Zaki MS, Gleeson JG, Calame DG, Pehlivan D, Yilmaz HI, Gezdirici A, Rad A, Abumansour IS, Oprea G, Bereketoğlu MB, Banneau G, Julia S, Zeighami J, Ashoori S, Shariati G, Sedaghat A, Sabri A, Hamid M, Parvas S, Tajudin TA, Abdullah U, Baig SM, Chung WK, Glazunova OO, Sabine S, Cheema HA, Zifarelli G, Bauer P, Sidpra J, Mankad K, Vona B, Fry AE, Varshney GK, Houlden H, Fu D. Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder. Am J Hum Genet, 2025 April, PMID: 40245862

Myers JM, Sandel C, Alvarez K, Garman L, Wiley G, Montgomery C, Gaffney P, Stavrakis S, Fairweather D, Bruno KA, Zhao YD, Cooper LT, Cunningham MW. Cardiac autoantibodies promote a fibrotic transcriptome and reduced ventricular recovery in human myocarditis. Front Immunol 16:1500909, 2025 March, PMID: 40181955, PMCID: PMC11965655

Murach KA, Englund DA, Chambers TL, Dungan CM, Porter HL, Wren JD, Freeman WM, Dupont-Versteegden EE, Wen Y. A satellite cell-dependent epigenetic fingerprint in skeletal muscle identity genes after lifelong physical activity. FASEB J 39:e70435, 2025 March, PMID: 40047419, PMCID: PMC11884312

Burge KY, Georgescu C, Zhong H, Wilson AP, Gunasekaran A, Yu Z, Franca A, Eckert JV, Wren JD, Chaaban H. Spatial transcriptomics delineates potential differences in intestinal phenotypes of cardiac and classical necrotizing enterocolitis. iScience 28:112166, 2025 March, PMID: 40201118, PMCID: PMC11978348

Lin SJ, Huang K, Petree C, Qin W, Varshney P, Varshney GK. Optimizing gRNA selection for high-penetrance F0 CRISPR screening for interrogating disease gene function. Nucleic Acids Res 53, 2025 February, PMID: 40103232, PMCID: PMC11915512

Gui H, Lessard CJ, Liu J, Li M, Adrianto I. Editorial: Integrative genetics and multi-omics of complex human disorders. Front Genet 16:1574431, 2025 February, PMID: 40061127, PMCID: PMC11885495

Scofield RH, Wren JD, Lewis VM. The toll like receptor 7 pathway and the sex bias of systemic lupus erythematosus. Front Immunol 16:1479814, 2025 February, PMID: 40051623, PMCID: PMC11882868

De Kumar B, Krishnan J. Guidelines to Analyze ChIP-Seq Data: Journey Through QC and Analysis Considerations. Methods Mol Biol 2889:193-206, 2025 January, PMID: 39745614

2024

Li R, Taliun SAG, Liao K, Flickinger M, Sobell JL, Genovese G, Locke AE, Chiu RR, LeFaive J, Martins T, Chapman S, Neumann A, Handsaker RE, Arnett DK, Barnes KC, Boerwinkle E, Braff D, Cade BE, Fornage M, Gibbs RA, Hoth KF, Hou L, Kooperberg C, Loos RJF, Metcalf GA, Montgomery CG, Morrison AC, Qin ZS, Redline S, Reiner AP, Rich SS, Rotter JI, Taylor KD, Viaud-Martinez KA, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Genomic Psychiatry Cohort investigators, Bigdeli TB, Gabriel S, Zollner S, Smith AV, Abecasis G, McCarroll S, Pato MT, Pato CN, Boehnke M, Knowles J, Kang HM, Ophoff RA, Ernst J, Scott LJ. Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia. medRxiv, 2024 December, PMID: 39763555, PMCID: PMC11703280

Mortensen L, Koenigsberg CK, Kimbrough TG, Ping J, Adeva GS, Wuertz BR, Gaffney P, Ondrey FG. Analysis of nuclear receptor expression in head and neck cancer. Cancer Genet 290-291:61-71, 2024 December, PMID: 39754894, PMCID: PMC11800142

Isola JVV, Biswas S, Jayarathne H, Hubbart CR, Hense JD, Matsuzaki S, Kinter MT, Humphries KM, Ocañas SR, Sadagurski M, Stout MB. Canagliflozin treatment prevents follicular exhaustion and attenuates hallmarks of ovarian aging in genetically heterogenous mice. Geroscience, 2024 December, PMID: 39672978

