Biobank Participants’ Perspectives on Receiving Genetic Risk Information from a Biobank – The case of Haemochromatosis

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In addition to the large-scale population level data sets, the professional, standardized and legislated operating environment of the biobanks has enabled their growing footprint in the field of personalized medicine. Moreover, the biobank participants in The Finnish Red Cross Blood Service (FRCBS) Biobank have expressed high willingness to receive information relevant to their health. In this study we screened the FRCBS Biobank genome data, N = 43,868, for HFE C282Y (+/+) and returned the clinically verified results to 82 biobank participants. In addition, we conducted a survey on their experience on receiving genetic risk information from a biobank. We demonstrate a high occurrence of blood donors not being aware of their genetic risk, a relatively high penetrance of the HFE C282Y (+/+) and a clear acceptance of receiving genetic risk information from the biobank by the participants. We show how genetic information stored in a biobank can be used in a precisely defined context, such as blood donation. Further comprehensive studies are needed to fully understand the possibilities biobanks could offer in personalized medicine. HFE C282Y haemochromatosis biobank blood donor genetic information actionable genotype Figures Figure 1 Figure 2 Introduction Precision medicine has become attractive in past years, due to its potential in enabling more efficient treatment, increasing the quality of life and providing significant cost efficiency 1 . Especially in the field of pharmacogenomics and oncology, genetic based precision medicine is widely used. Several countries have established national genome projects to enhance the usage of genome data to promote health 2 , including Finland 3 . Large population-based biobanks in professional, standardized and legislated operating environment, can serve as an excellent basis for piloting and implementing the use of genetic information in personalized health care 4,5 . Prerequisites for returning genetic information to sample donors are evidence-based scientific results. Only genetic variants for which the potential morbidity penetrance threshold is met and for which efficacious intervention measures exist should be returned 6,7 . According to the Finnish Biobank Act, biobank participants’ have the right, upon request, to receive information about health-related factors determined from their biobank sample 8,9 . In addition, when consenting for biobank in Finland, the sample donors are also asked for a consent to receive health-relevant information. Of the biobank participants in the Finnish Red Cross Blood Service, >99% have consented for receiving health-related information. Real life examples of actively returning genetic information from biobanks exist; genetic risk information related to several disease-associated genetic variants such as ovarian and breast cancer 10 and familial hypercholesterolemia 11 has previously been returned from the Estonian biobank 5 . In Finland, breast cancer related genetic risk information has been returned to sample donors from all hospital biobanks (unpublished data). To date, the European Society of Human Genetics (ESHG) recommends screening of actionable genotypes to be performed as pilot studies rather than routine screening to gain understanding on several uncertainties 12 , while the American College of Medical Genetics (ACMG) recommends active screening on several identified genetic variants in along with clinical exome sequencing in health care 7 . Hereditary haemochromatosis is an iron accumulation disease caused by mainly founder mutations C282Y and H63D in the HFE gene 13,14 that are common in Northern European populations 15 . According to ACMG recommendation, HFE C282Y (+/+) is as an actionable finding as potential morbidity meets the penetrance threshold and efficacious interventions exist 7 . Despite of the ACMG recommendation, the low penetrance of the HFE C282Y variant raises questions. In Finland, post donation iron supplementation is supplied for all frequently donating blood donors and all women under 50 years of age, to help to replenish the iron deficit caused by the blood loss. However, individuals with HFE C282Y (+/+) genotype probably should avoid iron supplementation in this context 16 . In this work, we identified biobank participants with genetic predisposition for haemochromatosis, informed them about the finding and provided a recommendation to seek further advice from health care with information enclosed for the health care professional. The aim was to improve blood donor health by not providing futile and potentially harmful iron supplementation in future donations for donors with HFE C282Y (+/+) genotype. Furthermore, we conducted a survey to understand the biobank participants’ perspectives of receiving genetic risk information and if the primary finding resulted in clinical endpoints, such as clinical haemochromatosis diagnose (ICD10: E83.1). Material and methods Identification of HFE C282Y homozygotes The Blood Service Biobank data, N = 43,868, previously produced in the FinnGen project, was screened for HFE C282Y (+/+) (NM_000410.4:c.845G > A, rs1800562). In brief, the biobank samples were genotyped as part of the FinnGen project with the FinnGen ThermoFisher Axiom custom array v1 or v2. Genotyping, quality control, and genome imputation protocols, R11, are described in detail in FinnGen Gitbook 17 . Shortly, genotype calling was performed with AxiomGT1 algorithm. Prior the imputation, genotyped samples were pre-phased with Eagle 2.3.5 with the default parameters, except the number of conditioning haplotypes was set to 20,000. Genotype