Use of the PsycheMERGE Network to Investigate the Association Between Depression Polygenic Scores and White Blood Cell Count

Abstract

Importance: Although depression is a common psychiatric disorder, its underlying biological basis remains poorly understood. Pairing depression polygenic scores with the results of clinical laboratory tests can reveal biological processes involved in depression etiology and in the physiological changes resulting from depression.

Objective: To characterize the association between depression polygenic scores and an inflammatory biomarker, ie, white blood cell count.

Design, setting, and participants: This genetic association study was conducted from May 19, 2019, to June 5, 2021, using electronic health record data from 382 452 patients across 4 health care systems. Analyses were conducted separately in each health care system and meta-analyzed across all systems. Primary analyses were conducted in Vanderbilt University Medical Center's biobank. Replication analyses were conducted across 3 other PsycheMERGE sites: Icahn School of Medicine at Mount Sinai, Mass General Brigham, and the Million Veteran Program. All patients with available genetic data and recorded white blood cell count measurements were included in the analyses. Primary analyses were conducted in individuals of European descent and then repeated in a population of individuals of African descent.

Exposures: Depression polygenic scores.

Main outcomes and measures: White blood cell count.

Results: Across the 4 PsycheMERGE sites, there were 382 452 total participants of European ancestry (18.7% female; median age, 57.9 years) and 12 383 participants of African ancestry (61.1% female; median age, 39.0 [range, birth-90.0 years]). A laboratory-wide association scan revealed a robust association between depression polygenic scores and white blood cell count (β, 0.03; SE, 0.004; P = 1.07 × 10-17), which was replicated in a meta-analysis across the 4 health care systems (β, 0.03; SE, 0.002; P = 1.03 × 10-136). Mediation analyses suggested a bidirectional association, with white blood cell count accounting for 2.5% of the association of depression polygenic score with depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10-70) and depression diagnosis accounting for 9.8% of the association of depression polygenic score with white blood cell count (95% CI, 8.4%-11.1%; P = 1.78 × 10-44). Mendelian randomization provided additional support for an association between increased white blood count and depression risk, but depression modeled as the exposure showed no evidence of an influence on white blood cell counts.

Conclusions and relevance: This genetic association study found that increased depression polygenic scores were associated with increased white blood cell count, and suggests that this association may be bidirectional. These findings highlight the potential importance of the immune system in the etiology of depression and may motivate future development of clinical biomarkers and targeted treatment options for depression.

Figure 1.. Laboratory-wide Association Scan (LabWAS) of Depression Polygenic Scores (PGS)

Results of the initial LabWAS of depression PGS in Vanderbilt University Medical Center (A), and the LabWAS controlling for diagnoses for depression, anxiety, adjustment reaction, tobacco use disorder, and median body mass index across the electronic health record (B). The orange line indicates Bonferroni significance (P < 1.58 × 10⁻⁴), and the blue line represents P = .05. The direction of the arrow indicates the direction of effect between the laboratory and depression PGS. BUN indicates blood urea nitrogen; Ca, calcium; CO₂, carbon dioxide; D25OHT, 25-hydroxyvitamin D; FT4, free thyroxine; Gluc, glucose; HDL-C, high-density lipoprotein cholesterol; MonAbs, absolute monocyte count; NtAbs, absolute neutrophil count; ob/gyn, obstetrics and gynecology; Trigs, triglycerides; TRPI, troponin I; URBC, urinary red blood cell; UWBC, urinary white blood cell; WBC, white blood cell; X25HyD3, calcidiol.

Figure 2.. Analyses Controlled for Common Phenotypes Between Depression Polygenic Scores (PGS) and White Blood Cell (WBC) Count

The association between depression PGS and WBC controlling for each “confounder” phenotype group in Vanderbilt University Medical Center. Group-based cases were any individual who was a case for any of a group’s phecodes and controls were individuals who were controls for all of a group’s phecodes. Associations were found using linear regressions controlled for each group. In the “All” analysis, all groups were controlled for in 1 regression. Whiskers indicate 95% CIs.

Figure 3.. Replication Within the PsycheMERGE Network

The association between depression polygenic scores (PGS) and median white blood cell levels was replicated across the PsycheMERGE Network with sensitivity analyses controlling for depression and anxiety diagnoses. Whiskers indicate 95% CIs.