1
Investigating the role of early childhood abuse and HPA axis genes in suicide attempters with bipolar disorder
Marie E. Breen, Fayaz Seifuddin, Peter P. Zandi, James B. Potash, Virginia L. Willour
Supplementary Table 2: Previous genetic and gene-by-environment findings for suicide and bipolar disorder in our chosen
HPA axis genes.
Gene
Symbol
BAG1
Link with Suicide Link with Bipolar Disorder
CRH
CRHBP
None
No association with lifetime stress and attempted suicide
(Wasserman et al.
, 2008)
No association or interaction with suicidal behavior and childhood trauma (Roy et al.
, 2012)
Associated with suicide attempts in schizophrenia (De
Luca et al.
, 2010)
Suggestive significance in suicide attempters with childhood trauma (Roy et al.
, 2012)
None
No association or linkage with bipolar disorder (Stratakis et al.
, 1997, Alda et al.
, 2000)
No evidence of association (Ceulemans et al.
, 2011)

2
CRHR1
Association and linkage with suicide attempts in depressed males with low stress (Wasserman et al.
, 2008)
Association with increasing depression in male suicide attempters (Wasserman et al.
, 2009)
No association or interaction with attempted suicide and
No single SNP or haplotype association (Ceulemans et al.
,
2011, Szczepankiewicz et al.
, 2013) childhood abuse (physical/sexual) (Murphy et al.
, 2011)
Interaction with female suicide attempters and physical
Association with psychotic (Leszczynska-Rodziewicz et al.
, 2012) and excitement (Leszczynska-Rodziewicz et al.
, abuse (under eighteen years old) and male suicide attempters and physical abuse (over eighteen years old)
(Ben-Efraim et al.
, 2011)
2013a) dimensions of bipolar disorder.
No association with melancholic depression in bipolar disorder (Leszczynska-Rodziewicz et al.
, 2013b)
No interaction with suicidal behavior and childhood trauma but one protective SNP found (Roy et al.
, 2012)
No association or linkage with suicide attempt
(Leszczynska-Rodziewicz et al.
, 2013c)

3
CRHR2
FKBP4
Haplotype association with severity of suicidal events in bipolar disorder (De Luca et al.
, 2007)
No interaction with suicidal behavior and childhood trauma
Suggestive protective association (Ceulemans et al.
, 2011)
(Roy et al.
, 2012)
None None

4
FKBP5
HSP90AA1
HSP90AB1
HSP90B1
HSPA1B
Association with bipolar disorder altered by suicide attempt
Association with depressive episodes in mood disorders
(including bipolar disorder) (Binder et al.
, 2004) covariate (Willour et al.
, 2009)
Association with suicidal events (ideation, intent or
No association in case-control analysis (Gawlik et al.
,
2006) attempt) (Brent et al.
, 2010)
Association with suicide attempt and interaction with
Association in family-study with bipolar disorder (Willour et al.
, 2009) childhood trauma on suicide attempt (Roy et al.
, 2010)
No evidence of association (Ceulemans et al.
, 2011)
Additive effect with CRHBP in suicide attempters with childhood trauma (Roy et al.
, 2012)
No association with psychotic or melancholic depression dimensions in bipolar subjects (Leszczynska-Rodziewicz
Haplotype association with suicidal behavior in Japanese
(Supriyanto et al.
, 2011) and European (Leszczynskaet al.
, 2014)
No association with bipolar disorder (Szczepankiewicz et
Rodziewicz et al.
, 2014) cohorts al.
, 2014)
None
None
Significant association with HSP90B1 in Japanese cohort but not in European-American replication (Kakiuchi et al.
,
2007)
Association with bipolar disorder but not treatment

HSPA1L
MC2R
MRAP
NCOA1
No significant association with attempted suicide in schizophrenia subjects (De Luca et al.
, 2010)
None
None response (Pae et al.
, 2009)
None
None
None
5

