Comprehensive Sex-Stratified Genetic Analysis of 28 Blood Biomarkers and Depression Reveals a Significant Association between Depression and Low Levels of Total Protein in Females

Jacqueline Kiewa; Samantha Meltzer-Brody; Jeannette Milgrom; Jerry Guintivano; Ian B Hickie; David C Whiteman; Catherine M Olsen; Sarah E Medland; Nicholas G Martin; Naomi R Wray; Enda M Byrne

doi:10.1159/000538058

Comprehensive Sex-Stratified Genetic Analysis of 28 Blood Biomarkers and Depression Reveals a Significant Association between Depression and Low Levels of Total Protein in Females

Complex Psychiatry. 2024 Feb 28;10(1-4):19-34. doi: 10.1159/000538058. eCollection 2024 Jan-Dec.

Authors

Jacqueline Kiewa^{1

2}, Samantha Meltzer-Brody³, Jeannette Milgrom^{4

5}, Jerry Guintivano³, Ian B Hickie⁶, David C Whiteman⁷, Catherine M Olsen⁷, Sarah E Medland⁷, Nicholas G Martin⁷, Naomi R Wray^{2

8}, Enda M Byrne¹

Affiliations

¹ Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia.
² Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
³ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁴ Parent-Infant Research Institute, Austin Health, Melbourne, VIC, Australia.
⁵ Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne, VIC, Australia.
⁶ Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
⁷ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁸ Department of Psychiatry, University of Oxford, Oxford, UK.

Abstract

Introduction: Major depression (MD) is more common amongst women than men, and MD episodes have been associated with fluctuations in reproductive hormones amongst women. To investigate biological underpinnings of heterogeneity in MD, the associations between depression, stratified by sex and including perinatal depression (PND), and blood biomarkers, using UK Biobank (UKB) data, were evaluated, and extended to include the association of depression with biomarker polygenic scores (PGS), generated as proxy for each biomarker.

Method: Using female (N = 39,761) and male (N = 38,821) UKB participants, lifetime MD and PND were tested for association with 28 blood biomarkers. A GWAS was conducted for each biomarker and genetic correlations with depression subgroups were estimated. Using independent data from the Australian Genetics of Depression Study, PGS were constructed for each biomarker, and tested for association with depression status (n [female cases/controls] = 9,006/6,442; n [male cases/controls] = 3,106/6,222). Regions of significant local genetic correlation between depression subgroups and biomarkers highlighted by the PGS analysis were identified.

Results: Depression in females was significantly associated with levels of twelve biomarkers, including total protein (OR = 0.90, CI = [0.86, 0.94], p = 3.9 × 10^-6) and vitamin D (OR = 0.94, CI = [0.90, 0.97], p = 2.6 × 10^-4), and PND with five biomarker levels, also including total protein (OR = 0.88, CI = [0.81, 0.96], p = 4.7 × 10^-3). Depression in males was significantly associated with levels of eleven biomarkers. In the independent Australian Genetics of Depression Study, PGS analysis found significant associations for female depression and PND with total protein (female depression: OR = 0.93, CI = [0.88, 0.98], p = 3.6 × 10^-3; PND: OR = 0.91, CI = [0.86, 0.96], p = 1.1 × 10^-3), as well as with vitamin D (female depression: OR = 0.93, CI = [0.89, 0.97], p = 2.0 × 10^-3; PND: OR = 0.92, CI = [0.87, 0.97], p = 1.4 × 10^-3). The male depression sample did not report any significant results, and the point estimate of total protein (OR = 0.98, CI = [0.92-1.04], p = 4.7 × 10^-1) did not indicate any association. Local genetic correlation analysis highlighted significant genetic correlation between PND and total protein, located in 5q13.3 (r_G = 0.68, CI = [0.33, 1.0], p = 3.6 × 10^-4).

Discussion and conclusion: Multiple lines of evidence from genetic analysis highlight an association between total serum protein levels and depression in females. Further research involving prospective measurement of total protein and depressive symptoms is warranted.

Keywords: Biomarker; GWAS; Genetic correlation; Major depression; Perinatal depression; Polygenic scores; Sex stratification.

Grants and funding

The Australian Genetics of Depression Study was primarily funded by National Health and Medical Research Council (NHMRC) of Australia Grant 1086683. This work was further supported by NHMRC Grants 1145645, 1078901 and 1087889, and generously supported by a donation from the Axelsen family. The QSkin study is supported by National Health and Medical Research Council of Australia Grants APP1073898 and APP1058522. J.K. has been supported by a UQ Research Training Program scholarship, and E.M.B. received funding from an NHMRC Centre for Research Excellence (APP1198304) and the University of Queensland Health Research Accelerator Program. S.M.-B. receives sponsored research grants from Sage Therapeutics. D.C.W. is supported by a Research Fellowship from the National Health and Medical Research Council of Australia (APP1155413).