1. 1Department of Adult Psychiatry E-mail: janusz.rybakowski@gmail.com
Temperamental dimensions of TEMPS-A and clock genes polymorphisms
Janusz K Rybakowski1 , Monika Dmitrzak-Węglarz2, Daria Dembinska-Krajewska1, Joanna Hauser2, Karen K Akiskal3, Hagop S Akiskal3
1Department of Adult Psychiatry
2Psychiatric Genetic Unit Poznań University of Medical Sciences, Poznań, Poland
3International Mood Center, Paris, France and La Jolla, USA

2. Measuring five temperaments
TEMPS-A
Temperament Scale of Memphis, Pisa, Paris and San Diego – Autoquestionnaire (Akiskal at al. 2005)
Measuring five temperaments
Depressive (items 1-21)
Cyclothymic (items 22-42)
Hyperthymic (items 43-63)
Irritable (items 64-84)
Anxious (items )
Polish validation of the scale (Borkowska et al. 2010)

3. Genetics of theTEMPS-A
Association between hyperthymic temperament and the Met allele of Val66Met BDNF gene polymorphism
(+) Savitz et al., 2008
(-) Tsutsumi et al., 2011
Association between cyclothymic temperament and s allele of the 5-HTTLPR polymorphism
(+) Gonda et al., 2006
(-) Landaas et al., 2011
Genome wide association studies (Greenwood et al., 2012, 2013)
Hyperthymic temperament – 1q44, 2q16, 6q16, 14q23
Depressive temperament – 3p21, 13q34
Irritable temperament – 6q24

4. TEMPS-A and lithium response
The most significant positive correlation (p<0.01) was obtained with hyperthymic temperament
Significant negative correlations were obtained with anxious (p<0.05) and cyclothymic (p<0.05) temperaments and borderline significance (p=0.05) with depressive temperament.
No correlation was found with irritable temperament (Rybakowski et al., 2013)

5. Circadian rhythm regulation
by "clock" genes

6. Association of clock genes with bipolar disorder and lithium response
Association of the ARNTL, CLOCK, PER3, and TIM genes with bipolar disorder
(Nievergelt et al., 2006; Mansour et al., 2006, 2009; Shi et al., 2008; Soria et al., 2010)
Association of the ARNTL (six SNPs) and TIM genes (two SNPs) with lithium response
(Rybakowski et al., 2014)

7. The aim of the study
To investigate an association between multiple single nucleotide polymorhisms (SNPs) of four clock genes (CLOCK, ARNTL, TIM, PER3) and temperamental dimensions of the TEMPS-A in bipolar patients

8. 70 patients with bipolar mood disorders 20 males, 50 females
Patients studied
70 patients with bipolar mood disorders
20 males, 50 females
Aged years
Consensus diagnosis according to SCID (First et al., 1996)

9. Genotyping CLOCK gene 9 SNPs ARNTL gene 18 SNPs TIM gene 6 SNPs
PER3 gene 9 SNPs
CLOCK: circadian locomotor output cycle kaput
ARNTL: aryl hydrocarbon receptor nuclear translocator-like
TIM: timeless circadian clock
PER3: period circadian clock3

10. Association of the ARNTL gene polymorphisms and temperamental dimensions of the TEMPS-A scalers rs rs rs
Depressive -
Cyclothymic
Hyperthymic
p<0.01
p<0.05
Irritable
Anxious
Rs associated with bipolar disorder and lithium response (Mansour et al., 2006, Rybakowski et al., 2014)
Rs associated with lithium response (Rybakowski et al., 2014)

11. Association of the TIM and PER3 gene polymorphisms and temperamental dimensions of the TEMPS-A scalers Rs
PER3
rs228727
Depressive -
p<0.05
Cyclothymic
Hyperthymic
Irritable
Anxious

12. Conclusions
The clock genes: ARNTL, TIM and PER3 may be associated with temperamental dimensions measured by TEMPS-A
Each of this gene may be specific to given temperament (ARNTL – hyperthymic, anxious, TIM – cyclothymic, PER3 – depressive)
Some polymorphisms of ARNTL genes associated with temperament are also connected with predisposition to bipolar mood disorder and/or lithium response

13. References Akiskal HS et al. J Affect Disord 2005; 85: 3-16.
Borkowska A et al. J Affect Disord 2010; 123:
Gonda X et al. J Affect Disord 2006; 91:
Greenwood TA et al. Biol Psychiatry 2012; 72:
Greenwood TA et al. J Affect Disord 2013; 150:
Landaas ET et al., J Affect Disord 2011; 129:
Mansour HA et al., Genes Brain Behav 2006; 5:
Mansour HA et al., Bipolar Disord 2009; 11:
Nievergelt CM et al., Am J Med Genet 2006; 141B:
Rybakowski JK et al., J Affect Disord 2013; 145:
Rybakowski JK et al., Bipolar Disord 2014; 16;
Savitz J et al., Genes Brain Behav 2008; 7:
Shi J et al., Am J Med Genet 2008; 147B:
Soria V et al., Neuropsychopahmacology 2010; 35:
Tsutsumi T et al., J Affect Disord 2011; 131: