A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis
Abstract 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 g...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Human Genomics |
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| Online Access: | https://doi.org/10.1186/s40246-024-00585-w |
| _version_ | 1797259121346478080 |
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| author | Andrei-Emil Constantinescu David A. Hughes Caroline J. Bull Kathryn Fleming Ruth E. Mitchell Jie Zheng Siddhartha Kar Nicholas J. Timpson Borko Amulic Emma E. Vincent |
| author_facet | Andrei-Emil Constantinescu David A. Hughes Caroline J. Bull Kathryn Fleming Ruth E. Mitchell Jie Zheng Siddhartha Kar Nicholas J. Timpson Borko Amulic Emma E. Vincent |
| author_sort | Andrei-Emil Constantinescu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T23:04:23Z |
| format | Article |
| id | doaj.art-076fa3065a87429d9b406f6aa47196de |
| institution | Directory Open Access Journal |
| issn | 1479-7364 |
| language | English |
| last_indexed | 2024-04-24T23:04:23Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Human Genomics |
| spelling | doaj.art-076fa3065a87429d9b406f6aa47196de2024-03-17T12:32:38ZengBMCHuman Genomics1479-73642024-03-0118111510.1186/s40246-024-00585-wA genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesisAndrei-Emil Constantinescu0David A. Hughes1Caroline J. Bull2Kathryn Fleming3Ruth E. Mitchell4Jie Zheng5Siddhartha Kar6Nicholas J. Timpson7Borko Amulic8Emma E. Vincent9MRC Integrative Epidemiology Unit, University of BristolMRC Integrative Epidemiology Unit, University of BristolMRC Integrative Epidemiology Unit, University of BristolSchool of Cellular and Molecular Medicine, University of BristolMRC Integrative Epidemiology Unit, University of BristolDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineMRC Integrative Epidemiology Unit, University of BristolMRC Integrative Epidemiology Unit, University of BristolSchool of Cellular and Molecular Medicine, University of BristolMRC Integrative Epidemiology Unit, University of BristolAbstract 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.https://doi.org/10.1186/s40246-024-00585-wMalariaNeutrophil countMendelian randomizationGWASAfrican ancestry |
| spellingShingle | Andrei-Emil Constantinescu David A. Hughes Caroline J. Bull Kathryn Fleming Ruth E. Mitchell Jie Zheng Siddhartha Kar Nicholas J. Timpson Borko Amulic Emma E. Vincent A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis Human Genomics Malaria Neutrophil count Mendelian randomization GWAS African ancestry |
| title | A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis |
| title_full | A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis |
| title_fullStr | A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis |
| title_full_unstemmed | A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis |
| title_short | A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis |
| title_sort | genome wide association study of neutrophil count in individuals associated to an african continental ancestry group facilitates studies of malaria pathogenesis |
| topic | Malaria Neutrophil count Mendelian randomization GWAS African ancestry |
| url | https://doi.org/10.1186/s40246-024-00585-w |
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