Bhaskaran S, Piekarz KM, Brown J, Yang B, Ocañas SR, Wren JD, Georgescu C, Bottoms C, Murphy A, Thomason J, Saunders D, Smith N, Towner R, Van Remmen H. The nitrone compound OKN-007 delays motor neuron loss and disease progression in the G93A mouse model of amyotrophic lateral sclerosis. Front Neurosci 18:1505369, 2024 November, PMID: 39633896, PMCID: PMC11614777

Blankenship HE, Carter KA, Pham KD, Cassidy NT, Markiewicz AN, Thellmann MI, Sharpe AL, Freeman WM, Beckstead MJ. VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction. Nat Commun 15:9673, 2024 November, PMID: 39516200, PMCID: PMC11549218

Zhang Y, Liu Y, Qin W, Zheng S, Xiao J, Xia X, Yuan X, Zeng J, Shi Y, Zhang Y, Ma H, Varshney GK, Fei JF, Liu Y. Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish. Nat Commun 15:9526, 2024 November, PMID: 39496611, PMCID: PMC11535530

Barish S, Lin SJ, Maroofian R, Gezdirici A, Alhebby H, Trimouille A, Biderman Waberski M, Mitani T, Huber I, Tveten K, Holla ØL, Busk ØL, Houlden H, Ghayoor Karimiani E, Beiraghi Toosi M, Shervin Badv R, Najarzadeh Torbati P, Eghbal F, Akhondian J, Al Safar A, Alswaid A, Zifarelli G, Bauer P, Marafi D, Fatih JM, Huang K, Petree C, Calame DG, von der Lippe C, Alkuraya FS, Wali S, Lupski JR, Varshney GK, Posey JE, Pehlivan D. Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia. Am J Hum Genet, 2024 October, PMID: 39471804, PMCID: PMC11568760

Patterson AS, Dugdale J, Koleilat A, Krauss A, Hernandez-Herrera GA, Wallace JG, Petree C, Varshney GK, Schimmenti LA. Vital Dye Uptake of YO-PRO-1 and DASPEI Depends Upon Mechanoelectrical Transduction Function in Zebrafish Hair Cells. J Assoc Res Otolaryngol, 2024 October, PMID: 39433714, PMCID: PMC11683040

Ree R, Lin SJ, Sti Dahl LO, Huang K, Petree C, Varshney GK, Arnesen T. Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish. Life Sci Alliance 7, 2024 October, PMID: 39384430, PMCID: PMC11465159

Chucair-Elliott AJ, Pham K, Cleuren ACA, Schafer CM, Griffin CT, Ocanas SR, Freeman WM, Elliott MH. Comparative Analysis of In vivo Endothelial Cell Translatomes Across Central Nervous System Vascular Beds. Exp Eye Res:110101, 2024 September, PMID: 39303842, PMCID: PMC11532013

Pollalis D, Nair GKG, Leung J, Bloemhof CM, Bailey JK, Pennington BO, Kelly KR, Khan AI, Yeh AK, Sundaram KS, Clegg DO, Peng CC, Xu L, Georgescu C, Wren JD, Lee SY. Dynamics of microRNA secreted via extracellular vesicles during the maturation of embryonic stem cell-derived retinal pigment epithelium. J Extracell Biol 3:e70001, 2024 September, PMID: 39281021, PMCID: PMC11393772

Kim H, Ranjit R, Claflin DR, Georgescu C, Wren JD, Brooks SV, Miller BF, Ahn B. Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle. Aging Cell:e14323, 2024 September, PMID: 39223708, PMCID: PMC11634730

Banks E, Francis V, Lin SJ, Kharfallah F, Fonov V, Lévesque M, Han C, Kulasekaran G, Tuznik M, Bayati A, Al-Khater R, Alkuraya FS, Argyriou L, Babaei M, Bahlo M, Bakhshoodeh B, Barr E, Bartik L, Bassiony M, Bertrand M, Braun D, Buchert R, Budetta M, Cadieux-Dion M, Calame DG, Cope H, Cushing D, Efthymiou S, Elmaksoud MA, El Said HG, Froukh T, Gill HK, Gleeson JG, Gogoll L, Goh ES, Gowda VK, Haack TB, Hashem MO, Hauser S, Hoffman TL, Hogue JS, Hosokawa A, Houlden H, Huang K, Huynh S, Karimiani EG, Kaulfuß S, Korenke GC, Kritzer A, Lee H, Lupski JR, Marco EJ, McWalter K, Minassian A, Minassian BA, Murphy D, Neira-Fresneda J, Northrup H, Nyaga DM, Oehl-Jaschkowitz B, Osmond M, Person R, Pehlivan D, Petree C, Sadleir LG, Saunders C, Schoels L, Shashi V, Spillmann RC, Srinivasan VM, Torbati PN, Tos T, Undiagnosed Diseases Network, Zaki MS, Zhou D, Zweier C, Trempe JF, Durcan TM, Gan-Or Z, Avoli M, Alves C, Varshney GK, Maroofian R, Rudko DA, McPherson PS. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy. Nat Commun 15:7239, 2024 August, PMID: 39174524, PMCID: PMC11341845

