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. Author manuscript; available in PMC: 2016 Jun 1.
Published in final edited form as: Psychiatr Genet. 2015 Jun;25(3):106–111. doi: 10.1097/YPG.0000000000000082

Investigating the role of early childhood abuse and HPA axis genes in suicide attempters with bipolar disorder

Marie E Breen a,*, Fayaz Seifuddin b,*, Peter P Zandi b,c, James B Potash a, Virginia L Willour a
PMCID: PMC4412784  NIHMSID: NIHMS657404  PMID: 25714448

Abstract

Objective

Genes and environment both play a major role in risk for attempted suicide, and environments harboring stressors, such as early childhood abuse, have been linked to suicidal behavior. Such environments also disrupt the Hypothalamic-Pituitary-Adrenal (HPA) axis pathway, which has been hypothesized to play a role in suicidal behavior. We investigated whether the risk for attempted suicide was attributable in part to the interaction between childhood physical and/or sexual abuse and genetic variation in nineteen genes (± 5kb) integral to the HPA axis pathway.

Materials and Methods

Using the Genetic Association Information Network Bipolar Disorder (GAIN-BP) and Translational Genomics Research Institute (TGEN) cohorts we implemented PLINK’s logistic regression-based “interaction” approach to search for evidence of an interaction between 235 genotyped HPA axis single nucleotide polymorphisms (SNPs) and early childhood abuse. Our study included 631 BP suicide attempters and 657 BP non-attempters with information regarding abuse.

Results

After correction for multiple testing, no significant interaction between the 235 HPA axis SNPs and early childhood abuse was found. Our strongest interaction was found with rs2664008 in the corticotropin releasing hormone receptor 1 (CRHR1) gene with a nominal interaction P-value of 1.22 × 10−2 and interaction odds ratio of 0.47.

Conclusion

Our findings suggest further work and larger sample sizes are required to elucidate the link between early childhood abuse and the HPA axis in suicidal behavior.

Keywords: suicidal behavior, bipolar disorder, gene-by-environment, early childhood abuse

Introduction

Suicide is the tenth leading cause of death in the U.S. (Centers for Disease Control and Prevention, 2010) and approximately one million Americans attempt suicide each year (Crosby et al., 2011). Compelling evidence from family, twin and adoption studies (Brent and Mann, 2005, Brent and Melhem, 2008, Brezo et al., 2008a) suggest both a genetic and environmental component to suicidal behavior, which includes both completed and attempted suicide. This gives us cause to investigate not only the genetic variation found in individuals with suicidal behavior, but also interacting environmental factors that may increase the risk of this phenotype, such as a history of early childhood trauma (Brent and Mann, 2005, Enns et al., 2006, Brodsky and Stanley, 2008).

The Hypothalamic-Pituitary-Adrenal (HPA) system, which controls the response to stressors, involves the interaction of numerous hormones, chaperones and receptors and genetic variation in any of these genes may interfere with the functioning of this pathway. Disruption of this system has previously been observed in suicidal behavior (Coryell and Schlesser, 1981, Nemeroff et al., 1988, Kamali et al., 2012) and in individuals with a history of childhood trauma (Heim et al., 2008). A study by Roy et al. (2010) suggested that an interaction between genetic variation in FKBP5, a negative regulator of the glucocorticoid receptor (GR), and childhood trauma increased the risk of suicidal behavior. Another study noted that a significant interaction between a single nucleotide polymorphism (SNP) in CRHR1 and childhood sexual abuse affected decision-making in suicide attempters (Guillaume et al., 2013). Further HPA axis studies have identified a sex-specific link between suicidal behavior, CRHR1, and physical assault in childhood and adolescence (Ben-Efraim et al., 2011).

The aim of this study was to investigate whether genetic variation in nineteen genes important to the HPA axis interacts with a history of early childhood physical and/or sexual abuse to increase the risk of suicidal behavior in 631 suicide attempters and 657 non-attempters.

