Cercetare

Promovarea cercetarilor genetice psihiatrice romanesti
BIOMETRIC PSYCHIATRIC GENETICS RESEARCH UNIT

ALEXANDRU OBREGIA PSYCHIATRIC HOSPITAL

CURRENT INTERNATIONAL PROJECT :

CEEX-M3 Contract 122/ 2006 (2006-2008)

Project title:

Promotion of Romanian psychiatric genetics research through international partnership in genetic and epigentic studies of bipolar I disorder (BPGEN)

Sponsor:

The Romanian Ministry of Research and Education

Project coordinator:

Prof. Dr. Maria Grigoroiu-Serbanescu, Ph.D.
Senior Researcher (CPI)
Biometric Psychiatric Genetics Research Unit – Alexandru Obregia Psychiatric Hospital, Bucharest

e-mail: maria.serbanescu@googlemail.com).
Tel: 0040-(0) 21-332.39.29

Partners:

Institute of Virology of The Romanian Academy, Bucharest, Romania
Institute of Medical Genetics , Rheinische Friedrich-Wilhelm University Bonn, Germany
Institute of Human Genetics, Rheinische Friedrich-Wilhelm University Bonn, Germany
Central Institute of Mental Health, Mannheim, Germany
Institute of Neuropathology, Rheinische Friedrich-Wilhelm University Bonn, Germany
Alexandru Obregia Psychiatric Hospital

Project objectives:

- The first objective of the project is the extention of the Romanian involvement in international psychiatric genetics projects through adding the biological molecular dimension to the clinical-biometric level and the setting up of a psychiatric genetics research group in Romania able to participate in international collaborative projects.

- The second objective of the project is the informational and technological transfer through the training of Romanian researchers in Germany in genetic techniques (genome scan, sequencing, identification of new genes) and epigenetics [the microarray techniques DMH (differential methylation hybridization); MSPCR (Methylation Specific PCR)]. These methods will be applied in a pilot study intended to replicate some candidate genes for bipolar disorder (G72 and TPH2 (triptophane hydroxylase 2)) and to explore their methylation pattern in a Romanian sample of about 400 patients and controls.

 
Previous scientific performances of the project coordinator:

a) Relevant publications for the genetics of bipolar I disorder and of major affective disorders

1. Grigoroiu-Serbanescu M., Nöthen MM, Ohlraun S, Propping P, Maier W, Wickramaratne P , Georgescu MJ, Prelipceanu D, Grimberg M, Sima D, Rietschel M (2005). Family History Influences Age of Onset in Bipolar I Disorder in Females but not in Males. American Journal of Medical Genetics – Neuropsychiatric Genetics, 133B, 6-11 (Wiley)

2. Grigoroiu-Serbanescu M, Martinez M, Nöthen MM, Propping P (2001). Different Familial Transmission Patterns in Bipolar I Disorder with Onset Before and After Age 25. American Journal of Medical Genetics – Neuropsychiatric Genetics, 105, 765-773. (Wiley)

3. Grigoroiu-Serbanescu M., Martinez M, Noethen M.M., Propping P., Milea S., Mihailescu R., Patterns of parental transmission and familial aggregation models in bipolar affective disorder. American Journal of Medical Genetics – Neuropsychiatric Genetics, 81, 397-404, 1998 (Wiley),

4. Grigoroiu-Serbanescu M., Wickramaratne P.J., Hodge S.E., Milea S., Mihailescu R., Genetic anticipation and imprinting in bipolar I illness. The British Journal of Psychiatry, 170,(Royal College of Psychiatrists) 162-166, 1997

5. Grigoroiu-Serbanescu M, Nothen M, Propping P, Poustka F, Magureanu S, Vasilescu R,Marinescu E, Ardelean V (1995). Clinical evidence for genomic imprinting in the bipolar Idisorder, Acta Psychiatrica Scandinavica, 1995, 92, 365-370 (Blackwell Synergy)

6. Grigoroiu-Serbanescu M, A trial to apply the concept of imprinting to the manic-depressive illness, The Romanian Journal of Neurology and Psychiatry, 30, 4, 1992, 265-277.

