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. Author manuscript; available in PMC: 2024 Sep 6.
Published in final edited form as: Psychosom Med. 2023 Sep 6;85(9):813–819. doi: 10.1097/PSY.0000000000001251

Associations of Germline Genetic Variants with Depression and Fatigue among Hematologic Cancer Patients Treated with Allogeneic Hematopoietic Cell Transplantation

Aasha I Hoogland a, Brian D Gonzalez a, Jong Y Park b, Brent J Small c,d, Steven K Sutton d, Joseph A Pidala e, Kristen S Smith a, Julienne E Bower f, Paul B Jacobsen a, Heather SL Jim a
PMCID: PMC10915106  NIHMSID: NIHMS1928644  PMID: 37678326

Abstract

Objective:

Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and fatigue in the year after allogeneic HCT.

Methods:

Blood was collected from patients and their donors prior to HCT. Patients completed self-report measures of depression and fatigue prior to HCT (T1), 90 days post-HCT (T2), and one year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate adjusted p value of <0.05.

Results:

The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time (p-values>.41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 (p=3.0x10−4) and rs6311 (p=2.0x10−4) in HTR2A. Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 (p=6.0x10−5) and a patient-donor interaction at rs1885884 in HTR2A (p<1.0x10−4).

Conclusions:

Data suggest that variants in genes regulating the serotonergic system (HTR2A) and lipid metabolism (SORL1) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients’ own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.

Keywords: cancer, depression, fatigue, genetics, hematopoietic cell transplant

1. Introduction

Allogeneic hematopoietic cell transplant (HCT) is an arduous treatment for hematologic cancer in which patients receive high-dose chemotherapy followed by infusion of hematopoietic cells by a donor. Patients are likely to experience significant side effects of high-dose chemotherapy (e.g., mucositis and enteritis), opportunistic infection, and acute and chronic graft-versus-host disease (GVHD). GVHD occurs when engrafted donor hematopoietic cells attack host tissue, resulting in a range of morbidities including nausea, vomiting, diarrhea, mouth sores, skin thickening, shortness of breath, and joint pain. In addition to physical morbidity, allogeneic HCT exacts a high psychosocial toll on patients. They are typically hospitalized for three weeks during the acute transplant period and must live near the transplant center, often in temporary housing, until 90 days post-transplant. Once home, patients typically face an extended convalescence with periodic flare-ups of GVHD which can restrict daily activities.

Perhaps not surprisingly, rates of depression and fatigue in this population are high and associated with a variety of negative outcomes. Approximately 6-16% of HCT recipients report clinically-significant depression before HCT, 31-38% during hospitalization, and 11-14% during long-term survivorship.(1–5) Across studies, clinically-significant fatigue has been reported by 95% of patients before HCT,(6) by 81% at day 100 after HCT,(7) and by 31% during long-term survivorship.(5) Fatigue alone has been shown to be a strong independent predictor of worse quality of life among hematologic cancer survivors treated with HCT.(8) Depressive symptoms prior to HCT may increase risk for mortality and overall survival,(9, 10) as well as a higher incidence of acute GVHD.(11) Similarly, a recent study found that greater fatigue before and after HCT and depression symptoms following HCT predicted a higher risk for mortality up to 6 years post-HCT.(12) Post-HCT fatigue is also associated with self-reported cognitive concerns,(13) less efficient sleep and more sedentary behavior,(14) and gut microbiome imbalances;(15) and depression is associated with self-reported cognitive concerns.(13) These findings indicate that depression and fatigue are significant problems among HCT recipients.

Interestingly, relatively few risk factors have been identified for depression and fatigue after HCT. A cross-sectional study of 1,188 patients treated with allogeneic HCT found that depression was associated with female sex, younger age, self-reported severity of chronic GVHD, and the presence of chronic pain. Fatigue was associated with female sex, more recent transplant, self-reported severity of chronic GVHD, and the presence of chronic pain.(5) Consistent with other research,(3, 16) clinical variables such as previous total body irradiation, myeloablative conditioning, graft source, and proxies for early post-HCT complications (i.e., length of hospital stay, time to engraftment, maximum mucositis score) were not significant risk factors.

