David B. Goldstein, PhD
My research focuses on many aspects of human genetic variation including human genetic diversity, the genetics of disease, and pharmacogenetics. First at Duke University and now at Columbia University, my group, along with large networks of collaborators, has been responsible for a number of well-known discoveries including the gene responsible for Alternating Hemiplegia of Childhood and the role of the IL28B gene in treatment response to Hepatitis C infection. As Director of the Sequencing, Biostatistics, and Bioinformatics Core for the Epi4K Consortium, I have led the collaboration that discovered three novel epilepsy genes to date. My group has also been involved in some of the early applications of next-generation sequencing in the study of undiagnosed diseases. In addition, my group developed a genome-wide scoring system ranking human genes in terms of their intolerance to standing functional genetic variation in the human population.
We demonstrated that the use of this intolerance scoring system facilitates interpreting the clinical significance of mutations found in patients with serious genetic diseases. My group also has a focus on understanding the molecular mechanisms associated with disease-causing variants. In the case of proteins implicated in epilepsies, multielectrode arrays (MEAs) are used to evaluate the effect of mutations on spontaneous neuronal activity. Using MEAs, candidate drugs can also be screened for their efficacy in returning mutant activity profiles to wild-type activity.
Hayeck TJ, Stong N, Wolock CJ, Copeland B, Kamalakaran S, Goldstein DB, Allen AS. Improved pathogenic variant localization via a hierarchical model of sub-regional intolerance. Am J Hum Genet. 2019 Jan 18. [Epub ahead of print]
Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Li Y, Zhang J, Nestor J, Krithivasan P, Lam WY, Mitrotti A, Piva S, Kil BH, Chatterjee D, Reingold R, Bradbury D, DiVecchia M, Snyder H, Mu X, Mehl K, Balderes O, Fasel DA, Weng C, Radhakrishnan J, Canetta P, Appel GB, Bomback AS, Ahn W, Uy NS, Alam S, Cohen DJ, Crew RJ, Dube GK, Rao MK, Kamalakaran S, Copeland B, Ren Z, Bridgers J, Malone CD, Mebane CM, Dagaonkar N, Fellström BC, Haefliger C, Mohan S, Sanna-Cherchi S, Kiryluk K, Fleckner J, March R, Platt A, Goldstein DB, Gharavi AG. Diagnostic utility of exome sequencing for kidney disease.N Engl J Med. 2019 Jan 10;380(2):142-151.
International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun. 2018 Dec 10;9(1):5269.
Gelfman S, Wang Q, Lu YF, Hall D, Bostick CD, Dhindsa R, Halvorsen M, McSweeney KM, Cotterill E, Edinburgh T, Beaumont MA, Frankel WN, Petrovski S, Allen AS, Boland MJ, Goldstein DB, Eglen SJ. meaRtools: An R package for the analysis of neuronal networks recorded on microelectrode arrays. PLoS Comput Biol. 2018 Oct 1;14(10):e1006506.
Kleinstein SE, Rein M, Abdelmalek MF, Guy CD, Goldstein DB, Mae Diehl A, Moylan CA.Whole-Exome Sequencing Study of Extreme Phenotypes of NAFLD. Hepatol Commun. 2018 Sep 5;2(9):1021-1029.
Hemati P, Revah-Politi A, Bassan H, Petrovski S, Bilancia CG, Ramsey K, Griffin NG, Bier L, Cho MT, Rosello M, Lynch SA, Colombo S, Weber A, Haug M, Heinzen EL, Sands TT, Narayanan V, Primiano M, Aggarwal VS, Millan F, Sattler-Holtrop SG, Caro-Llopis A, Pillar N, Baker J, Freedman R, Kroes HY, Sacharow S, Stong N, Lapunzina P, Schneider MC, Mendelsohn NJ, Singleton A, Loik Ramey V, Wou K, Kuzminsky A, Monfort S, Weiss M, Doyle S, Iglesias A, Martinez F, Mckenzie F, Orellana C, van Gassen KLI, Palomares M, Bazak L, Lee A, Bircher A, Basel-Vanagaite L, Hafström M, Houge G; C4RCD Research Group; DDD study, Goldstein DB, Anyane-Yeboa K. Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature. Am J Med Genet A. 2018 Nov;176(11):2259-2275.
Mulhern MS, Stumpel C, Stong N, Brunner HG, Bier L, Lippa N, Riviello J, Rouhl RPW, Kempers M, Pfundt R, Stegmann APA, Kukolich MK, Telegrafi A, Lehman A; CAUSES study, Lopez-Rangel E, Houcinat N, Barth M, den Hollander N, Hoffer MJV, Weckhuysen S; EuroEPINOMICS-RES-MAE working group, Roovers J, Djemie T, Barca D, Ceulemans B, Craiu D, Lemke JR, Korff C, Mefford HC, Meyers CT, Siegler Z, Hiatt SM, Cooper GM, Bebin EM, Snijders Blok L, Veenstra-Knol HE, Baugh EH, Brilstra EH, Volker-Touw CML, van Binsbergen E, Revah-Politi A, Pereira E, McBrian D, Pacault M, Isidor B, Le Caignec C, Gilbert-Dussardier B, Bilan F, Heinzen EL, Goldstein DB, Stevens SJC, Sands TT. NBEA: Developmental disease gene with early generalized epilepsy phenotypes. Ann Neurol. 2018 Nov;84(5):788-795.
Wattacheril J, Shea PR, Mohammad S, Behling C, Aggarwal V, Wilson LA, Yates KP, Ito J, Fishbein M, Stong N, Lavine JE, Goldstein DB. Exome sequencing of an adolescent with nonalcoholic fatty liver disease identifies a clinically actionable case of Wilson disease. Cold Spring Harb Mol Case Stud. 2018 Oct 1;4(5). pii: a003087.
Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R; Alzheimer's Disease Sequencing Project. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 May 24;5(7):832-842.
Shashi V, Schoch K, Spillmann R, Cope H, Tan QK, Walley N, Pena L, McConkie-Rosell A, Jiang YH, Stong N, Need AC, Goldstein DB; Undiagnosed Diseases Network. A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative. Genet Med. 2019 Jan;21(1):161-172.
Kleinstein SE, Shea PR, Allen AS, Koelle DM, Wald A, Goldstein DB. Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2). Genes Immun. 2018 Feb 28. doi: 10.1038/s41435-018-0013-4. [Epub ahead of print]
Kleinstein SE, Shea PR, Stamm LM, Sulkowski M, Goldstein DB, Naggie S. Association of CYP2B6 Single-Nucleotide Polymorphisms Altering Efavirenz Metabolism With Hepatitis C Virus (HCV) Treatment Relapse Among Human Immunodeficiency Virus/HCV-Coinfected African Americans Receiving Ledipasvir/Sofosbuvir in the ION-4 Trial. Clin Infect Dis. 2018 Jun 1;66(12):1953-1956.
Gussow AB, Copeland BR, Dhindsa RS, Wang Q, Petrovski S, Majoros WH, Allen AS, Goldstein DB. Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics. PLoS One. 2017 Aug 10;12(8):e0181604. Erratum in: PLoS One. 2018 Jan 11;13(1):e0191298.
Dugger SA, Platt A, Goldstein DB. Drug development in the era of precision medicine. Nat Rev Drug Discov. 2018 Mar;17(3):183-196.
Zhu X, Padmanabhan R, Copeland B, Bridgers J, Ren Z, Kamalakaran S, O'Driscoll-Collins A, Berkovic SF, Scheffer IE, Poduri A, Mei D, Guerrini R, Lowenstein DH, Allen AS, Heinzen EL, Goldstein DB. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations. PLoS Genet. 2017 Nov 29;13(11):e1007104.
Revah-Politi A, Ganapathi M, Bier L, Cho MT, Goldstein DB, Hemati P, Iglesias A, Juusola J, Pappas J, Petrovski S, Wilson AL, Aggarwal VS, Anyane-Yeboa K. Loss-of-function variants in NFIA provide further support that NFIA is a critical gene in 1p32-p31 deletion syndrome: A four patient series. Am J Med Genet A. 2017 Dec;173(12):3158-3164.
Gelfman S, Wang Q, McSweeney KM, Ren Z, La Carpia F, Halvorsen M, Schoch K, Ratzon F, Heinzen EL, Boland MJ, Petrovski S, Goldstein DB. Annotating pathogenic non-coding variants in genic regions. Nat Commun. 2017 Aug 9;8(1):236.
Petrovski S, Todd JL, Durheim MT, Wang Q, Chien JW, Kelly FL, Frankel C, Mebane CM, Ren Z, Bridgers J, Urban TJ, Malone CD, Finlen Copeland A, Brinkley C, Allen AS, O'Riordan T, McHutchison JG, Palmer SM, Goldstein DB. An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. Am J Respir Crit Care Med. 2017 Jul 1;196(1):82-93
McSweeney KM, Gussow AB, Bradrick SS, Dugger SA, Gelfman S, Wang Q, Petrovski S, Frankel WN, Boland MJ, Goldstein DB. Inhibition of microRNA 128 promotes excitability of cultured cortical neuronal networks.Genome Res. 2016 Oct;26(10):1411-1416. Epub 2016 Aug 11.
Petrovski S, Goldstein DB. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. 2016 Jul 14;17(1):157.