Ma H, Stanford D, Freeman WM, Ding XQ. Transcriptomic Analysis Reveals That Excessive Thyroid Hormone Signaling Impairs Phototransduction and Mitochondrial Bioenergetics and Induces Cellular Stress in Mouse Cone Photoreceptors. Int J Mol Sci 25, 2024 July, PMID: 39000540, PMCID: PMC11242393

Qin W, Liang F, Lin SJ, Petree C, Huang K, Zhang Y, Li L, Varshney P, Mourrain P, Liu Y, Varshney GK. ABE-ultramax for high-efficiency biallelic adenine base editing in zebrafish. Nat Commun 15:5613, 2024 July, PMID: 38965236, PMCID: PMC11224239

Cox JEJ, Pham KD, Keck AW, Wright Z, Thomas MA, Freeman WM, Ocañas SR. Flow Cytometry Analysis of Microglial Phenotypes in the Murine Brain During Aging and Disease. Bio Protoc 14:e5018, 2024 June, PMID: 38948260, PMCID: PMC11211077

Kang S, Ko EY, Andrews AE, Shin JE, Nance KJ, Barman PK, Heeger PS, Freeman WM, Benayoun BA, Goodridge HS. Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging. J Neuroinflammation 21:150, 2024 June, PMID: 38840206, PMCID: PMC11155174

Keener R, Chhetri SB, Connelly CJ, Taub MA, Conomos MP, Weinstock J, Ni B, Strober B, Aslibekyan S, Auer PL, Barwick L, Becker LC, Blangero J, Bleecker ER, Brody JA, Cade BE, Celedon JC, Chang YC, Cupples LA, Custer B, Freedman BI, Gladwin MT, Heckbert SR, Hou L, Irvin MR, Isasi CR, Johnsen JM, Kenny EE, Kooperberg C, Minster RL, Naseri T, Viali S, Nekhai S, Pankratz N, Peyser PA, Taylor KD, Telen MJ, Wu B, Yanek LR, Yang IV, Albert C, Arnett DK, Ashley-Koch AE, Barnes KC, Bis JC, Blackwell TW, Boerwinkle E, Burchard EG, Carson AP, Chen Z, Chen YI, Darbar D, de Andrade M, Ellinor PT, Fornage M, Gelb BD, Gilliland FD, He J, Islam T, Kaab S, Kardia SLR, Kelly S, Konkle BA, Kumar R, Loos RJF, Martinez FD, McGarvey ST, Meyers DA, Mitchell BD, Montgomery CG, North KE, Palmer ND, Peralta JM, Raby BA, Redline S, Rich SS, Roden D, Rotter JI, Ruczinski I, Schwartz D, Sciurba F, Shoemaker MB, Silverman EK, Sinner MF, Smith NL, Smith AV, Tiwari HK, Vasan RS, Weiss ST, Williams LK, Zhang Y, Ziv E, Raffield LM, Reiner AP, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology and Hemostasis Working Group, TOPMed Structural Variation Working Group, Arvanitis M, Greider CW, Mathias RA, Battle A. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes. Nat Commun 15:4417, 2024 May, PMID: 38789417, PMCID: PMC11126610

Lincoln MR, Connally N, Axisa PP, Gasperi C, Mitrovic M, van Heel D, Wijmenga C, Withoff S, Jonkers IH, Padyukov L, International Multiple Sclerosis Genetics Consortium, Rich SS, Graham RR, Gaffney PM, Langefeld CD, Vyse TJ, Hafler DA, Chun S, Sunyaev SR, Cotsapas C. Genetic mapping across autoimmune diseases reveals shared associations and mechanisms. Nat Genet, 2024 May, PMID: 38741015

Chucair-Elliott AJ, Ocañas SR, Pham K, Machalinski A, Plafker S, Stout MB, Elliott MH, Freeman WM. Age- and sex- divergent translatomic responses of the mouse retinal pigmented epithelium. Neurobiol Aging 140:41-59, 2024 May, PMID: 38723422, PMCID: PMC11173338

