Play all audios:
ABSTRACT Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous linkage studies have identified a 451 kb
region of 2q33–35 that exhibited significant evidence of linkage to Mood Disorders among women (but not men) from families with recurrent, early-onset MDD (RE-MDD), a severe and strongly
familial subtype of MDD. This 451 kb region includes _CREB1_, an attractive susceptibility gene for MDD and related disorders. Sequence variations in the _CREB1_ promoter and intron 8 have
been detected that cosegregate with Mood Disorders, or their absence, in women from these families, identifying _CREB1_ as a sex-limited susceptibility gene for unipolar Mood Disorders.
These findings implicate the cAMP signaling pathway in the pathophysiology of Mood Disorders and related conditions. Access through your institution Buy or subscribe This is a preview of
subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only
$21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout
ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS SEX DIFFERENCES IN THE
GENETIC ARCHITECTURE OF DEPRESSION Article Open access 18 June 2020 THE GENETIC BASIS OF MAJOR DEPRESSIVE DISORDER Article Open access 26 January 2023 THE GENETICS OF SEVERE DEPRESSION
Article 15 October 2024 REFERENCES * American Psychiatric Association. _Diagnostic and Statistical Manual of Mental Disorders_, 4th edn. American Psychiatric Association: Washington, DC,
1994. * Robins LN, Regier DA . _Psychiatric Disorders in America: The Epidemiologic Catchment Area Study_. The Free Press: New York, 1991. Google Scholar * US Department of Health and Human
Services. _Mental Health: a Report Of The Surgeon General—Executive Summary_. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center
for Mental Health Services, National Institutes of Health, National Institute of Mental Health: Rockville, MD, 1999. * Angst J, Angst F, Stassen HH . Suicide risk in patients with major
depressive disorder. _J Clin Psychiatry_ 1999; 60(Suppl 2): 57–62. PubMed Google Scholar * US Public Health Service. _The Surgeon General's Call to Action to Prevent Suicide_.
Washington, DC, 1999. URL: http://www.surgeongeneral.gov/library/calltoaction/calltoaction.htm * Zubenko GS, Zubenko WN, Spiker DG, Giles DE, Kaplan BB . Malignancy of recurrent, early-onset
major depression: a family study. _Am J Med Genet (Neuropsychiatr Genet)_ 2001; 105: 690–699. Article CAS Google Scholar * Murray CJ, Lopez AD . Evidence-based health policy: lessons
from the Global Burden of Disease Study. _Science_ 1996; 274: 740–743. Article CAS PubMed Google Scholar * Maher BS, Marazita ML, Zubenko WN, Spiker DG, Giles DE, Kaplan BB _et al_.
Genetic segregation analysis of recurrent, early-onset major depression: evidence for single major locus transmission. _Am J Med Genet (Neuropsychiatr Genet)_ 2002; 114: 214–221. Article
Google Scholar * Zubenko GS, Hughes III HB, Stiffler JS, Zubenko WN, Kaplan BB . Genome survey for susceptibility loci for recurrent, early-onset major depression: results at 10 cM
resolution. _Am J Med Genet (Neuropsychiatr Genet)_ 2002; 114, 413–422. Article Google Scholar * Zubenko GS, Hughes III HB, Maher BH, Stiffler JS, Zubenko WN, Marazita ML . Genetic linkage
of region containing the _CREB1_ gene to depressive disorders in women from families with recurrent, early-onset, major depression. _Am J Med Genet (Neuropsychiatr Genet)_ 2002; 114:
980–987. Article Google Scholar * National Center for Biotechnology Information (NCBI), National Library of Medicine, National Institutes of Health. Entrez Human Map Viewer, Build 30, June
24, 2002. Chromosome 2 Map. URL: http://www.ncbi.nlm.nih.gov. * Mayr B, Montminy M . Transcriptional regulation by the phosphorylation-dependent factor CREB. _Nat Rev Mol Cell Biol_ 2001;
2: 599–609. Article CAS PubMed Google Scholar * Rossby SP, Sulser F . Antidepressants: events beyond the synapse. In: Skolnick P (ed.). _Antidepressants: New Pharmacological Strategies_.