A large and growing body of evidence suggests that germline genetic variants are involved in depression and fatigue outside the context of HCT. To our knowledge, no studies have been conducted among patients already treated with HCT. Among cancer patients not treated with HCT, variants in BDNF, IFNGR1, IL1B, IL6, IL8, IL10, and TNFA are associated with depression and fatigue,(17–29) although results are not consistent.(30) While studies of cancer patients have focused primarily on inflammation pathways, studies of major depressive disorder and chronic fatigue syndrome have identified a variety of other potentially relevant genes, including those involved in neurotransmission (e.g., DRD4, MAOA, SLC6A4),(31–35) circadian rhythms (e.g., CRY1, NPAS2, TIMELESS),(36, 37) and vasoconstriction (e.g., ACE).(38)

The goal of the current study was to explore associations of germline genetic variants with changes in depression and fatigue among patients treated with allogeneic HCT in the short-term (first 90 days after transplant) and longer-term (first year after transplant). Demographic and clinical risk factors for fatigue and depression have already been established, thus the goal of this study was to examine genetic risk factors only. Because patients treated with allogeneic HCT have two sets of germline DNA, their donor’s in reconstituted hematopoietic cells and their own in other tissues, genetic studies in this population may help to localize sites of action. For example, significant associations of donor variants would suggest that hematopoietic cells may be involved in the pathogenesis of depression and fatigue; associations of patient variants would suggest potential involvement of other cells (e.g., neurons, muscle cells). The main effects of patient and donor genotype on depression and fatigue as well as their interaction were explored.

2. Methods

2.1. Participants

Patients and their donors were recruited as part of a larger study examining cognition and quality of life after allogeneic HCT. After approval by Institutional Review Boards at the University of South Florida and the National Marrow Donor Program (NMDP), patients and related donors were recruited at an outpatient appointment prior to HCT between October 2010 and February 2013. Unrelated donors were recruited through the NMDP. Following informed, patients completed self-reported measures prior to HCT (T1), 90 days post-HCT (T2), and one year post-HCT (T3). Patients also provided a blood sample for genotyping at T1. Donors provided only a blood sample (i.e., no self-report data were collected). Eligibility criteria for patients were that they: a) be diagnosed with hematologic cancer; b) be scheduled to receive allogeneic HCT with peripheral blood stem cells at Moffitt Cancer Center; c) be at least 18 years of age; d) have no history of stroke, head trauma with loss of consciousness within the past five years, and brain damage/brain injury; e) have completed six or more years of formal education; f) be capable of speaking and reading standard English; and g) be willing to provide written informed consent. Participants included in the current analyses were disease-free at follow-up assessments. Data are available upon reasonable request from the corresponding author.

2.2. Measures

Self-reported sociodemographic characteristics were assessed in patients prior to HCT (i.e., age, sex, race, ethnicity, marital status, education, annual household income). Clinical information (e.g., cancer type, donor relationship, date of HCT) was obtained from the Moffitt Cancer Center Blood and Marrow Transplant Department Registry.

Depression was assessed using the 20-item Center for Epidemiological Studies – Depression Scale (CES-D).(39) Participants rated how frequently they have experienced each depressive symptom in the past week on a four-point scale (0 = rarely or none of the time; 3 = most or all of the time). Items are summed to a total score ranging from 0 to 60. The CES-D has good internal consistency with alphas of .85 for the general population and .90 for a psychiatric population.(39) The reliability and validity of the CES-D has been demonstrated with a wide range of populations, including cancer patients.(40)

The 14-item Fatigue Symptom Inventory (FSI)(41) was used to assess fatigue. A total fatigue severity score was computed by averaging participants’ ratings of current fatigue as well as the most, least, and average severity of fatigue in the past week on an 11-point scale (0 = not at all fatigued; 10 = as fatigued as I could be). Previous research has demonstrated the reliability and validity of the FSI with individuals diagnosed with cancer.(41, 42)

2.3. Single Nucleotide Polymorphism (SNP) Selection and Genotyping

SNPs were selected based on published evidence of associations with fatigue, depression, cognition, or circadian rhythms in cancer patients and other clinical or non-clinical populations (e.g., major depressive disorder,(43) chronic fatigue syndrome,(30, 44) Alzheimer’s disease(45)). Preference was given to variants located in coding regions or known transcription factor binding sites, non-synonymous polymorphisms, and those with a minor allele frequency (MAF) of ≥.20 in the HapMap CEU population.(46) A total of 494 SNPs were initially identified and 384 retained for genotyping following an iterative custom panel design process. Genomic DNA was extracted from blood obtained using Gentra Puregene tissue kits (Valencia, CA). DNA samples were genotyped using the Illumina VeraCode GoldenGate microarray (Illumina, San Diego, CA) and genotyped using the BeadStudio algorithm by the Moffitt Cancer Center Molecular Genomics Core.

