A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis.

Autor: Constantinescu AE; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.; School of Translational Health Sciences, University of Bristol, Bristol, UK., Hughes DA; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.; Louisiana State University, Louisiana, USA., Bull CJ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.; School of Translational Health Sciences, University of Bristol, Bristol, UK.; Health Data Research UK, London, UK., Fleming K; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK., Mitchell RE; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK., Zheng J; Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases, National Health Commission, Shanghai, People's Republic of China.; Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China., Kar S; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.; Early Cancer Insitute, University of Cambridge, Cambridge, UK., Timpson NJ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK., Amulic B; School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK. borko.amulic@bristol.ac.uk., Vincent EE; MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. emma.vincent@bristol.ac.uk.; Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK. emma.vincent@bristol.ac.uk.; School of Translational Health Sciences, University of Bristol, Bristol, UK. emma.vincent@bristol.ac.uk.
Jazyk: angličtina
Zdroj: Human genomics [Hum Genomics] 2024 Mar 15; Vol. 18 (1), pp. 26. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1186/s40246-024-00585-w
Abstrakt: Background: 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056).
Results: We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r 2  = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null.
Conclusion: Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.
(© 2024. The Author(s).)
Databáze: MEDLINE
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