Medical Genetics

Erlenmeyer-Kimling, L., Ph.D., Chief, Research Scientist VII
Baron, Miron, M.D., Psychiatrist (Research) II
Corcoran, Cheryl, M.D., Assistant Professor of Clinical Psychiatry
Friedman, David, Ph.D., Research Scientist VI
Harkavy-Friedman, Jill, Ph.D., Assistant Professor of Clinical Psychiatry
Kaufmann, Charles, M.D., Psychiatrist (Research) II
Knowles, James, M.D., Ph.D., Psychiatrist (Research) II
Malaspina, Dolores, M.D., M.P.H., Psychiatrist (Research) II
Ott, Salome, Ph.D., Research Scientist III
Printz, David, M.D., Assistant Clinical Professor
Terwilliger, Joseph, Ph.D., Research Scientist V
Wexler, Nancy S., Ph.D., Higgins Professor, Neurology

OVERVIEW
The Department of Medical Genetics, with 12 investigators (5 M.D., 6 Ph.D., 1 M.D., Ph.D.) and 27 support staff, has 15 federal grants and 3 foundation grants to continue its varied studies of schizophrenia, bipolar disorder, Huntington’s disease, Alzheimer’s disease, obsessive-compulsive disorder, panic disorder, primary pulmonary hypertension, autism, and substance abuse. Huntington’s disease is a single-gene disorder, as may be Alzheimer’s disease and primary familial pulmonary hypertension. Schizophrenia, bipolar disorder and others, however, are complex disorders, each involving a number of genes, as well as environmental influences. Thus, a wide range of approaches to the different disorders is represented in the Department. For schizophrenia and bipolar disorder, for example, these include: genome scans to identify susceptibility alleles, studies of candidate regions; searches for behavioral (neuropsychological, motoric or social deficits) endophenotypes that may predict future development of this disorder in children at genetic risk; searches for environmental and epigenetic factors that may modify phenotypic aspects of the disorder; studies in schizophrenia patients, and recently, a clinic designed to study and offer services to adolescents who are showing disturbed behavior during the putative prepsychotic prodrome of schizophrenia or bipolar psychosis.

CURRENT RESEARCH
Prediction of adult psychopathology has been the goal of an important research study led by Dr. Erlenmeyer-Kimling and her colleagues, in which children of parents with schizophrenia or affective illness as well as children of psychiatrically normal parents have been followed for close to 33 years. A previous finding was that, in children at risk for schizophrenia, deficits in attention, verbal working memory, and neuromotor skills seen in childhood (mean age of about 9.5 years) predict future schizophrenia with good sensitivity and high specificity. Recent findings by Dr. Salome Ott in this same longitudinal study indicate that different forms of thought disorder at about 9.5 years old in childhood are differentially related to later schizophrenia and affective psychoses--that is while both negative and positive symptoms are seen in children who develop adulthood schizophrenia, whereas children who are future bipolar psychotics show only positive symptoms in childhood, and those who develop other nonpsychotic Axis I and no disorder later on show neither negative nor positive symptoms.

Dr. Dolores Malaspina’s group focuses on the heterogeneity and neurobiology of schizophrenia and other nonaffective psychoses. Her work on prenatal determinants of schizophrenia has uncovered a link to paternal age, a finding that is being modeled in inbred mouse strains to identify genetic mechanisms potentially underlying paternal age-related schizophrenia. Dr. Cheryl Corcoran has established a new clinic intended to evaluate and offer preventive intervention to adolescents who appear to be exhibiting prepsychotic prodromal signs of schizophrenia.

Dr. James Knowles’ Molecular Genetics laboratory, with other investigators at Columbia, previously has identified (1) the first autosomal recessive gene for Retinitis pigmentosa, (2) the gene for Primary Pulmonary Hypertension, and (3) both the COMT and AD0RA2A genes as risk factors in the development of panic disorder. In the past year, a region on chromosome 13q has been identified for a newly described disorder syndrome. The lab has also localized several possible loci for bipolar disorder.

Other investigators in the Department of Medical Genetics (Drs. Miron Baron, David Friedman, Jill Harkavy-Friedman, Charles Kaufmann, David Printz, Joe Terwilliger, Nancy Wexler) continue important work, respectively on, identifying bipolar disorder, including collaboration with Dr. Knowles’ lab to localize susceptibility genes; brain electrophysiology in Alzheimer’s disease and normal aging; suicide in schizophrenia; genetic modeling of schizophrenia; treatment and assessment of bipolar patients; application and development of statistical genetics methodology; and collection of neuropsychological, as well as clinical and genetic data in Huntington’s disease families from part of one huge pedigree established in Columbia by a single couple.