2.4. Statistical Analyses

Analyses were restricted to patients who provided genetic data, with a donor who also provided genetic data, and who had baseline and at least one follow-up assessment. Mixed models were used to examine change over time in fatigue and depression. To evaluate the main effects of patient and donor genotype on residualized change in fatigue and depression from T1 to T2 and T1 to T3, independent, additive, dominant, and recessive models were examined using linear regression in JMP Genomics 7.0 (Cary, NC). The independent model consisted of a three-way group comparison among participants with zero, one, or two variants The additive test evaluated the number of variants as an ordinal predictor. The dominant model compared participants homozygous for the major allele and heterozygous to participants homozygous for the minor allele. The recessive model compared participants homozygous for the minor allele and heterozygous to participants homozygous for the major allele. To evaluate the interaction between patient and donor genotype on residualized change in fatigue and depression, the sum of variants within recipient-donor pairs was calculated and entered as a predictor variable in linear regressions using SAS 9.3 (Cary, NC). Analyses were restricted to variants in Hardy-Weinberg equilibrium in donor DNA (p<0.05), demonstrating a minor allele frequency (MAF) of ≥20% in the sample, and a call rate of ≥80% in the current sample. A false discovery rate (FDR) was used to control for multiple variants analyzed in each test; variants with an FDR-adjusted p value of <0.05 were considered statistically significant to cast a wide net in this initial, exploratory study.(47) Because ancestry informative markers were not measured and few participants self-identified as non-White (n=7), genetic analyses were limited to the 59 recipient-donor pairs in which recipients self-identified as White to reduce extraneous variance due to ancestry. For significant variants on the same gene, linkage disequilibrium (LD) was examined using LDpop.(48, 49) For pairs of variants in high LD (r2 > .80), only one variant is presented. Covariates were not included in analyses due to the limited sample size.

3. Results

Of the 225 patients who signed consent to the larger study, 59 were eligible for inclusion in analyses (i.e., had a blood sample and questionnaire data at baseline and at least one follow-up and had a corresponding donor blood sample).

A total of 51 patients provided data at T2 and 42 at T3 (i.e., 8 patients who did not provide data at T2 did so at T3). The most common reason for attrition was death (i.e., 12 patients). This sample size resulted in 80% power to detect a significant mean difference in depression and fatigue of 0.052 with a standard deviation of 0.1. Participant characteristics are shown in Table 1. Participants’ mean age was 51 and most were male (65%), non-Hispanic (93%), and married (68%). Just under half (48%) of the sample reported a median household income of $40,000 a year or more. Patients were diagnosed with acute myeloid leukemia (27%), myelodysplastic syndrome/myeloproliferative disease (25%), non-Hodgkin’s lymphoma (23%), or other hematologic cancers (25%). The majority of patients (66%) received stem cells from an unrelated donor. Mixed models analyses indicated that on average, fatigue and depression did not change significantly over time (see Table 2) (p values >.41).

Table 1.

Sociodemographic and clinical characteristics of patient participants.

Full sample (N=59) Time 1/Time 2 analyses (n=51) Time 1/Time 3 analyses (n=42)
Age: mean (SD) 51.0 (13.4) 51.6 (12.6) 51.7 (14.2)
Sex: n (%) male 38 (64%) 31 (61%) 26 (62%)
Race: n (%) White 59 (100%) 51 (100%) 42 (100%)
Ethnicity: n (%) non-Hispanic 55 (93%) 47 (92%) 38 (90%)
Marital status: n (%) married 40 (68%) 36 (71%) 29 (67%)
Education: n (%) college graduate 22 (37%) 20 (39%) 15 (36%)
Annual household income: n (%) ≥ $40,000 29 (49%) 25 (49%) 19 (45%)
Time since diagnosis: mean (range) months 38.7 (3.8-177.1) 43.2 (4.1-177.1) 48.4 (3.8-177.1)
Diagnosis: n (%)
   AML 16 (27%) 14 (27%) 10 (24%)
   MDS/MPD 15 (25%) 12 (24%) 12 (29%)
   NHL 14 (23%) 11 (22%) 12 (29%)
   Other (e.g., ALL, CLL, CML) 14 (24%) 14 (27%) 8 (19%)
Donor type: n(%) related 20 (33%) 18 (35%) 13 (31%)
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ALL: acute lymphoblastic leukemia, AML: acute myelogenous leukemia, CLL: chronic lymphocytic leukemia, CML: chronic myelogenous leukemia, MDS: myelodysplastic syndrome, MPD: myeloproliferative disease, NHL: non-Hodgkin’s lymphoma, SD: standard deviation. Demographic data were not collected from donors.

