The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders

Nis Borbye-Lorenzen; Zhihong Zhu; Esben Agerbo; Clara Albiñana; Michael E Benros; Beilei Bian; Anders D Børglum; Cynthia M Bulik; Jean-Christophe Philippe Goldtsche Debost; Jakob Grove; David M Hougaard; Allan F McRae; Ole Mors; Preben Bo Mortensen; Katherine L Musliner; Merete Nordentoft; Liselotte V Petersen; Florian Privé; Julia Sidorenko; Kristin Skogstrand; Thomas Werge; Naomi R Wray; Bjarni J Vilhjálmsson; John J McGrath

doi:10.1016/j.xgen.2023.100457

The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders

Cell Genom. 2023 Dec 13;3(12):100457. doi: 10.1016/j.xgen.2023.100457.

Authors

Nis Borbye-Lorenzen¹, Zhihong Zhu², Esben Agerbo^{2

3

4}, Clara Albiñana^{2

3}, Michael E Benros^{5

6}, Beilei Bian⁷, Anders D Børglum^{3

8

9}, Cynthia M Bulik^{10

11

12}, Jean-Christophe Philippe Goldtsche Debost^{2

13}, Jakob Grove^{3

9

14

15}, David M Hougaard^{3

16}, Allan F McRae⁷, Ole Mors^{3

17}, Preben Bo Mortensen^{2

3

4}, Katherine L Musliner¹⁸, Merete Nordentoft^{3

19

20}, Liselotte V Petersen², Florian Privé², Julia Sidorenko⁷, Kristin Skogstrand¹, Thomas Werge^{3

20

21

22}, Naomi R Wray^{7

23

24

25}, Bjarni J Vilhjálmsson^{2

3

15}, John J McGrath^{2

23

26}

Affiliations

¹ Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
² National Center for Register-Based Research, Aarhus University, 8210 Aarhus V, Denmark.
³ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8210 Aarhus V, Denmark.
⁴ Center for Integrated Register-based Research, Aarhus University, CIRRAU, 8210 Aarhus V, Denmark.
⁵ Copenhagen Research Center for Mental Health, Mental Health Center Copenhagen, Copenhagen University Hospital, Hellerup, Denmark.
⁶ Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁸ Department of Biomedicine and the iSEQ Center, Aarhus University, Aarhus, Denmark.
⁹ Center for Genomics and Personalized Medicine, CGPM, Aarhus, Denmark.
¹⁰ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹² Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Psychosis, Aarhus University Hospital Skejby, Aarhus Nord, Denmark.
¹⁴ Department of Biomedicine (Human Genetics), Aarhus University, Aarhus, Denmark.
¹⁵ Bioinformatics Research Center, Aarhus University, 8000 Aarhus C, Denmark.
¹⁶ Department for Congenital Disorders, Statens Serum Institut, 2300 Copenhagen S, Denmark.
¹⁷ Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
¹⁸ Department of Affective Disorders, Aarhus University and Aarhus University Hospital -Psychiatry, Aarhus, Denmark.
¹⁹ Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, 2100 Copenhagen, Denmark.
²⁰ Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark.
²¹ Department of Clinical Medicine, Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, University of Copenhagen, 2200 Copenhagen N, Denmark.
²² Lundbeck Center for Geogenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.
²³ Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.
²⁴ Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK.
²⁵ Big Data Institute, University of Oxford, Oxford OX3 7LF, UK.
²⁶ Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Brisbane, QLD 4076, Australia.

Abstract

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.

Keywords: C3; C4; Mendelian randomization; autoimmune disorders; complement component; dried blood spots; genome-wide association study; phenome-wide association study; psychiatric disorders; schizophrenia.

Abstract

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