Humana Press: Totowa NJ, 1997, pp 195–212. Google Scholar * Vaidya VA, Duman RS . Depression-emerging insights from neurobiology. _Br Med Bull_ 2001; 57: 61–79. Article CAS PubMed
Google Scholar * Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM . Neurobiology of depression. _Neuron_ 2002; 34: 13–25. Article CAS PubMed Google Scholar * Weeber EJ,
Sweatt JD . Molecular biology of human cognition. _Neuron_ 2002; 33: 845–848. Article CAS PubMed Google Scholar * Zubenko GS . Do susceptibility loci contribute to the expression of
more than one mental disorder? A view from the genetics of Alzheimer's disease. _Mol Psychiatry_ 2000; 5: 131–136. Article CAS PubMed Google Scholar * Lazennec G, Thomas JA,
Katznellenbogen BS . Involvement of cyclic AMP response element binding protein (CREB) and estrogen receptor phosphorylation in the synergistic activation of the estrogen receptor by
estradiol and protein kinase activators. _J Steroid Biochem Mol Biol_ 2001; 77: 193–203. Article CAS PubMed Google Scholar * McEwen BS . Estrogens effects on the brain: multiple sites
and molecular mechanisms. _J Appl Physiol_ 2001; 91: 2785–2801. Article CAS PubMed Google Scholar * Tremblay A, Giguere V . Contribution of steroid receptor co-activator-1 and CREB
binding protein in ligand-independent activity of estrogen receptor _β_. _J Steroid Biochem Mol Biol_ 2001; 77: 19–27. Article CAS PubMed Google Scholar * Spitzer RL, Endicott J .
_Schedule for Affective Disorders and Schizophrenia—Lifetime Version_. New York State Psychiatric Institute, Biometrics Research: New York, 1975. Google Scholar * Puig-Antich J, Orvaschel
H, Tabrizi MA, Chambers W . The Schedule for Affective Disorders and Schizophrenia for School Children—Epidemiologic Version (Kiddie-SADS-E) 3rd edn. New York State Psychiatric Institute and
Yale University School of Medicine, New York, 1980. * Andreasen NC, Rice J, Endicott J, Reich T, Coryell W . The family history approach to diagnosis. How useful is it? _Arch Gen
Psychiatry_ 1986; 43: 421–429. Article CAS PubMed Google Scholar * Weissman MM, Merikangas KR, John K, Wickramaratne P, Prusoff BA, Kidd KK . Family genetic studies of psychiatric
disorders. _Arch Gen Psychiatry_ 1986; 43: 1104–1116. Article CAS PubMed Google Scholar * Endicott J, Andreasen N, Spitzer RL . _Family History—Research Diagnostic Criteria_. New York
State Psychiatric Institute, Biometrics Research: New York, 1975. Google Scholar * Spitzer RL, Endicott J, Robins E . Research diagnostic criteria. Rationale and reliability. _Arch Gen
Psychiatry_ 1978; 35: 773–782. Article CAS PubMed Google Scholar * Zubenko GS, Stiffler JS, Hughes III HB, Fatigati MJ, Zubenko WN . Genome survey for loci that influence successful
aging: sample characterization, method validation, and initial results for the Y chromosome. _Am J Geriatr Psychiatry_ 2002; 10: 619–630. Article PubMed Google Scholar * Zubenko GS,
Hughes HB III, Stiffler JS, Zubenko WN, Kaplan BB . D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women. _Mol Psychiatry_ 2002; 7: 460–467.
Article CAS PubMed Google Scholar * Rozen S, Skaletsky HJ . Primer 3 on the www for general users and for biologist programmers. In: Krawetz S, Misener S (eds). _Bioinformatics Methods
and Protocols: Methods in Molecular Biology_. Humana Press: Totowa, NJ, 2000, pp 365–386. Google Scholar * S.A.G.E. Statistical analysis for genetic epidemiology, Release 4.2. Computer
program package available from the Department of Epidemiology and Biostatistics, Case Western Reserve University, 2002. * Lander ES, Green P . Construction of multilocus genetic maps in
humans. _Proc Natl Acad Sci USA_ 1987; 84: 2363–2367. Article CAS PubMed PubMed Central Google Scholar * Sobel E, Lange K . Descent graphs in pedigree analysis: applications to
haplotyping, location scores, and marker-sharing statistics. _Am J Hum Genet_ 1996; 58: 1323–1337. CAS PubMed PubMed Central Google Scholar * Olson JM . A general conditional-logistic
model for affected-relative-pair linkage studies. _Am J Hum Genet_ 1999; 65: 1760–1769. Article CAS PubMed PubMed Central Google Scholar * Risch N . Linkage strategies for genetically
complex traits. III. The effect of marker polymorphism on analyses of affected relative pairs. _Am J Hum Genet_ 1990; 46: 242–253. CAS PubMed PubMed Central Google Scholar * Goddard KAB,
Witte JS, Suarez BK, Catalona WJ, Olson JM . Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. _Am J Hum Genet_ 2001; 68: 1197–1206.