Materials and Methods

This study utilized the Genetic Association Information Network Bipolar Disorder (GAIN-BP) and Translational Genomics Research Institute (TGEN) cohorts within our bipolar disorder (BP) attempted suicide genome-wide association study (Smith et al., 2009, Smith et al., 2011, Willour et al., 2012). This provided genotype data from 982 BP suicide attempters and 1,143 BP non-attempters all of whom were unrelated and of European-American ancestry. Subjects were originally ascertained, assessed and consented as part of the NIMH Genetics Initiative for BP (see Supplementary Materials for details). Prior to enrollment, all participants signed IRB-approved written informed consent forms. Subjects were defined as suicide attempters if they answered “yes” to the Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al., 1994) question O.1. “Have you ever tried to kill yourself?”

From this, 631 BP suicide attempters and 657 BP non-attempters provided information regarding early childhood abuse (as described in Supplementary Table 1). In total, 297 suicide attempters and 199 non-attempters had a history of physical and/or sexual abuse, as determined by answering the question: “Were you physically abused by any one [between the ages of 3 – 12]?” Respondents were allowed to include sexual abuse in their answers. The abuse question was taken from the Early Life Events Scale (ELES), developed by William Lawson and Elliot Gershon for the NIMH Genetics Initiative (unpublished). The rates of early childhood abuse based on this question were significantly higher (P<1 × 10−5) in suicide attempters (47.07%) versus non-attempters (30.29%), which is consistent with expectation, indicating the validity of the question.

Both datasets were merged and quality control filters were applied to exclude individuals with missing data rates ≥ 5% and exclude SNPs with a minor allele frequency (MAF) < 1%, with missing data rates ≥ 5% and Hardy-Weinberg equilibrium P-values of < 1 × 10−6.

Nineteen genes from the genome-wide dataset were chosen for study due to their integral role in the HPA axis pathway as determined by a literature search (see Table 1 and Supplementary Table 2). All genotyped SNPs in our merged and filtered dataset that were within 5kb of our chosen genes were considered in the analysis, leaving 235 variants to include in the study.

Table 1.

The selected nineteen HPA axis genes and their role in the HPA axis.