7. Grigoroiu-Serbanescu M., Bipolar disorder – an imprinted disorder ?, in POUSTKA, F., Basic Approaches to Genetic and Molecular Biological Developmental Psychiatry, Quintessenz Verlag, München-London-Chicago, 1994, 139-153.

8. Grigoroiu-Serbanescu M, Christodorescu D, Jipescu I, Totoescu A, Marinescu E, Ardelean V (1989). Psychopathology in children aged 10-17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology, Journal of Affective Disorders, 16, 1989, 167-179 (Elsevier);

9. Grigoroiu-Serbanescu M, Christodorescu D, Magureanu S, Jipescu I, Totoescu A, Marinescu E, Ardelean V, Popa S (1991), Adolescent offspring of endogenous unipolar depressive parents and of normal parents, Journal of Affective Disorders, 21, 1991, 185-198, (Elsevier).

10. Grigoroiu-Serbanescu M, Christodorescu D, Totoescu A, Jipescu I, Marinescu E, Ardelean V, Depressive disorders and depressive personality traits in offspring aged 10-17 of bipolar I and normal parents, The Journal of Youth and Adolescence, 2, 1991, 135-148 (Plenum Press).

11. Grigoroiu-Serbanescu M., Kinder psychisch kranker Eltern (Children of mentally disordered parents), in Markefka M, Nauck B.(Eds.), Handbuch der Kindheitsforschung (Handbook of childhood research), Luchterhand Verlag, Neuwied,1993, 649-663.

12. Bellivier F, Leroux M, Etain B, Golmard JL, Grigoroiu-Serbanescu M, Henry Ch, Rietschel M, Schulze T, Malafosse A, Leboyer M (2006). Suicidal behavior and age at onset in bipolar affective disorder. Biological Psychiatry, 59, 435-436. (Elsevier)

13. Grigoroiu-Serbanescu M, Wickramaratne P, Noethen MM (2007). Gender-related effect of parental age on age-at-onset in bipolar disorder, European Psychiatry, 22, S252 (Elesevier)

14. Grigoroiu-Serbanescu M, Golmard JL, Prelipceanu D, Georgescu MJ, Grimberg M, Sima D, Mihailescu R. (2005). Paternal age after 35 years diminishes the age of onset of bipolar disorder only in females. American Journal of Medical Genetics – Neuropsychiatric Genetics, (Wiley).

15. Serbanescu M, Rietschel M , Noethen M, Propping P, Ohlraun S (2002). Age of Onset in Bipolar I Disorder: Impact of Family History. American Journal of Medical Genetics – Neuropsychiatric Genetics, 114, 2002, 771.

16. Serbanescu M, Noethen MM, Propping P, Rietschel M, Ohlraun S.. Does the sex of affected grandparents influence the age of onset in bipolar disorder ? (2002). American Journal of Medical Genetics (B) – Neuropsychiatric Genetics, 114, , 772

17. Serbanescu M, Rietschel M, Noethen MM, Propping P. Parental age at child’s birth and age of onset in BP I disorder American Journal of Medical Genetics – Neuropsychiatric Genetics, 114, 2002, 772.

18. Serbanescu M, Golmard JL (2002). Admixture analysis of bipolar onset in a Romanian sample. Am J Medical Genetics (B) – Neuropsychiatric Genetics, 114, 771 .

19. Grigoroiu-Serbanescu M, Martinez M, Nöthen MM, Grinberg M, Sima D, Propping P (2001).Different Inheritance Models by Age of Onset in Bipolar I Disorder, Am. J. Med. Genetics -Neuropsychiatric Genetics, 105, 7 , 2001, p. 579.

20. Serbanescu M, Martinez M, Nothen MM, Sima D, Grinberg M, Propping P (2000). Gender rates of affective disorders in relatives of bipolar probands with positive and negative anticipation of the age of onset. American Journal of Medical Genetics – Neuropsychiatric Genetics, 83, 534-535, (Wiley),

21. Grigoroiu-Serbanescu M, Martinez M, Nöthen MM, Propping P (1998). Segregation models and parental transmission in bipolar I disorder, Am J Medical Genetics (B) – Neuropsychiatric Genetics, 81, 465-466, (Wiley).

b) Results:

1) Clinical indicators of genomic imprinting:

We described for the first time in the literature the clinical familial indicators suggesting that the bipolar disorder could be affected by genomic imprinting (Grigoroiu-Serbanescu et al., 1992; 1995; 1997; 1998). Our findings were considered by other researchers and confirmed at clinical and molecular level by: Kato et al., 1996, Am J Medical Genetics, 67: 546-550; McMahon et al, 1996, Am J Medical Genetics, 67: 229-231; Noethen et al., 1999, Molecular Psychiatry (Nature Publishing Group), 4: 76-84; Morrison et al., 1998, Human Molecular Genetics, 7: 1599-1609; Falls et al., 1999, Am J. Pathology, 154: 635-647; Jirtle RL, 1999, Experimental Cell Research, 248, 18-24;

Rojas K et al, 2000, Molecular Psychiatry, 5, 389-395; Cichon et al., 2001, Human Molecular Genetics, 10: 2933-2944; Hanson et al., 2001, Am J Human Genetics, 68: 951-962; Muglia et al. (2002), Molecular Psychiatry, 7, 860-866; Schumacher et al, 2002, Der Nervenartzt, 7, 581-594; McInnis. et al., 2003, Molecular Psychiatry, 8: 288-298; Segurado et al. 2003, Am. J. Human Genetics, 73, 49-62; Mendlevicz et al, 2004, Am J Med Genetics, 128B, 71-75; Kennedy et al, 2005, Psychological Medicine, 35, 855-863; Am J Medical Genetics, 128B, 71-75; Schiffer et al, 2007, Am J Med Genetics (B), 144B, 20-26; Benedetti et al., 2004, Neuroscience Letters, 355, 37-40, etc.

The paper „Clinical evidence for genomic imprinting in bipolar I disorder” (Acta Psychiatrica Scandinavica, 1995, 92, 365-370) was included in the USA Patent no. 6,998,235 (J. Kennedy and P. Muglia, 2006) concerning the method for determining the presence of a polymorphism in the variable number of tandem repeat (VNTR) region of the DRD4 gene located on 11p15.5 that confers susceptibility for bipolar disorder.

2) Genetic anticipation

We showed for the first time that the presence of the genetic anticipation (decreasing age of onset and increasing severity in successive generations) in bipolar disorder is associated only with the paternal transmission (Grigoroiu-Serbanescu et al, 1997, Brit J Psychiatry). Independent clinical and molecular studies confirmed the phenomenon described by us ( Ohara et al., 1998, Psychiatry Research, 79: 191-198; Zander et al, 1998, Genom Research, 8: 1085-1094; Margolis et al, 1999, Arch General Psychiatry, 56, 1019-1031; Kornberg et al., 2000, J. Affective Disorders, 59, 183-192; Merette et al, 2000, Am J Medical Genetics, 96: 61-68; Visscher et al., 2001, Psychiatric Genetics, 11, 129-137; O’Donovan et al., 2003, Am J Medical Genetics, 123C: 10-17; Lindblad et al, 1998, Molecular Psychiatry, 3: 406-410; Mendlevicz et al., 2004, Am J Med Genetics, 128B, 71-75; Petronis, 2003, Am J Med Genetics, 123C: 65-75; Massat et al (2005), Molecular Psychiatry, 10, 598-605).

3) Parent-of-origin effects.

In segregation analyses we showed for the first time that the genetic transmission modes of the bipolar illness differ according to the parental transmitting side (Grigoroiu-Serbanescu et al, 1998): the paternal transmission is associated with a non-Mendelian major gene model with polygenic background, while the maternal transmission is multifactorial. The findings of this study were taken over by McMahon et al, Am J Psychiatry, 2000; Kato & Kato, Bipolar Disorders, 2000; Potash, Bipolar Disorders, 2000; Petronis, Neuropsychopharmacology, 2000; Kato et al., Molecular Psychiatry, 2001; Kato et al, J. Affective Disorders, 2001, Kato et al., Am J. Med. Genetics (Part B), 2000; Segurado et al, Am J. Hum Genetics, 2003; Stassen et al, Am J. Med. Genetics (Part B), 2004, Lan et al, Psychiatric Genetics, 2007.

4) Age-of-onset.

