Academic Journal
Unraveling genotype-phenotype relationships in hereditary hemochromatosis through integrated biobank data analysis.
| Τίτλος: | Unraveling genotype-phenotype relationships in hereditary hemochromatosis through integrated biobank data analysis. |
|---|---|
| Συγγραφείς: | Nurm M; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia. miriam.nurm@ut.ee., Annilo T; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., May-Wilson S; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland., Reigo A; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Mägi R; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Võsa U; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Tõnisson N; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.; Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia., Haller T; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia. toomas.haller@ut.ee. |
| Συλλογικό Έργο: | Estonian Biobank Research Team |
| Πηγή: | BMC genomics [BMC Genomics] 2026 Mar 16; Vol. 27 (1). Date of Electronic Publication: 2026 Mar 16. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: BioMed Central Country of Publication: England NLM ID: 100965258 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2164 (Electronic) Linking ISSN: 14712164 NLM ISO Abbreviation: BMC Genomics Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : BioMed Central, [2000- |
| Ιατρικοί όροι (MeSH): | Hemochromatosis*/genetics , Biological Specimen Banks* , Genetic Association Studies*, Hemochromatosis Protein/genetics ; Humans ; Phenotype ; Female ; Genome-Wide Association Study ; Genotype ; Male ; Middle Aged ; Estonia ; UK Biobank ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide |
| Περίληψη: | BACKGROUND: Type I hereditary hemochromatosis (HH), caused by pathogenic HFE variants, is among the most common autosomal recessive disorders in Northern Europe. HH genotype–phenotype associations have been difficult to predict due to variable variant penetrance and expressivity. In this study, population-based biobank data were used to conduct a large-scale analysis of symptoms associated with different HH genotypes and their potential genetic modifiers. METHODS: Linked genotypic and electronic health records from the Estonian Biobank (n = 211,994) and UK Biobank (n = 405,931) were used to investigate HH genotype–phenotype associations. Pathogenic variants of all HH types in the Estonian Biobank sample were identified. Clinical markers derived from laboratory measurements and diagnosis codes were compared between HFE pathogenic variant carriers and controls [chi-squared test, phenome-wide association study (PheWAS)]. Carrier subgroups were defined according to the presence of p.C282Y, p.H63D, p.S65C, and all pairwise combination genotypes. Kruskal–Wallis and Mann–Whitney U tests were used to identify ICD-10 codes and genotype groups with significantly different mean ages at first diagnosis. Genome-wide association studies (GWAS) based on ceruloplasmin and ferritin concentrations were conducted to identify potential genetic modifiers. Fine-mapping was used to identify putatively causal single nucleotide polymorphisms (credible sets) in the Estonian Biobank GWAS results. Fixed-effects meta-analyses of combined GWAS results from both biobanks were performed. RESULTS: We conducted the largest PheWAS with data from HFE variant carriers to date and catalogued pathogenic HH variants in the Estonian population. p.S65C homozygotes and p.C282Y/p.S65C heterozygotes in the Estonian Biobank sample were diagnosed with urogenital conditions (ICD-10 codes N42 and N50.8) at significantly higher rates than were controls. On average, N42 was first diagnosed 11 years earlier in p.S65C compound heterozygotes and homozygotes than in controls. We also identified a novel GWAS hit, CP rs61733458, with a significant impact on the ceruloplasmin level and ties to iron metabolism–related diseases. CONCLUSIONS: Our results suggest that the p.S65C variant is more clinically relevant than previously thought and should be integrated more into HH testing guidelines. CP variant rs61733458 is a potential genetic modifier associated with iron metabolism–related diseases. |