Gene Gene
Symbol		 Function No. of SNPs
analyzed
BCL2-associated athanogene BAG1 Negative regulator of Glucocorticoid Receptor (GR) (Grad and Picard, 2007, Bourke et al., 2013). 5
Corticotropin Releasing Hormone CRH Stimulates adrenocorticotropic hormone (ACTH) secretion (Vale et al., 1981). 5
Corticotropin Releasing Hormone Binding Protein CRHBP Regulates activation of the HPA axis by sequestering CRH (Orth and Mount, 1987). 4
Corticotropin Releasing Hormone Receptor 1 CRHR1 Binds to CRH following stress and stimulates the release of ACTH (Smith et al., 1998, Reul and Holsboer, 2002). 71
Corticotropin Releasing Hormone Receptor 2 CRHR2 Involved in the negative feedback control of the HPA axis (Coste et al., 2000, Reul and Holsboer, 2002). 18
FK506 Binding Protein 4, 59kDa FKBP4 Replaces FKBP5 in the GR/HSP90 complex causing receptor activation and translocation (Davies et al., 2002). 1
FK506 Binding Protein 5 FKBP5 Co-chaperone which inactivates GR by decreasing cortisol affinity and translocation (Binder, 2009). 18
Heat Shock Protein 90kDa Alpha (Cytosolic), Class A Member 1 HSP90AA1 Chaperone and positive regulator of GR ligand binding and translocation to the nucleus (Grad and Picard, 2007). 11
Heat Shock Protein 90kDa Alpha (Cytosolic), Class B Member 1 HSP90AB1 5
Heat Shock Protein 90kDa Beta (Grp94), Member 1 HSP90B1 8
Heat Shock 70kDa Protein 1B HSPA1B Chaperone and negative regulator of GR ligand binding (Grad and Picard, 2007). 1
Heat Shock 70kDa Protein 1-Like HSPA1L 1
Melanocortin 2 Receptor (Adrenocorticotropic hormone) MC2R Binds to circulating ACTH in the adrenal cortex leading to secretion of cortisol (Dores et al., 2014). 19
Melanocortin 2 Receptor Accessory Protein MRAP Involved in the translocation of MC2R to the cell surface, MC2R signaling and ligand binding (Metherell et al., 2005, Hinkle and Sebag, 2009). 10
Nuclear Receptor Co-Activator 1 NCOA1 Facilitates DNA binding and transcriptional regulation by GR (Onate et al., 1995, Winnay et al., 2006). 28
Nuclear Receptor Subfamily 3, Group C, Member 1 NR3C1 NR3C1 encodes for GR protein. Cortisol binds to GR causing activation and translocation to the nucleus where it binds to glucocorticoid response elements as a transcriptional regulator (Chandler et al., 1983, Mangelsdorf et al., 1995). 17
Proopiomelanocortin POMC ACTH is synthesized from posttranslational modifications of POMC (Nakanishi et al., 1979). 7
peptidylprolyl isomerase D PPID Co-chaperone assisting GR translocation into the nucleus (Kumar et al., 2001, Bourke et al., 2013). 2
Prostaglandin E Synthase 3 (cytosolic) PTGES3 Co-chaperone linked with HSP90 which helps stabilize the complex (Dittmar et al., 1997, Grad and Picard, 2007). 4
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SNP and gene information collated from RefSeq genes and dbSNP Build 130 using NCBI Build 36/hg18 from the University of California Santa Cruz (UCSC) Genome Browser.

Gene regions include ±5kb.

We implemented PLINK’s v1.07 (Purcell et al., 2007; http://pngu.mgh.harvard.edu/purcell/plink/) logistic regression-based “interaction” approach to search for evidence of an interaction between 235 genotyped HPA axis SNPs and a history of early childhood abuse. SNP genotypes were coded assuming an additive model. We controlled for sex, study and the top three principal components (PCs) which allowed us to account for population stratification. The top PCs were determined using EIGENSTRAT in EIGENSOFT 3.0 (Price et al., 2006) and a linkage disequilibrium pruned subset of the genome-wide SNPs. Age was not controlled for as it was not significantly different between suicide attempters and non-attempters with abuse data (P=0.586).

Results

We investigated whether the risk for attempted suicide was attributable in part to the interaction between a history of childhood physical and/or sexual abuse and genetic variation in the HPA axis pathway. To do this, we tested for interactions between genotypes at 235 SNPs in nineteen HPA axis pathway genes and a history of early childhood abuse in 631 suicide attempters and 657 non-attempters. A total of five SNPs had an interaction P-value < 0.05 (see Table 2 and Supplementary Table 3). However, none of the interactions were significant after correction for multiple testing using the conservative Bonferroni correction (P<2.13 × 10−4). As shown in Table 2, the most significant interaction was found with rs2664008 in the first intron of the CRHR1 gene with an interaction P-value of 1.22 × 10−2 and an interaction odds ratio of 0.47 (MAF in suicide attempters=0.083, MAF in non-attempters=0.088). The second top SNP, rs6727239, located in the fifteenth intron of the NCOA1 gene had an interaction P-value of 1.78 × 10−2 and an interaction odds ratio of 2.77 (MAF in suicide attempters=0.040, MAF in non-attempters=0.059).

Table 2.

The ten most associated SNPs from the interaction analysis.