Table 2.

Estimated means and 95% confidence intervals of depression and fatigue in the full sample over time.

Depression: M (95% CI) Fatigue: M (95% CI)
Pre-HCT 11.86 (9.72, 14.00) 3.40 (2.97, 3.83)
90 days post-HCT 12.08 (10.08, 14.08) 3.45 (3.08, 3.82)
360 days post-HCT 12.76 (10.30, 15.20) 3.59 (3.02, 4.16)
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A total of 267 variants passed quality control and were included in genetic analyses (see Table S1, Supplemental Digital Content). Regarding depression from T1 to T2, no variants were significant. Regarding change in depression from T1 to T3, rs1928040 and rs6311 in HTR2A (LD R2=0.59) were significantly associated in analyses examining patient-donor interactions in the additive model. Patient-donor pairs with greater numbers of the A allele at rs1928040 showed greater increases in depression over time (p=3.0x10−4, pFDR=2.8x10−2, Fig. 1C); the same pattern was found for rs6311 (p=2.0x10−4, pFDR=2.8x10−2, data not shown).

Figure 1.

Figure 1.

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Bar graphs of differences in change in depression and fatigue over the first year after hematopoietic cell transplant by genotype in in patients and patient-donor pairs among variants that were significantly different at an adjusted p value of p<0.05 . T1 is baseline, T2 is 90 days post-treatment, and T3 is 360 days post-treatment. Error bars represent 95% confidence intervals. Positive scores indicate worsening depression and fatigue from baseline to later time points, whereas negative scores indicate improvement. Clinically meaningful change is typically defined as 0.5 SD,(87) which for the CES-D depression scale corresponds to approximately 6 points and on the FSI fatigue scale 2 points in this sample.

Regarding fatigue, two polymorphisms were significantly associated with change from T1 to T2. One variant in patient SORL1, rs689021, was significant in the independent model (p=6.0x10−5, pFDR=1.4x10−2, Fig. 1B). Patients with the GG or AA genotype at rs689021 demonstrated improvements in fatigue from T1 to T2 relative to heterozygous patients who showed worsening fatigue over time. A patient-donor interaction was found at rs1885884 in HTR2A in the dominant model; patient-donor pairs who both had a GG genotype showed improvement in fatigue over time, while patient-donor pairs in which one member had GG and one had GA showed no change in fatigue over time and patient-donor pairs both homozygous for the A allele showed worsening fatigue (p<1.0x10−4,pFDR=1.2x10−2, Fig. 1C). No variants were associated with changes in fatigue from T1 to T3.

4. Discussion

The goal of the current study was to explore associations of candidate germline gene variants with short-term and longer-term changes in depression and fatigue in hematologic cancer patients treated with allogeneic HCT. Because allogeneic HCT patients have two sets of germline DNA after transplant, patient and donor variants were analyzed as main effects and also interactions. Results indicated no change in fatigue and depression on average in the year after HCT. However, results also indicated that genetic variants in pathways related to the serotonergic system (HTR2A) and lipid metabolism (SORL1) were significantly associated with changes in depression and fatigue. Improvements in depression and fatigue in one genotype may have been offset by worsening in another genotype. Of significant variants, one originated from patients and three from patient-donor interactions. These data are intriguing because they suggest new potential mechanisms of depression and fatigue in cancer patients beyond the inflammation pathways identified in previous literature.(17–23, 26, 27) Specifically, we theorized that DNA from hematopoietic stem cells might have functional relevance in fatigue and depression if donor variants were significantly associated with these outcomes in recipients. Conversely, significant associations of recipient DNA with depression and fatigue would suggest other types of cells not originating from hematopoietic stems cells were functionally relevant. Our results identified variants from both patient and donor DNA, suggesting that putative mechanisms may be localized in hematopoietic cells as well as cells expected to express patient DNA such as neurons or muscle cells.