6
NR3C1
POMC
PPID
PTGES3
Associated with suicide attempts in schizophrenia (De
Luca et al.
, 2010)
No association or linkage with suicide attempt
(Leszczynska-Rodziewicz et al.
, 2013c)
None
None
None
Reviewed in (Mandelli and Serretti, 2013).
Association with depressive episodes (Szczepankiewicz et al.
, 2011).
Significant haplotype analysis in mood disorders
(including bipolar disorder) (Ceulemans et al.
, 2011)
Association with seasonal episodes (Spijker et al.
, 2011)
No association with psychotic dimensions of bipolar disorder (Leszczynska-Rodziewicz et al.
, 2012)
No association with dimensions of bipolar disorder
(Leszczynska-Rodziewicz et al.
, 2013a)
No association with melancholic depression in bipolar disorder (Leszczynska-Rodziewicz et al.
, 2013b)
No association with bipolar disorder (Szczepankiewicz et al.
, 2014)
None
None
None

References
Alda, M, Turecki, G, Grof, P, Cavazzoni, P, Duffy, A, Grof, E , et al.
(2000). Association and linkage studies of CRH and PENK genes in bipolar disorder: a collaborative IGSLI study. Am J Med Genet, 96 , 178-81.
Ben-Efraim, YJ, Wasserman, D, Wasserman, J & Sokolowski, M. (2011). Gene-environment interactions between CRHR1 variants
7 and physical assault in suicide attempts. Genes Brain Behav, 10 , 663-72.
Binder, EB, Salyakina, D, Lichtner, P, Wochnik, GM, Ising, M, Putz, B , et al.
(2004). Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet, 36 , 1319-25.
Brent, D, Melhem, N, Ferrell, R, Emslie, G, Wagner, KD, Ryan, N , et al.
(2010). Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am J Psychiatry, 167 , 190-7.
Ceulemans, S, De Zutter, S, Heyrman, L, Norrback, KF, Nordin, A, Nilsson, LG , et al.
(2011). Evidence for the involvement of the glucocorticoid receptor gene in bipolar disorder in an isolated northern Swedish population. Bipolar Disord, 13 , 614-23.
De Luca, V, Tharmalingam, S & Kennedy, JL. (2007). Association study between the corticotropin-releasing hormone receptor 2 gene and suicidality in bipolar disorder. Eur Psychiatry, 22 , 282-7.
De Luca, V, Tharmalingam, S, Zai, C, Potapova, N, Strauss, J, Vincent, J , et al.
(2010). Association of HPA axis genes with suicidal behaviour in schizophrenia. J Psychopharmacol, 24 , 677-82.
Gawlik, M, Moller-Ehrlich, K, Mende, M, Jovnerovski, M, Jung, S, Jabs, B , et al.
(2006). Is FKBP5 a genetic marker of affective psychosis? A case control study and analysis of disease related traits. BMC Psychiatry, 6 , 52.

8
Kakiuchi, C, Ishiwata, M, Nanko, S, Kunugi, H, Minabe, Y, Nakamura, K , et al.
(2007). Association analysis of HSP90B1 with bipolar disorder. J Hum Genet, 52 , 794-803.
Leszczynska-Rodziewicz, A, Maciukiewicz, M, Szczepankiewicz, A, Poglodzinski, A & Hauser, J. (2013a). Association between
OPCRIT dimensions and polymorphisms of HPA axis genes in bipolar disorder. J Affect Disord, 151 , 744-7.
Leszczynska-Rodziewicz, A, Szczepankiewicz, A, Dmitrzak-Weglarz, M, Rajewska-Rager, A, Skibinska, M & Hauser, J. (2013b). No association between polymorphisms and haplotypes of the AVPR1b, CRHR1 and NR3C1 genes and depression with melancholic features in the course of bipolar disorder. Psychiatry Res, 207 , 140-2.
Leszczynska-Rodziewicz, A, Szczepankiewicz, A, Dmitrzak-Weglarz, M, Skibinska, M & Hauser, J. (2012). Association between functional polymorphism of the AVPR1b gene and polymorphism rs1293651 of the CRHR1 gene and bipolar disorder with psychotic features. J Affect Disord, 138 , 490-3.
Leszczynska-Rodziewicz, A, Szczepankiewicz, A, Narozna, B, Skibinska, M, Pawlak, J, Dmitrzak-Weglarz, M , et al.
(2014). Possible association between haplotypes of the FKBP5 gene and suicidal bipolar disorder, but not with melancholic depression and psychotic features, in the course of bipolar disorder. Neuropsychiatr Dis Treat, 10 , 243-8.
Leszczynska-Rodziewicz, A, Szczepankiewicz, A, Pawlak, J, Dmitrzak-Weglarz, M & Hauser, J. (2013c). Association, haplotype, and gene-gene interactions of the HPA axis genes with suicidal behaviour in affective disorders. ScientificWorldJournal, 2013 ,
207361.