SNP Chr. Nearest
Gene		 Location Minor
Allele		 MAF in
Attempters(a) 		MAF in
Non-attempters(a) 		Interaction
Odds
Ratio(b) 		Interaction
P-value
rs2664008 17q21.31 CRHR1 Intronic A 0.083 0.088 0.47 1.22 × 10−02
rs6727239 2p23.3 NCOA1 Intronic C 0.040 0.059 2.77 1.78 × 10−02
rs6724282 2p23.3 NCOA1 Downstream G 0.040 0.059 2.54 2.94 × 10−02
rs10495750 2p23.3 NCOA1 Downstream G 0.040 0.060 2.47 3.08 × 10−02
rs1724425 17q21.31 CRHR1 Intronic T 0.448 0.440 1.42 4.08 × 10−02
rs1526123 17q21.31 CRHR1 Intronic C 0.455 0.455 1.39 5.36 × 10−02
rs6503447 17q21.31 CRHR1 Intronic T 0.309 0.303 1.42 6.06 × 10−02
rs11655764 17q21.31 CRHR1 Intronic A 0.306 0.294 1.41 6.62 × 10−02
rs2267716 7p15.1 CRHR2 Intronic C 0.246 0.242 0.72 9.18 × 10−02
rs6719226 2p23.3 POMC Upstream G 0.046 0.048 2.01 1.04 × 10−01
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Abbreviations: SNP denotes Single Nucleotide Polymorphism; Chr. denotes Chromosome Position; MAF denotes Minor Allele Frequencies.

SNP and gene information collated from RefSeq genes and dbSNP Build 130 using NCBI Build 36/hg18 from the University of California Santa Cruz (UCSC) Genome Browser.

(a)

MAF calculated only for subjects with abuse data.

(b)

The odds ratio is determined for the minor allele.

Discussion

This study sought to identify an interaction between the HPA axis and a history of early childhood abuse in suicide attempters. While we did not detect any study-wide significant results, we did see a number of nominally significant ones. Our strongest association signal was identified in the CRHR1 gene, one of the main G protein-coupled receptors of CRH, the stress hormone. Genetic studies investigating CRHR1 and suicide have produced mixed results. In an African-American sample set, a variant in CRHR1 specific to this ancestry showed evidence of association with suicidal behavior (Roy et al., 2012). No significant associations between CRHR1 and suicide attempt was found in two European studies (Murphy et al., 2011, Leszczynska-Rodziewicz et al., 2013) and one schizophrenia cohort (De Luca et al., 2010).

CRHR1 studies that include both gene and environment have been just as complex. A family trio study stratifying by stress levels found both an association and linkage with suicide attempt in depressed males with low stress (Wasserman et al., 2008). An expansion of this study linked female suicide attempters with a history of physical abuse (before the age of eighteen) and a genetic variant in CRHR1 and male suicide attempters with a history of physical abuse (after the age of eighteen) and a genetic variant in CRHR1 (Ben-Efraim et al., 2011). However, other studies found no gene-by-environment interactions with CRHR1 (Murphy et al., 2011, Roy et al., 2012). These studies illuminate the complexity of not only suicidal behavior, but also the specific environmental stressors that affect this phenotype.

Our second most significant result was found in NCOA1, a co-activator of nuclear receptors, including the GR. This regulator is highly expressed in the brain (Meijer et al., 2000) and mouse knock-out studies have shown the necessity of NCOA1 (also known as SRC-1) for HPA axis regulation (Winnay et al., 2006). To the best of our knowledge this is the only study to test for an association between NCOA1, early childhood abuse and suicidal behavior.

FKBP5 is one of the most extensively studies HPA axis genes in relation to suicide. It is a component of the inactivating complex, which decreases cortisol binding and prevents GR translocation to the nucleus. Previous haplotype studies have found suggestive evidence of an association with FKBP5 and suicidal behavior in European (Leszczynska-Rodziewicz et al., 2014) and Japanese populations (Supriyanto et al., 2011). Genetic studies also identified an association between FKBP5 and suicidal events (which includes suicidal ideation and attempt) (Brent et al., 2010). FKBP5 studies that include gene and environment have also shown promise. Most notably, Roy et al. identified an interaction with FKBP5, childhood trauma and African-American suicide attempters (Roy et al., 2010, Roy et al., 2012).