In the current study, HTR2A demonstrated the greatest number of associations with depression and fatigue, with two variants (i.e., rs6311, rs1928040) in patient-donor pairs associated with increases in depression from pre-HCT to one year post-HCT. One other variant from patient-donor pairs (i.e., rs1885884) was associated with changes in fatigue from pre-HCT to 90 days post-HCT. HTR2A codes for the serotonin 2A receptor, which is expressed in a variety of cells in the brain and periphery (including hematopoietic cells) and is a primary target for serotonin signaling.(50) Variants in HTR2A have been associated with a variety of psychiatric disorders, including major depressive disorder and response to anti-depressants, although results are not consistent.(51–54) There is also literature to suggest that the gene may play an important role in chronic fatigue syndrome.(55, 56) We are aware of only one previous study of HTR2A in cancer patients, which found no association of rs6311 with depression in women with breast cancer.(24) Outside of cancer populations, one study reported that rs6311 was associated with an increased risk for suicide attempts among individuals with eating disorders.(57)

Variation in patient SORL1 (i.e., rs689021) was associated with changes in fatigue from pre-HCT to 90 days post-HCT. SORL1, which is predominantly expressed in the central nervous system, binds low-density lipoprotein and transports it into cells through endocytosis. Included in the current study due to its associations with Alzheimer’s disease, formation of amyloid plaques,(68, 69) intrinsic network connectivity,(70) and cognitive aging,(71–73) SORL1 is involved in the migration of vascular smooth muscle cells. SORL1 is also a marker for lymphoma and leukemia(74–76) and helps to regulate cellular adhesion of hematopoietic cells to bone marrow.(77, 78) Consequently, the relationship between SORL1 and fatigue in this study may be mediated by transplant-related mechanisms such as neutrophil engraftment. Although a large study(5) of allogeneic HCT recipients did not find a relationship between neutrophil engraftment and fatigue, participants were surveyed a mean of 13 years after HCT. Neutrophil engraftment may have more relevance to fatigue in the acute transplant period, although further research is needed.

Strengths of this pilot study include a clinically and biologically significant research question, validated longitudinal measures of depression and fatigue, and an understudied population of allogeneic HCT recipients. Limitations should also be noted, however. Analyses were limited to patients who self-identified as White. Although this decision was made to reduce variation due to ancestry which could have potentially obscured significant relationships, findings cannot be generalized to HCT patients of other ancestries. Additional research is needed among allogeneic HCT recipients of other ancestral groups. The sample size was relatively small, consisting of 59 patient-donor pairs. Our retention rate was 70% over one year due to morbidity and mortality, which compares favorably to other studies of this patient population but further limited sample size. We did not collection information from donors. Thus, we were unable to run multivariate analyses including donor characteristics (aside from genotype) as predictors of change in recipient fatigue and depression. There was limited statistical power to examine clinical and demographic risk factors of change in fatigue and depression. Future, larger studies should include well-established risk factors as covariates. The small sample size also limited statistical power to detect smaller associations between genetic variants and outcomes; sample variation may have contributed to spurious associations. Because findings from small candidate gene studies are often not replicated in larger samples,(86) results from the current study should be considered preliminary until larger studies are conducted. In addition, because a candidate gene approach was used, there may be other variants that were not identified in the current study that are associated with fatigue and depression among allogeneic HCT patients. Genome-wide association studies in larger samples are warranted to confirm these findings.

In summary, results from this pilot study suggest that patient and donor genetic variations show an association with changes of fatigue and depression after allogeneic HCT. Of note, genetic variants were significant predictors above and beyond baseline depression and fatigue, suggesting that genetic information may provide unique predictive information about patient outcomes after allogeneic HCT. These data support additional research specifically on donors to understand the functional relevance of the identified variants, as well as the role of donor DNA and other donor characteristics in fatigue and depression among HCT recipients. As genetic testing becomes more widely available and cost-effective, routine analysis of germline variants may become a standard part of personalized cancer medicine. The current variants, if replicated, may be used to personalize proactive supportive care for allogeneic HCT recipients at risk for worsened fatigue and depression. Continued research on genetic and other risk factors for fatigue and depression after allogeneic HCT may thus contribute to better patient outcomes.

Supplementary Material

FINAL PRODUCTION FILE: SDC

Source of funding:

This work has been supported in part by NCI K07-CA138499 (PI: Jim), the Molecular Genomics Core, and the Participant Research, Interventions, and Measurement (PRISM) Core Facility at Moffitt Cancer Center, an NCI designated Comprehensive Cancer Center (P30-CA76292).

Abbreviations:

HCT

hematopoietic cell transplant

HTR2A

5-Hydroxytryptamine Receptor 2A

SORL1

Sortilin Related Receptor 1

Footnotes

Conflicts of interest: BDG: consultant for SureMed Compliance, KemPharm, Elly Health, Inc.; HSLJ: consultant for SBR Bioscience, grant funding from Kite Pharma. For the remaining authors no conflicts of interest were declared.

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