Alexander B. Niculescu III, M.D., Ph.D.
Professor of Psychiatry
Director, Laboratory of Neurophenomics
1991 University of Bucharest Carol Davila School of Medicine, M.D.
1997 The Scripps Research Institute Kellogg School of Science and Technology, Ph.D., Molecular Biology
Convergent Functional Genomics and Phenomics of Bipolar and Related Disorders.
We have developed an approach, termed Convergent Functional Genomics (CFG), for identifying candidate genes, pathways and mechanisms for neuropsychiatric disorders. The approach is based on the integration of gene expression profiling in an appropriate animal model of the illness with human genetic linkage studies. We have applied this approach to bipolar and related disorders, and are currently engaged in pursuing collaborative studies using this approach in alcohol abuse. The candidate genes identified by CFG are pursued at two levels: 1) genetic association studies of functional polymorphisms in families and patients, and 2) studies in transgenic mice. We are particularly interested in circadian clock genes as candidate genes for cycling and switching in bipolar disorders, and are studying the knock-out mouse of the clock gene DBP (D-box binding protein).At a mechanistic level, our work so far has pointed to, among other things, an overlap between mood and pain, and between mood and appetite regulating mechanisms.
Another line of work in our group involves the study of phenotypes- phenomics. The imprecise nature of psychiatric phenotypes has been a rate-limiting step for clinical research and practice in general, and for psychiatric genetics in particular. We have developed an approach, termed PhenoChipping, that applies microarray paradigms and methodology to the empirical study of phenotypes. Our ongoing work in this area is focused on major psychotic disorders (schizophrenia, schizoaffective, bipolar). We are particularly interested in building a bank of blood samples from the subjects that are PhenoChipped, for repeated mining by studies integrating genetic and genomics with phenomics.
Niculescu AB, Chen X, Smeets M, Hengst L, Prives C, Reed SI. Effects of p21 Cip1/Waf1 at both the G1/S and G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and preventing endoreduplication. Molecular and Cellular Biology. 1998; 18: 629-643.
*Niculescu AB. Prophylactic antidepressant treatment before patients are admitted
Lancet 2000; 355: 406-7.
Niculescu AB. Will to live, suicide and euthanasia. Archives of Internal Medicine 2000; 160:1706.
*Niculescu AB, Segal D, Kuczenski R, Barrett T, Hauger R, Kelsoe JR. Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiological Genomics 2000; 4: 83-91.
*Niculescu AB, Kelsoe JR. Convergent functional genomics: application to bipolar disorder. Annals of Medicine 2001; 33:263-271.
*Niculescu AB, Akiskal HS. Proposed endophenotypes of dysthymia: evolutionary, clinical and pharmacogenomic considerations. Molecular Psychiatry 2001; 6: 363-366.
*Niculescu AB, Kelsoe JR. The Human Genome: Genetic Testing and Animal Models. American Journal of Psychiatry 2001; 158:1587
*Niculescu AB, Akiskal HS. Sex hormones, Darwinism and depression. Archives of General Psychiatry 2001; 58:1083-1084.
*Niculescu AB, Kelsoe JR. Finding Genes for Bipolar Disorder in the Functional Genomics Era: From Convergent Functional Genomics to Phenomics and Back. CNS Spectrums 2002; 7: 215-226.
Lohr JB, Kuczenski R, Niculescu AB. Oxidative Mechanisms and Tardive Dyskinesia. CNS Drugs 2003; 17:47-62.
Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB, Kuczenski R, *Niculescu AB. Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Molecular Psychiatry 2004; 9(11):1007-1029.
*Niculescu AB. Genomic studies of mood disorders: the brain as a muscle? Genome Biology. 2005. 6(4):215. Epub 2005 Mar 24.
Bertsch B, Ogden CA, Sidhu K, Le-Niculescu H, Kuczenski R, *Niculescu AB. Convergent functional genomics: a Bayesian candidate gene identification approach for complex disorders. Methods 2005; 37(3):274-279.
Caligiuri MP, Brown GG, Meloy MJ, Eberson S, Niculescu AB, Lohr JB. Striatopallidal regulation of affect in bipolar disorder. The Journal of Affective Disorders 2006; 91(2-3):235-42.
*Niculescu AB, Lulow L, Ogden CA, Le-Niculescu H, Salomon DR, Schork NJ, Caligiuri MP, Lohr JB. PhenoChipping of psychotic disorders: a novel approach for deconstructing and quantitating psychiatric phenotypes. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2006. 141(6):653-662.
Rodd ZA, Bertsch B , Strother WN, Le-Niculescu H, Jerome RE, Lumeng L, Nurnberger JI Jr., Edenberg HJ, McBride WJ, and *Niculescu AB. Candidate genes, pathways and mechanisms for alcoholism and related disorders: an expanded convergent functional genomics approach. The Pharmacogenomics Journal 2007;7(4):222-56.
*Niculescu AB. Polypharmacy in oligopopulations: what psychiatric genetics can teach biological psychiatry. Psychiatric Genetics. 2006. 16(6):241-244.