| Competing Interests: | Declarations. Ethics approval and consent to participate: This study received approval from the Estonian Committee on Bioethics and Human Research. The activities of the Estonian Biobank are regulated by the Human Genes Research Act, which was adopted in 2000 specifically for the operations of the Estonian Biobank. Individual-level data analysis at the Estonian Biobank for the purpose of this study was carried out under ethical approval nos. 1.1–12/2356 and 1.1–12/624 (and all further amendments) from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs), using data according to release application no. U37 6–7/GI/14569 from the Estonian Biobank. UK Biobank data has approval from the North West Multi-centre Research Ethics Committee (MREC) (REC reference: 16/NW/0274). This research was conducted with the UK Biobank Resource under project 78537. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. |
| References: | JAMA. 2022 Nov 8;328(18):1862-1863. (PMID: 36346422) BMJ. 2024 Dec 9;387:e079147. (PMID: 39653412) Am J Clin Nutr. 1998 May;67(5 Suppl):972S-977S. (PMID: 9587138) Genet Test. 2002 Spring;6(1):59-62. (PMID: 12180078) Blood. 2024 Aug 15;144(7):693-707. (PMID: 38728387) Nat Commun. 2025 Apr 05;16(1):3270. (PMID: 40188112) Commun Biol. 2021 Feb 3;4(1):156. (PMID: 33536631) Eur J Epidemiol. 2001;17(3):213-6. (PMID: 11680538) Parkinsons Dis. 2010 Oct 17;2011:827693. (PMID: 20981230) Anticancer Res. 2002 Nov-Dec;22(6B):3797-9. (PMID: 12552996) Nature. 2020 May;581(7809):434-443. (PMID: 32461654) J Mol Cell Biol. 2024 Apr 4;15(9):. (PMID: 37771074) J Manag Care Spec Pharm. 2019 Dec;25(12):1377-1386. (PMID: 31778618) Front Genet. 2022 Jul 19;13:936131. (PMID: 35928446) Nucleic Acids Res. 2025 Jan 6;53(D1):D998-D1005. (PMID: 39530240) Dan Med Bull. 1991 Aug;38(4):385-93. (PMID: 1914539) BMJ. 2019 Jan 16;364:k5222. (PMID: 30651232) Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):516-22. (PMID: 22075249) Int J Lab Hematol. 2015 May;37 Suppl 1:25-30. (PMID: 25976957) Vox Sang. 2024 Jan;119(1):34-42. (PMID: 38018286) J Eur Acad Dermatol Venereol. 2025 May;39(5):976-986. (PMID: 38752605) Eur J Hum Genet. 2025 Nov;33(11):1499-1508. (PMID: 39674827) Brain Res. 1996 Nov 4;738(2):265-74. (PMID: 8955522) J Hepatol. 2021 Oct;75(4):1003-1004. (PMID: 34023349) JAMA. 2020 Nov 24;324(20):2048-2057. (PMID: 33231665) World J Gastroenterol. 2007 Sep 21;13(35):4690-8. (PMID: 17729390) Nature. 2023 Jan;613(7944):508-518. (PMID: 36653562) J Hepatol. 2021 Sep;75(3):506-513. (PMID: 33774058) Nat Commun. 2017 Nov 28;8(1):1826. (PMID: 29184056) Ann Hematol. 2015 Feb;94(2):343-4. (PMID: 25015053) Curr Neuropharmacol. 2019;17(6):539-549. (PMID: 29737252) Nat Genet. 2021 Jul;53(7):1097-1103. (PMID: 34017140) Bioinformatics. 2010 Sep 1;26(17):2190-1. (PMID: 20616382) Int J Mol Sci. 2021 Jan 27;22(3):. (PMID: 33513852) Hepatology. 2008 Sep;48(3):991-1001. (PMID: 18752323) Nature. 2018 Oct;562(7726):203-209. (PMID: 30305743) N Engl J Med. 2008 Jan 17;358(3):221-30. (PMID: 18199861) Semin Liver Dis. 2005 Nov;25(4):381-91. (PMID: 16315132) Public Health Genomics. 2010;13(2):106-15. (PMID: 19556749) Am J Med. 1999 Jun;106(6):619-24. (PMID: 10378618) Mol Neurobiol. 2021 Jun;58(6):2812-2823. (PMID: 33507490) Scand J Gastroenterol. 2000 Dec;35(12):1301-7. (PMID: 11199371) J R Stat Soc Series B Stat Methodol. 2020 Dec;82(5):1273-1300. (PMID: 37220626) PLoS Med. 2015 Mar 31;12(3):e1001779. (PMID: 25826379) Bioinformatics. 2023 Nov 1;39(11):. (PMID: 37930895) Fam Cancer. 2024 Nov 15;24(1):3. (PMID: 39546056) Nucleic Acids Res. 2014 Jan;42(Database issue):D980-5. (PMID: 24234437) Cancer Epidemiol Biomarkers Prev. 2022 Sep 2;31(9):1780-1787. (PMID: 35709753) Am J Hum Genet. 2015 Oct 1;97(4):512-20. (PMID: 26365338) Sci Rep. 2024 Apr 2;14(1):7694. (PMID: 38565889) Brain. 2013 May;136(Pt 5):1476-87. (PMID: 23518715) Am J Hum Genet. 2017 Oct 5;101(4):539-551. (PMID: 28942963) Neurology. 2004 Nov 23;63(10):1912-7. (PMID: 15557511) |
| Grant Information: | PRG1291 Eesti Teadusagentuur |
| Contributed Indexing: | Investigator: A Metspalu; L Milani; T Esko; M Nelis; G Hudjashov Keywords: Biobank; Electronic health records; Genome-wide association study; Hereditary hemochromatosis; Phenome-wide association study |
| Substance Nomenclature: | 0 (Hemochromatosis Protein) 0 (HFE protein, human) |
| Entry Date(s): | Date Created: 20260317 Date Completed: 20260627 Latest Revision: 20260813 |
| Update Code: | 20260913 |
| PubMed Central ID: | PMC13104239 |
| DOI: | 10.1186/s12864-026-12746-3 |
| PMID: | 41840493 |
| Βάση Δεδομένων: | MEDLINE |
καταχωρήστε σχόλιο πρώτοι!