Article CAS PubMed PubMed Central Google Scholar * Broman KW, Murray JC, Sheffield VC, White RL, Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in
recombination. _Am J Hum Genet_ 1998; 63: 861–869. Article CAS PubMed PubMed Central Google Scholar * Meyer TE, Waeber G, Lin J, Beckmann W, Habener JF . The promoter of the gene
encoding 3′,5′-cyclic adenosine monophosphate (cAMP) response element binding protein contains cAMP response elements: evidence for positive autoregulation of gene transcription.
_Endocrinology_ 1993; 132: 770–780. Article CAS PubMed Google Scholar * Petrij F, Giles R, Breuning M and Hennekam RCM . Rubinstein-Taybi syndrome. In: Shriver CR, Baudet A, Sly W, Valle
D (eds). _The Metabolic and Molecular Basis of Inherited Disease_. McGraw-Hill: New York, 2002, pp 6167–6182. Google Scholar * Levitas AS, Reid CS . Rubenstein–Taybi syndrome, and
psychiatric disorders. _J Intellect Disabil Res_ 1998; 42: 284–292. Article PubMed Google Scholar * Murata T, Kurokawa R, Krones A, Tatsumi K, Ishii M, Taki T . Defect of histone
acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein–Taybi syndrome. _Hum Mol Genet_ 2001; 10: 1071–1076. Article CAS PubMed Google Scholar * Kalkoven
E, Roelfsema JH, Teunissen H, den Boer A, Ariyurek Y, Zantema A _et al_. Loss of CBP acetyltransferase activity by PHD finger mutations in Rubinstein–Taybi syndrome. _Hum Mol Genet_ 2003;
12: 441–450. Article Google Scholar * Selkoe DJ, Podlisny MB . Deciphering the genetic basis of Alzheimer's disease. _Annu Rev Genomics Hum Genet_ 2002; 3: 67–99. Article CAS PubMed
Google Scholar Download references ACKNOWLEDGEMENTS The previous contributions of the research staff of this project, and the families who participated, are gratefully acknowledged. This
work was supported by research project Grants MH48969 and MH60866 (GSZ). Automated DNA sequencing was performed by the Genomics and Proteomics Core Laboratories of the University of
Pittsburgh. Some of the results of this study were obtained using S.A.G.E., supported by US Public Health Service Resource Grant 1-P41-RR03655. GSZ was the recipient of Independent Scientist
Award MH00540 from the National Institute of Mental Health. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh,
PA, USA G S Zubenko, H B Hughes III, J S Stiffler, A Brechbiel, W N Zubenko & M L Marazita * Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of
Pittsburgh, Pittsburgh, PA, USA B S Maher & M L Marazita * Department of Biological Sciences, Mellon College of Science, Carnegie-Mellon University, Pittsburgh, PA, USA G S Zubenko *
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA M L Marazita Authors * G S Zubenko View author publications You can also search
for this author inPubMed Google Scholar * H B Hughes III View author publications You can also search for this author inPubMed Google Scholar * J S Stiffler View author publications You can
also search for this author inPubMed Google Scholar * A Brechbiel View author publications You can also search for this author inPubMed Google Scholar * W N Zubenko View author publications
You can also search for this author inPubMed Google Scholar * B S Maher View author publications You can also search for this author inPubMed Google Scholar * M L Marazita View author
publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to G S Zubenko. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS
ARTICLE CITE THIS ARTICLE Zubenko, G., Hughes, H., Stiffler, J. _et al._ Sequence variations in _CREB1_ cosegregate with depressive disorders in women. _Mol Psychiatry_ 8, 611–618 (2003).
https://doi.org/10.1038/sj.mp.4001354 Download citation * Received: 12 February 2003 * Revised: 06 March 2003 * Accepted: 11 March 2003 * Published: 08 July 2003 * Issue Date: 01 June 2003 *
DOI: https://doi.org/10.1038/sj.mp.4001354 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not
currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * genetics * _CREB1_ * depression * sex-specific * women