Neutrophils Drive Association Between Depression Polygenic Scores and White Blood Cell Count

STOCKPORT, UNITED KINGDOM – APRIL 17: Blood samples taken from volunteers are labelled and ready to be stored in the UK Biobank which will hold up to 15 million urine and blood samples, all controlled by robotics on April 17, 2007, Stockport, England. The new UK Biobank is the largest blood based research project in the world. The research project will involve 500,000 people across the UK and follow their health for next 30 years or more providing a resource for scientists battling diseases. (Photo by Christopher Furlong/Getty Images)
While depression is a common psychiatric disorder, the underlying biological basis isn’t quite understood. Researchers sought to pair depression polygenic scores with the results of clinical laboratory tests in an attempt to reveal the biological processes involved in depression etiology and in the physiological changes resulting from depression.

Depression polygenic scores (PGS) are associated with white blood cell (WBC) count in what may be a bidirectional capacity in White patients, researchers found in a study published in JAMA Psychiatry.

From May 2019 to June 2021, researchers analyzed the data of 382,452 individuals of European ancestry (81.3% male median age 57.9 years) in the PsycheMERGE Network of four biobanks.

After they conducted multiple testing correction, the researchers found in a laboratory-wide association scan (LabWAS) of 72,634 individuals of European ancestry in the VUMC biobank that depression PGS and white cell count are linked (β 0.03; SE 0.004; P =1.07 × 10-17).

They found the same results in their meta-analysis of the four biobanks (P =1.03 × 10-136; β, 0.03; SE, 0.002). Those results remained after controlling for depression and anxiety diagnoses (P = 8.23 × 10-100; β, 0.03; SE, 0.002).

WBC mediated 2.5% of the association between depression PGS and depression diagnosis (95% CI, 2.2%-20.8%; P = 2.84 × 10-70). When the researchers excluded participants in the Million Veteran Program from the meta-analysis, WBC mediated 0.5% of the association, which was not statistically significant (P =.06).

Across the biobanks, depression diagnosis mediated 9.8% of the association between depression PGS and WBC count (95% CI, 8.4%-11.1%; P = 1.78 × 10-44).

Investigators found in measuring WBC subtypes through multiple mediator analyses of complete blood count that neutrophils were primarily responsible for the association between depression PGS and depression diagnosis (1.9%, 95% CI, 0.2-3.1%).

Mendelian randomization analysis indicated increased depression risk was linked with increased WBC (P =.01 estimated effect of exposure on the outcome 0.27), but exposure to depression did not influence WBC.

Limitations of the study include a variety of health states of individuals that could impact WBC, the possibility that another heritable phenotype was unintentionally selected, and generalization outside of primarily European ancestry populations.

“In a laboratory-wide screen, increased polygenic depression risk was associated with increased inflammatory markers, including WBC count, even after controlling for depression, anxiety, multiple comorbid phenotypes, body mass index, and smoking, thus suggesting that depression PGS was an important risk factor for the proinflammatory state observed in depression,” the investigators said.

“These results suggested that genetic risk for depression, independent of depressive symptoms, was linked to a proinflammatory biomarker. The association of the depression PGS with WBC was modest across all biobanks, suggesting that individuals with high depression genetic liability may have an activated but not abnormal immune system. Nonetheless, sustained activation of the immune system could have important implications for the risk of developing depression.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Sealock JM, Lee YH, Moscati A, et al. Use of the PsycheMERGE network to investigate the association between depression polygenic scores and white blood cell count. JAMA Psychiatry. Published online October 20, 2021. doi:10.1001/jamapsychiatry.2021.2959: 10.1001/jamapsychiatry.2021.2959