Isola JVV, Hense JD, Osorio CAP, Biswas S, Alberola-Ila J, Ocanas SR, Schneider A, Stout MB. Inflammation, immune cells, and cellular senescence in the aging ovary. Reproduction, 2024 May, PMID: 38744316, PMCID: PMC11301429

Brown CA, Wren JD. AutoGDC: A Python Package for DNA Methylation and Transcription Meta-Analyses. bioRxiv, 2024 April, PMID: 38659836, PMCID: PMC11042378

Chen J, Ding Y, Jiang C, Qu R, Wren JD, Georgescu C, Wang X, Reuter DN, Liu B, Giles CB, Mayr CH, Schiller HB, Dai J, Stipp CS, Subramaniyan B, Wang J, Zuo H, Huang C, Fung KM, Rice HC, Sonnenberg A, Wu D, Walters MS, Zhao YY, Kanie T, Hays FA, Papin JF, Wang DW, Zhang XA. CD151 Maintains Endolysosomal Protein Quality to Inhibit Vascular Inflammation. Circ Res, 2024 April, PMID: 38557119, PMCID: PMC11081830

Komaravolu RK, Mehta-D'souza P, Conner T, Allen M, Lumry J, Batushansky A, Pezant NP, Montgomery CG, Griffin TM. Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis. Osteoarthritis Cartilage, 2024 March, PMID: 38527663, PMCID: PMC11330734

Winnicki MJ, Brown CA, Porter HL, Giles CB, Wren JD. BioVDB: biological vector database for high-throughput gene expression meta-analysis. Front Artif Intell 7:1366273, 2024 March, PMID: 38525301, PMCID: PMC10957786

Fu Y, Kelly JA, Gopalakrishnan J, Pelikan RC, Tessneer KL, Pasula S, Grundahl K, Murphy DA, Gaffney PM. Massively Parallel Reporter Assay Confirms Regulatory Potential of hQTLs and Reveals Important Variants in Lupus and Other Autoimmune Diseases. HGG Adv:100279, 2024 February, PMID: 38389303, PMCID: PMC10943488

Xiong Y, Kullberg S, Garman L, Pezant N, Ellinghaus D, Vasila V, Eklund A, Rybicki BA, Iannuzzi MC, Schreiber S, Müller-Quernheim J, Montgomery CG, Grunewald J, Padyukov L, Rivera NV. Corrigendum: Sex differences in the genetics of sarcoidosis across European and African ancestry populations. Front Med (Lausanne) 11:1382584, 2024 February, PMID: 38449888, PMCID: PMC10915398

Banks E, Francis V, Lin SJ, Kharfallah F, Fonov V, Levesque M, Han C, Kulasekaran G, Tuznik M, Bayati A, Al-Khater R, Alkuraya FS, Argyriou L, Babaei M, Bahlo M, Bakhshoodeh B, Barr E, Bartik L, Bassiony M, Bertrand M, Braun D, Buchert R, Budetta M, Cadieux-Dion M, Calame D, Cope H, Cushing D, Efthymiou S, Elmaksoud MA, El Said HG, Froukh T, Gill HK, Gleeson JG, Gogoll L, Goh ES, Gowda VK, Haack TB, Hashem MO, Hauser S, Hoffman TL, Hogue JS, Hosokawa A, Houlden H, Huang K, Huynh S, Karimiani EG, Kaulfuß S, Korenke GC, Kritzer A, Lee H, Lupski JR, Marco EJ, McWalter K, Minassian A, Minassian BA, Murphy D, Neira-Fresneda J, Northrup H, Nyaga D, Oehl-Jaschkowitz B, Osmond M, Person R, Pehlivan D, Petree C, Sadleir LG, Saunders C, Schoels L, Shashi V, Spillman RC, Srinivasan VM, Torbati PN, Tos T, Undiagnosed Diseases Network, Zaki MS, Zhou D, Zweier C, Trempe JF, Durcan TM, Gan-Or Z, Avoli M, Alves C, Varshney GK, Maroofian R, Rudko DA, McPherson PS. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy. medRxiv, 2024 January, PMID: 38352438, PMCID: PMC10863025

Isola JVV, Ocañas SR, Hubbart CR, Ko S, Mondal SA, Hense JD, Carter HNC, Schneider A, Kovats S, Alberola-Ila J, Freeman WM, Stout MB. A single-cell atlas of the aging mouse ovary. Nat Aging, 2024 January, PMID: 38200272, PMCID: PMC10798902