By means of segregation analysis we demonstrated the importance of the age at onset of bipolar disorder under or above 25 years for the molecular study. We showed that different inheritance models underlye the transmission of bipolar disorder depending on the age of onset younger or older than 25 years in probands (Grigoroiu-Serbanescu et al, 2001). The results of this study were recently used in genome scans of bipolar disorder and three studies confirmed the biometric findings at biological level (Ohlraun et al, Am J. Med. Genetics (Part B), 2003; Li et al. Am J. Hum. Genetics, 2005; Lin et al, Am J Psychiatry, 2006) showing that the bipolar illness with onset under the age 25 is linked to certain loci, while the bipolar illness with onset after age 25 is linked to other loci situated on different chromosomes. Similarly,. Segurado et al, 2003, Am J Human Genetics, 73: 49-62; Faraone & Tsuang , Am J Medical Genetics, 2003, 123C, 1-9; Schumacher et al, 2004, Molecular Psychiary, 9: 203-207; Fallin. et al, 2004, Am J Human Genetics, 75: 204-219; Faraone et al., 2004, Am J Psychiatry, 161: 625-630; Leboyer et al., Bipolar Disorders, 2005, Lin et al., 2006, Am J Psychiatry, 163, 240-246, etc) used the findings of our segregation analysis based on the age of onset.

5) Gender differences in the bipolar I disorder phenotype

In 2005 we described two unexpected characteristics of the bipolar disorder in a Romanian and a German sample of bipolar patients, namely :a) gender differences as to the age of onset depending on the family history type (bipolar + schizo-affective loading; unipolar major depression loading; no loading) and b) the variation of the age of onset by family history type occurs only in female bipolar probands and not in bipolar males (Grigoroiu-Serbanescu M et al, Am J Med Genet – Neuropsychiatric Genetics, 2005). These results have direct implications for the process of identifying the genes of bipolar disorder. Immediately after publication our paper was featured under “Breakining News” on the web site of the International Society for Bipolar Disorder Research (2005) (www. Bipolar Disorders.Org) in the USA.

Our papers on parent-of-origin, genomic imprinting, genetic anticipation and segregation analysis of the age-of-onset in bipolar I disorder were cited about 300 times in top journals and books.

6)
Developmental psychopathology research on offspring of parents with bipolar I disorder and recurrent unipolar major depression

 
Papers:

1) Grigoroiu-Serbanescu M et al, (1989). Psychopathology in children aged 10-17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology, Journal of Affective Disorders, 16, 1989, 167-179 (Elsevier);

2) Grigoroiu-Serbanescu M et al. (1991). Depressive disorders and depressive personality traits in offspring aged 10-17 of bipolar I and normal parents, The Journal of Youth and Adolescence, 2, 135-148 (Plenum Press).

3) Grigoroiu-Serbanescu M et al. (1991), Adolescent offspring of endogenous unipolar depressive parents and of normal parents, Journal of Affective Disorders, 21, 185-198, (Wiley) .

These papers were cited 72 times in journals like Archives of General Psychiatry, American Journal of Psychiatry, Biological Psychiatry, American Journal of Medical Genetics (B) – Neuropsychiatric Genetics, Journal of Affective Disorders, , Journal of the American Academy of Child and Adolescent Psychiatry, Jounal of Psychiatric Research, Journal of Nervous and Mental Diseases, Bipolar Disorders, etc.

 
Participation in international scientific manifestations in the frame of the BPGEN project:

XVth European Congress of Psychiatry, Madrid, 17-21th March, 2007.

1. Grigoroiu-Serbanescu M, Wickramaratne P, Noethen MM (2007). Gender-related effect of parental age on age-at-onset in bipolar I disorder, European Psychiatry (Elsevier), 22, S252

Training activities for young psychiatrists:

In the frame of the BPGEN project a course of clinical psychiatric genetics will take place at The Biometric Psychiatric Genetics Research Unit – A. Obregia Psychiatric Hospital in the time from 11th to 15th of June, 2007.

Speakers:

Dr. Maria-Grigoroiu-Serbanescu (Bucharest)
Dr. Alexander Georgi (Mannheim)

Contact:

Tel. 0040-021-332.39.29
e-mail: maria.serbanescu@googlemail.com

Research assistants in the Biometric Psychiatric Genetics Research
Unit: Elvira Marinescu, Mihaela Hrestic, Elena Canciu

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