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 E-mail: janusz.rybakowski@gmail.com

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 85-110) Polish validation of the scale (Borkowska et al. 2010)

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

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)

Circadian rhythm regulation by "clock" genes

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)

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

70 patients with bipolar mood disorders 20 males, 50 females Patients studied 70 patients with bipolar mood disorders 20 males, 50 females Aged 59+12 years Consensus diagnosis according to SCID (First et al., 1996)

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

Association of the ARNTL gene polymorphisms and temperamental dimensions of the TEMPS-A scale rs1481892 rs4146388 rs11022780 rs7107287 Depressive - Cyclothymic Hyperthymic p<0.01 p<0.05 Irritable Anxious Rs7107287 associated with bipolar disorder and lithium response (Mansour et al., 2006, Rybakowski et al., 2014) Rs 4146388 associated with lithium response (Rybakowski et al., 2014)

Association of the TIM and PER3 gene polymorphisms and temperamental dimensions of the TEMPS-A scale rs2271738 Rs10876890 PER3 rs228727 Depressive - p<0.05 Cyclothymic Hyperthymic Irritable Anxious

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

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