Le-Niculescu H, Balaraman Y, Patel S, Tan J, Sidhu K, Jerome RE, Kuczenski R, Geyer MA, Edenberg HJ, Nurnberger JI, Faraone SV, Tsuang MT and *Niculescu AB. Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2007; 144B (2):129-158.
Le-Niculescu H, McFarland MJ, Mamidipalli S, Ogden CA, Kuczenski R, Kurian SM, Salomon DR, Tsuang MT, Nurnberger Jr JI, *Niculescu AB. Convergent Functional Genomics of bipolar disorder: From animal model pharmacogenomics to human genetics and biomarkers. Neurosci Biobehav Rev. 2007 31(6):897-903.
Le-Niculescu H, McFarland MJ, Ogden CA, Balaraman Y, Tan J, Patel S , Rich ME, Paulus M, Edenberg HJ, Nurnberger JI, Rodd ZA, Geyer M , Glatt SJ, Faraone SV, Kuczenski R, Tsuang MT and *Niculescu AB. Phenomic, convergent functional genomic and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2008 Mar 5;147(2):134-66.
Liu L, Foroud T, Xuei X, Berrettini W, Byerley W, Coryell W, El-Mallakh R, Gershon E, Kelsoe J, Lawson W, MacKinnon D, McInnis M, McMahon F, Murphy D, Rice J, Scheftner W, Niculescu AB, Meyer ET, Edenberg HJ, Nurnberger Jr. JI. Evidence of association between brain-derived neurotrophic factor (BDNF) gene and bipolar disorder. Psychiatric Genetics. 2008;18(6):267-74.
Le-Niculescu H, Kurian SM , Yehyawi N, Dike C, Patel SD, Edenberg HJ, Tsuang MT, Salomon DR, Nurnberger Jr JI, *Niculescu AB. Identifying Blood Biomarkers For Mood Disorders Using Convergent Functional Genomics. Molecular Psychiatry 2009; 14(2):156-74. Epub 2008 Feb 26.
Le-Niculescu H, Patel SD, Bhat M, Kuczenski R, Faraone SV, Tsuang MT, McMahon F, Schork NJ , Nurnberger Jr. JI, *Niculescu AB. Convergent Functional Genomics of Genome-Wide Association Data for Bipolar Disorder: Comprehensive Identification of Candidate Genes, Pathways and Mechanisms. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2009 150B(2):155-181. Epub 2008 Nov21.
Caligiuri MP, Teulings HL, Dean CE, Niculescu AB, Lohr J. Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone. Hum Mov Sci. 2009 28(5):633-42. Epub 2009 Aug 18
*Niculescu AB, Schork NJ, Salomon DR. Mindscape: a convergent perspective on life, mind, consciousness and happiness. Journal of Affective Disorders 2010 123(1-3):1-8. Epub 2009 July10.
Kurian SM, Le-Niculescu H, Patel S, Bertram D, Davis J, Dike C, Yehyawi N, Lysaker P, Dustin J, Caligiuri M, Lohr J, Lahiri DK, Nurnberger JI, Faraone SV, Geyer MA, Tsuang MT, Schork NJ, Salomon DR, *Niculescu AB. Identification of Blood Biomarkers For Psychosis Using Convergent Functional Genomics. Molecular Psychiatry 2009. November 24 Epub ahead of print.
McGrath CL, Glatt SJ, Sklar P, Le-Niculescu H, Kuczenski R, Doyle EA, Biederman J, Mick E, Faraone SV, *Niculescu AB, Tsuang MT. Evidence for Genetic Association of RORB with Bipolar Disorder. BMC Psychiatry 2009. Nov 12;9:70.
Caligiuri MP, Teulings HL, Dean CE, Niculescu AB 3rd, Lohr JB. Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics. Psychiatry Res. 2010 May 15;177(1-2):77-83.
*Niculescu AB, Le-Niculescu H. Convergent Functional Genomics: What we have learned and can learn about genes, pathways and mechanisms. Neuropsychopharmacology 2010. 35(1):355-6.
*Niculescu AB, Hulvershorn L. Toward Early, Personalized, Rational Polypharmacy In Psychiatry: A Tri-Dimensional Approach. Psychopharm Review 2010. 45(2): 9-16.
*Niculescu AB, Le-Niculescu H. The P-Value Illusion: How to Improve (Psychiatric) Genetic Studies. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2010. Jun 5;153B(4):847-9.
Patel SD, Le-Niculescu H, Koller DL, Green SD, Lahiri DK, McMahon F, Nurnberger JI, *Niculescu AB. Coming to Grips With Complex Disorders: Genetic Risk Prediction in Bipolar Disorder Using Panels of Genes Identified Through Convergent Functional Genomics. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics). 2010. Jun 5;153B(4):850-77. Epub April 9.
Le-Niculescu H, Patel SD, *Niculescu AB. Convergent integration of animal model and human studies of bipolar disorder (manic-depressive illness). Current Opinion in Pharmacology.2010. September 1. Epub ahead of print.