{"doi":"10.1111/bjh.17101","title":"Investigating the missing heritability of fetal haemoglobin level in Africa","abstract":"Clinical expression of sickle cell disease (SCD) often shows considerable variation, such as the severity of anaemia, the frequency of painful vaso-occlusive crises, kidney dysfunctions, stroke, acute chest syndrome and mortality. High foetal haemoglobin (HbF) levels have long been associated with less severity,1 yet, HbF levels are under genetic control2 and have been shown to be amenable to therapeutic manipulation in a murine model.3 Genes and loci that control HbF levels, for example, BLL11A, a transcriptional repressor of HbF, are critical targets of current therapeutic approaches in increasing the production of HbF in SCD patients via gene editing techniques.4, 5 In their paper the authors6 have investigated additional genetic variations that significantly affect HbF levels in SCD in a modest sample of patients from Tanzania. Using a targeted single nucleotide polymorphisms (SNPs) approach, the authors have identified a novel variant on chromosome X (rs169988911-FRMPD4), that is associated with both F cells (and HbF) and haematological indices in SCD patients, and that could also account for the differential level of HbF between males and females, as suspected by other investigators nearly a decade ago.7 This finding is important for multiple reasons: the study was performed in Africa where most SCD patients live, and could contribute to furthering local scientific capacity; moreover, the study addresses the important research question of the missing heritability of HbF, in as much as the known variants in three major loci, HBB like gene cluster, HBS1L-MYB intergenic region, and BCL11A, explain only up to 20% of variation of HbF in most SCD patients of African ancestry investigated, (e.g. African American, Tanzanian, Cameroonian).8-10 While waiting for these data to be replicated in additional SCD patients with larger sample sizes, this research suggests that investigating the missing heritability of HbF in SCD will require revision of the current strategy that has been largely based, as for most quantitative traits, on a genome-wide association study (GWAS) performed in populations based in Europe and America.11-13 Data from Urio et al (2020) support exploring the use of deep sequencing of targeted loci that might not have reached GWAS significance in previous investigations. Moreover, the data emphasised the need for urgent initiation of additional GWAS in SCD in populations of African ancestry from multiple geographical locations and ethnolinguistic backgrounds, with an appropriate designed GWAS array and bioinformatic analytic tools that will account for huge African genetic diversity. Indeed, only one GWAS on HbF in SCD has been performed in patients in Africa (from Tanzania)14 and had replicated variants in two known HbF promoting loci, that is, HBS1L-MYB and BCL11A. It also identified novel suggestive loci that did not reach GWAS significance level; however, variants in these suggestive loci were not replicated in another African SCD cohort from Cameroon.15 This non-replication could be attributed to the allele frequency differences due to higher genetic diversity among African cohorts, sometimes associated with differential positive selection, allelic heterogeneity (multiple distinct variants at loci) or differential gene-environment interactions as well as novel population-specific association signals as, for example, reported for Hb F in Sardinians.13 However, the HbF GWAS previously performed in SCD patients in Tanzania14 used a DNA array that could not capture the depth of genetic variations known in African populations and, therefore, could have missed important variations associated with HbF levels. Indeed, based on a ‘pan-genome’ generated from 910 individuals of African descent, at least 300 million DNA variants (10%) are not found in the current human reference genome.16 In addition, most current GWAS findings that are used to inform disease diagnosis, clinical expression predications, disease care, and ","journal":"British Journal of Haematology","year":2020,"id":112876,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":78669,"name":"Ambroise Wonkam","orcid":"0000-0003-1420-9051","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-18T23:13:17.845093Z","pmid":"33094841","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}