Other genetic studies have investigated HPA axis related genes such as CRH, CRHBP, CRHR2, MC2R and NR3C1 (De Luca et al., 2007, Wasserman et al., 2008, De Luca et al., 2010, Roy et al., 2012, Leszczynska-Rodziewicz et al., 2013). Positive findings include NR3C1 and CRHBP which showed an association with attempted suicide (De Luca et al., 2007, De Luca et al., 2010). Variants in CRHBP have also been found to interact with childhood trauma to increase the risk of suicidal behavior (Roy et al., 2012). Finally, CRHR2 was linked with severity of suicidal behavior in subjects with bipolar disorder (De Luca et al., 2007).

There were certain limitations to our study. We had an estimated 80% power (calculated using Quanto v1.2.4; http://biostats.usc.edu/Quanto.html) to detect a locus with an interaction effect size ranging from 2.11 – 3.29 (depending on MAF) assuming a study-wide significance of 2.13 × 10−4. While this effect size has been described in other gene-by-environment studies (Ben-Efraim et al., 2011, Ben-Efraim et al., 2013) it suggests that more samples may be needed to help determine if we have false negative results.

Another limitation was the broad definition of a history of early childhood abuse, which did not separate physical and sexual abuse. These samples were collected over a five year period at eleven sites using the Early Life Events Scale (William Lawson and Elliot Gershon; unpublished) to assess childhood trauma. Statistical testing of our abuse data shows that a history of early childhood abuse is significantly associated with attempted suicide (P<1 × 10−5). The effect of child abuse on suicidal behavior has been shown to vary depending on the type of abuse (Brodsky and Stanley, 2008) and our study suggests that future investigations integrating a history of early childhood abuse data should separate physical and sexual abuse when possible or quantify abuse as a quantitative trait, as others have noted (Brezo et al., 2008b).

Other factors that may contribute to the differing results found in this study include sex and age. Some childhood trauma studies have indicated a sex-specific component to the interaction between physical and/or sexual abuse and suicidal behavior (Wasserman et al., 2009, Ben-Efraim et al., 2011), but we did not examine this due to sample size limitations. Our age range of between 3–12 years old does not match other more commonly used questionnaires, such as the Childhood Trauma Questionnaire (CTQ), where teenage years are taken into consideration (Bernstein, 1998).

A role for epigenetics in the relationship between HPA axis and suicidal behavior has been suggested, with increased DNA methylation within the NR3C1 promoter region correlating to decreasing expression levels in suicide completers with early childhood abuse (McGowan et al., 2009). In future studies, investigating both genetic and epigenetic features of the HPA axis may provide more significant interactions.

To date, this is one of the largest genetic assessments of early childhood abuse and the HPA axis in attempted suicide. No results reached study-wide significance. Future analyses using even larger-scale sample sets might have power to reveal more modest interactions than could be detected in our data.

Supplementary Material

Supplemental Data File _.doc_ .tif_ pdf_ etc.__1
Supplemental Data File _.doc_ .tif_ pdf_ etc.__2
Supplemental Data File _.doc_ .tif_ pdf_ etc.__3
Supplemental Data File _.doc_ .tif_ pdf_ etc.__4

Acknowledgements

This project was supported by the NIH Grant R01 MH079240 awarded to Virginia Willour and the Postdoctoral Fellowship Grant PDF-0-067-12 awarded to Marie Breen from the American Foundation for Suicide Prevention. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Foundation for Suicide Prevention.

Sources of Funding: This project was supported by the NIMH Grant R01 MH079240 awarded to Virginia Willour and the Postdoctoral Fellowship Grant PDF-0-067-12 awarded to Marie Breen from the American Foundation for Suicide Prevention.

Footnotes

Conflicts of interest: There are no conflicts of interest to declare.

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