Mandelli, L & Serretti, A. (2013). Gene environment interaction studies in depression and suicidal behavior: An update. Neurosci
Biobehav Rev, 37 , 2375-97.
Murphy, TM, Ryan, M, Foster, T, Kelly, C, Mcclelland, R, O'grady, J , et al.
(2011). Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms. Behav Brain Funct, 7 , 22.
9
Pae, CU, Drago, A, Mandelli, L, De Ronchi, D & Serretti, A. (2009). TAAR 6 and HSP-70 variations associated with bipolar disorder.
Neurosci Lett, 465 , 257-61.
Roy, A, Gorodetsky, E, Yuan, Q, Goldman, D & Enoch, MA. (2010). Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology, 35 , 1674-83.
Roy, A, Hodgkinson, CA, Deluca, V, Goldman, D & Enoch, MA. (2012). Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior. J Psychiatr Res, 46 , 72-9.
Spijker, AT, Giltay, EJ, Van Rossum, EF, Manenschijn, L, Derijk, RH, Haffmans, J , et al.
(2011). Glucocorticoid and mineralocorticoid receptor polymorphisms and clinical characteristics in bipolar disorder patients. Psychoneuroendocrinology,
36 , 1460-9.
Stratakis, CA, Sarlis, NJ, Berrettini, WH, Badner, JA, Chrousos, GP, Gershon, ES , et al.
(1997). Lack of linkage between the corticotropin-releasing hormone (CRH) gene and bipolar affective disorder. Mol Psychiatry, 2 , 483-5.
Supriyanto, I, Sasada, T, Fukutake, M, Asano, M, Ueno, Y, Nagasaki, Y , et al.
(2011). Association of FKBP5 gene haplotypes with completed suicide in the Japanese population. Prog Neuropsychopharmacol Biol Psychiatry, 35 , 252-6.

Szczepankiewicz, A, Leszczynska-Rodziewicz, A, Pawlak, J, Narozna, B, Rajewska-Rager, A, Wilkosc, M , et al.
(2014). FKBP5
10 polymorphism is associated with major depression but not with bipolar disorder. J Affect Disord, 164 , 33-7.
Szczepankiewicz, A, Leszczynska-Rodziewicz, A, Pawlak, J, Rajewska-Rager, A, Dmitrzak-Weglarz, M, Wilkosc, M , et al.
(2011).
Glucocorticoid receptor polymorphism is associated with major depression and predominance of depression in the course of bipolar disorder. J Affect Disord, 134 , 138-44.
Szczepankiewicz, A, Leszczynska-Rodziewicz, A, Pawlak, J, Rajewska-Rager, A, Wilkosc, M, Zaremba, D , et al.
(2013). Epistatic interaction between CRHR1 and AVPR1b variants as a predictor of major depressive disorder. Psychiatr Genet, 23 , 239-46.
Wasserman, D, Sokolowski, M, Rozanov, V & Wasserman, J. (2008). The CRHR1 gene: a marker for suicidality in depressed males exposed to low stress. Genes Brain Behav, 7 , 14-9.
Wasserman, D, Wasserman, J, Rozanov, V & Sokolowski, M. (2009). Depression in suicidal males: genetic risk variants in the
CRHR1 gene. Genes Brain Behav, 8 , 72-9.
Willour, VL, Chen, H, Toolan, J, Belmonte, P, Cutler, DJ, Goes, FS , et al.
(2009). Family-based association of FKBP5 in bipolar disorder. Mol Psychiatry, 14 , 261-8.