EDUCATION AND TRAINING

CLINICAL SERVICES

Bipolar Research Clinic
Co-Directors: Drs. David Printz and Laurie Stricks

Center of Prevention and Evaluation (COPE)
Director: Dr. Cheryl Corcoran

AWARDS AND HONORS
PI/ NARSAD Young Investigator Award: Cheryl Corcoran, M.D.
Dolores Malaspina, Mentor
A Prospective Study Of Life Events And Psychosis Onset In Prodromal Individuals

NARSAD Mentored Scientist Research Award: Carrie Salafia
Dolores Malaspina, M.D., Mentor
Preeclampsia And Schizophrenia

GRANTS

Federally Funded:
PI: Miron Baron, M.D.
#MH59602: MOLECULAR GENETICS OF BIPOLAR DISORDER

NIMH Mentored Clinical Scientist Development Award: Cheryl Corcoran, M.D.
#K23-MH066279-01A2: SCHIZOPHRENIA RISK TO ONSET: NEUROBIOLOGY AND PREVENTION

PI: L. Erlenmeyer-Kimling, Ph.D.
#N2 R01 MH19560-31: PROSPECTIVE STUDY OF CHILDREN OF SCHIZOPHRENIC PARENTS

PI: David Friedman, Ph.D.
#AG09988: AGE-RELATED ERP MEASURES IN ALZHEIMER’S DISEASE

PI: David Friedman, Ph.D.
#HD14959: THE MATURATION OF COGNITIVE-RELATED BRAIN POTENTIALS

PI: David Friedman, Ph.D.
#AG05213: EFFECTS OF AGE ON THE ERP AND CARDIAC WAVEFORM

PI: James A. Knowles, M.D., Ph.D.
#1RO1DA12190: GENETIC RISK FACTORS FOR NICOTINE ADDICTION

PI OF NYSPI SITE: James A. Knowles, M.D., Ph.D.
#1RO1MH50214: COLLLABORATIVE OCD GENETICS STUDY

PI OF NYSPI SITE: James A. Knowles, M.D., Ph.D
#R01DA12853: GENOME-WIDE ANALYSES FOR ADDICTION SUSCEPTIBILITY GENES

CO PI: James A. Knowles, M.D., Ph.D.
#1R0HL60056: GENETIC ASPECTS OF PULMONARY HYPERTENSION

PI: Dolores Malaspina, M.D.
#1K24 MH01699: MID-CAREER INVESTIGATOR AWARD IN CLINICAL SCHIZOPHRENIA RESEARCH

PI: Dolores Malaspina, M.D.
#RO1MH59114: JERUSALEM PERINATAL COHORT SCHZIOPHRENIA STUDY

PI: Dolores Malaspina, M.D.
#R01MH06642801A2: OLFACTORY PROCESSING AND SOCIAL FUNCTION IN SCHIZOPHRENIA

CO PI/TRAINING DIRECTOR: Dolores Malaspina, M.D.
#MH1887007: SCHIZOPHRENIA RESEARCH TRAINING GRANT

PI: Joseph D. Terwilliger, Ph.D
#MH63749: “THEORY R01”

Private Foundation or Industry:

CO-PIs: Cheryl Corcoran, M.D, Dolores Malaspina, M.D.
The Dreyfus Foundation
STRESS AND DILANTIN PROPHYLAXIS IN SCHIZOPHRENIA

PI: James A. Knowles, M.D., Ph.D.
NARSAD
ANXIETY DISORDER GENETICS IN A HOMOGENUS POPULATION

PI: Dolores Malaspina, M.D.
NARSAD
AN ENDOPHENOTYPE FOR SPORADIC SCHIZOPHRENIA

PI: Dolores Malaspina, M.D.
The G. Harold and Leila Y. Mathers Charitable Foundation
TRANSLATIONAL STUDIES OF PATERNAL AGE RELATED SCHIZOPHRENIA

BIBLIOGRAPHY
Abdalla, SA, Galliione CJ, Barst RJ, Horn EM, Knowles JA, Marchuk D, Letarte M, Morse JH: Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. European Respiratory Journal, 23(3): 373-377, 2004.

Brebion G, Bressan RA, Amador X, Malaspina D, Gorman JM: Medications and memory impairment in schizophrenia-the role of anticholinergic drugs. Psychological Medicine, 34:369–374, 2004.

Butler PD, DeSanti LA, Harkavy-Friedman JM, Amador XA, Goetz RR, Javitt DC, Gorman JM. Visual backward masking deficits in schizophrenia: relationship to visual pathway function and symptomatology. Schizophrenia Research, 59(2-3):199-209, 2003.

Corcoran C, Davidson L, Sills-Shahar R, Nickou C, Malaspina D, Miller T, McGlashan T: A qualitative research study of the evolution of symptoms in individuals identified as prodromal to psychosis. Psychiatry Quarterly, 74(4):313-332, 2003.

Corcoran C, Walker E, Huot R, Mittal R, Tessner K, Kestler L, Malaspina D: The Stress Cascade and Schizophrenia: Etiology and Onset. Schizophrenia Bulletin, 29(4):671-693, 2004.

Cycowicz YM, Friedman D, Duff M: Pictures and their colors: what do children remember? Journal of Cognitive Neuroscience, 15:759–768, 2003.

Erlenmeyer-Kimling L, Roberts SA, Rock D: Longitudinal prediction of schizophrenia in a prospective high-risk study. In: Behavior Genetic Principles - Development, Personality, and Psychopathology: Essays in Honor of Irving I. Gottesman (L. DiLalla, ed.). Washington, DC: American Psychological Association, pp.135-144, 2004.

Friedman D: Cognition and aging: a highly selective overview of event-related potential (ERP) data. Journal of Clinical and Experimental Neuropsychology, 25:702-720, 2003.

Friedman D, Cycowicz YM, Dziobek I: Cross-form conceptual relations between sounds: effects on the novelty P3. Cognitive Brain Research 18:58– 64, 2003.

Gaeta H, Friedman D, Hunt G: Stimulus nature and task category dissociate the anterior and posterior aspects of the novelty P3. Psychophysiology, 40:198-208, 2003.

Gaeta H, Friedman D, Ritter W: Auditory selective attention in young and elderly adults: the selection of single versus conjoint features. Psychophysiology, 40:389-406, 2003.

Goudsmit N, Coleman E, Seckinger RA, Wolitzky R, Stanford AD, Corcoran C, Goetz RR, Malaspina D: A brief smell identification test discriminates between deficit and non-deficit schizophrenia. Psychiatry Research, 120(2):155-64, 2003.

Hamilton SP, Slager SL, DeLeon AB, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA: Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder. Neuropsychopharmacology, 29(3):558-565, 2004.

Hamilton SP, Slager SL, Mayo D, Heiman GA, Klein DF, Hodge SE, Fyer AJ Weissman MN, Knowles JA: Investigation of polymorphisms in the CREM gene in panic disorder. Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 126B(1):111-115, 2004.

Harkavy-Friedman JM, Kimhy D, Nelson EA, Venarde DF, Malaspina D, Mann JJ. Suicide attempts in schizophrenia: the role of command auditory hallucinations for suicide. Journal of Clinical Psychiatry, 64(8):871-874, 2003.

Harkavy-Friedman JM, Nelson EA, Venarde DF, Rodenhiser J, Gorman JM, Mann JJ: Suicidal behavior in schizophrenia and schizoaffective disorder: examining the role of depression. Suicide and Life Threatening Behavior, 34(1):66-76, 2004.

Levinson DF, Zubenko GS, Crowe RR, DePaulo RJ, Scheftner WS, Weissman MM, Holmans P, Zubenko WN, Boutelle S, Murphy-Eberenz K, MacKinnon D, McInnis MG, Marta DH, Adams P, Sassoon S, Knowles JA, Thomas J., Chellis J: Genetics of recurrent early-onset depression (GenRED): design and preliminary clinical characteristics of a repository sample for genetic linkage studies. American Journal of Medical Genetics, 119B(1):118-130, 2003.

Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, Williams NM, Schwab SG, Pulver AE, Faraone SV, Brzustowicz LM, Kaufmann CA, Garver DL, Gurling HM, Lindholm E, Coon H, Moises HW, Byerley W, Shaw SH, Mesen A, Sherrington R, O'Neill FA, Walsh D, Kendler KS, Ekelund J, Paunio T, Lonnqvist J, Peltonen L, O'Donovan MC, Owen MJ, Wildenauer DB, Maier W, Nestadt G, Blouin JL, Antonarakis SE, Mowry BJ, Silverman JM, Crowe RR, Cloninger CR, Tsuang MT, Malaspina D, Harkavy-Friedman JM, Svrakic DM, Bassett AS, Holcomb J, Kalsi G, McQuillin A, Brynjolfson J, Sigmundsson T, Petursson H, Jazin E, Zoega T, Helgason T. Genome scan meta-analysis of schizophrenia and bipolar disorder (II) Schizophrenia. American Journal of Human Genetics, 73(1):34-48, 2003.

Lochner C, Hemmings SM, Kinnear CJ, Moolman-Smook JC, Corfield VA, Knowles JA, Niehaus DJ, Stein DJ: Gender in obsessive-compulsive disorder: clinical and genetic findings. European Neuropsychopharmacology, 14:105-113, 2004.

Malaspina D, Simon N, Corcoran C, Mujica-Parodi L, Goetz RR, Gorman J: Using figure ground perception to examine the unitary and heterogeneity models for psychopathology in schizophrenia. Schizophrenia Research, 59(2-3):297-9, 2003.

Mojabai R, Malaspina D, Susser E: The promise of primary prevention in schizophrenia: concepts and assumptions. Schizophrenia Bulletin, 29(4):791-802, 2004

Nenguke T, Aladjem MI, Gusella JF, Wexler NS, Arnheim N; Venezuela HD Project: Candidate DNA replication initiation regions at human trinucleotide repeat disease loci. Human Molecular Genetics, 12(9):1021-1028, 2003.

Nunes H, Humbert M, Sitbon O, Morse JH, Deng Z, Knowles JA, Le Gall C, Parent F, Garcia G, Herve P, Barst RJ, Simonneau G: Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine, 167:1433-1439, 2003.

Printz D, Clark J, Stricks L, Malaspina D: Weight gain in bipolar disorder: causes and treatments. Primary Psychiatry, 10(11), 2003.

Sautter FJ, Bissette G, Wiley J, Manguno-Mire G, Schoenbachler B, Myers L, Johnson JE, Cerbone A, Malaspina D: Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects. Biological Psychiatry, 54(12):1382-1388, 2003.

Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger JR, Craddock N, DePaulo JR, Baron M: Genome scan meta-analysis of schizophrenia and bipolar disorder. Part III: Bipolar disorder. American Journal of Human Genetics, 13:49-62, 2003.

Terwilliger JD, Weiss KM: Confounding, ascertainment bias and the blind quest for a genetic 'fountain of youth.’ Annals of Medicine, 35(7):532-44, 2003.

The U S -Venezuela Collaborative Research Project: Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayan J, Brocklebank D, Cherny SS, Cardon LR, Gray J, Dlouhy SR, Wiktorski S, Hodes ME, Conneally PM, Penney JB, Gusella J, Cha JH, Irizarry M, Rosas D, Hersch S, Hollingsworth Z, MacDonald M, Young AB, Andresen JM, Housman DE, De Young MM, Bonilla E, Stillings T, Negrette A, Snodgrass SR, Martinez-Jaurrieta MD, Ramos-Arroyo MA, Bickham J, Ramos JS, Marshall F, Shoulson I, Rey GJ, Feigin A, Arnheim N, Acevedo-Cruz A, Acosta L, Alvir J, Fischbeck K, Thompson LM, Young A, Dure L, O'Brien CJ, Paulsen J, Brickman A, Krch D, Peery S, Hogarth P, Higgins DS Jr, Landwehrmeyer B: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proceedings of the National Academy of Sciences of the United States of America, 101(10):3498-3503, 2004.

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Yonan AL, Alarcon M, Cheng R, Magnusson PK, Spence SJ, Palmer AA, Grunn A, Juo SH, Terwilliger JD, Liu J, Cantor RM, Geschwind DH, Gilliam TC: A genomewide screen of 345 families for autism-susceptibility loci. American Journal of Human Genetics, 73(4):886-897, 2003.

Yoon SR, Dubeau L, de Young M, Wexler NS, Arnheim N: Huntington disease expansion mutations in humans can occur before meiosis is completed. Proceedings of the National Academy of Sciences of the United States of America, 100(15):8834-8838, 2003.