imputation was performed using the population-specific imputation reference panel SISu v3 including 3775 high coverage (25–30x) whole genome sequence data, with Beagle 4.1 (version 08Jun17.d8b). Genotypes were called from VCF files under the following conditions: when imputed dosage score was ≥ 0 and ≤ 0.1, dosage value was considered as 0, when imputed dosage score was ≥ 0.9 and ≤ 1.1, dosage value was considered as 1 and finally when imputed dosage score was ≥ 1.9 and ≤ 2.0, dosage value was considered as 2. HFE C282Y (+/+) screening was performed in R 18 version 3.6.1 or later, with R Studio 19 . Clinical validation of the preliminary finding The preliminary HFE C282Y (+/+) findings were validated in an external EAK (Estonian Accreditation Centre, EA MLA member) accredited laboratory (EVS-EN ISO 15189) in SynLab Tallinn, SynLab (synlab.fi). The clinical grade confirmation of HFE C282Y (+/+) genotype was performed with accredited Taqman based genotyping method (B -Hemok-D KL 1858). Informing biobank participants Biobank participants with confirmed HFE C282Y (+/+) genotype were contacted via letter. The letter provided information about haemochromatosis, a recommendation to contact healthcare for further information and information about haemochromatosis for a physician. A recommendation of laboratory tests to be measured in the healthcare; basic blood count, ferritin, transferrin saturation, alanine aminotransferase and, due to the nature of biobank samples as research sample, a confirmatory clinical sample taken for validating the HFE C282Y (+/+) genotype, was included in the letter. The participants were given a possibility to contact a physician in The Finnish Red Cross Blood Service for any questions related to the information they had received. Along with the information letter, the biobank participants were asked to return a feedback form asking three questions: 1) Were you aware of your genetic predisposition to haemochromatosis?, 2) Can the finding be recorded to blood donation registry to avoid the iron supplementation in future blood donations? and 3) Are you willing to take part on survey regarding receiving genetic risk information from biobank? Survey A survey was sent to all those biobank participants, who agreed in the feedback form to participate in the survey, with an informed consent enclosed. The survey consisted of a total of 26 questions, which covered the participants’ experiences on receiving genetic risk information from the biobank, participants’ experiences on how their matter was handled among the health care providers, participants’ perspectives on the impact of the information received has on their lifestyle behavior and participants’ experiences on sharing the information with first degree family members. The survey form is available in the Supplementary File 1. Results Altogether 94 (0.2%) biobank participants were identified as HFE C282Y (+/+) and all these participants had consented for receiving information relevant to their health. Of these participants, 89 had DNA sample available in biobank for the confirmatory testing. All the preliminary HFE C282Y (+/+) findings, N = 89, were confirmed as HFE C282Y (+/+) in the external laboratory with accredited clinical grade method. Due to technical reasons (two participants with missing contact information, five participants with difficulty to interpret the biobank consent for recontacting), 82 biobank participants were contacted in the first phase (Fig. 1 A). (Since that, the genetic risk information has been returned to all seven biobank participants but due to the delay in informing, the participants are not included in this study) Of the 82 biobank participants, 63 returned the feedback form, resulting in response rate of 77%. Of the biobank participants 98% (N = 62) were willing to participate in the survey and 100% (N = 63) gave a permission to record the finding to blood donation registry. Seven biobank participants, 8.5%, contacted a physician in Blood Service after receiving the letter. Of the 82 biobank participants, only 13.4% (N = 11) were aware of their predisposition to haemochromatosis. The response rate in the survey was 68% (N = 38) among biobank participants who weren’t aware of their genetic tendency to haemochromatosis previously (N = 56). All survey results, including the clinical results, are self-reported. Demographic information of the survey participants is available in Table 1 . The sex distribution of the participants reflects to the overall sex distribution of the blood donors; female donors represented majority of the donors participating in the survey. The donation activity reflects well on the overall high donation activity of the biobank donors 20 : majority of the respondents, 79% of the females and males, had donated blood at least 21 times. The survey results are shown in more detail in Supplementary information. Table 1 Demographic characteristics of the participants. YearStarted refers to the year a participant started donating blood. DonationCount refers to the overall times the participant has donated blood. Characteristic N Female N = 24 1 Male N = 14 1 Age 38 52 (43, 62) 50 (42, 60) YearStarted 34 2000 (1990, 2007) 1997 (1982, 2002) Unknown 4 0 DonationCount 38 1–20 5 (21%) 3 (21%) 21–40 11 (46%) 6 (43%) 41–100+ 8 (33%) 5 (36%) 1 Median (Q1, Q3); N (%) Blood donors’ experiences on receiving genetic risk information Overall, the participants reported positive attitude towards receiving genetic results 21,22 . Most of the participants found the received information useful (89% strongly agreed and 8% partly agreed). Of the participants, 45% (N = 17) felt that receiving genetic information had caused worry in them. In participants’ opinion, the genetic information in biobanks should be used more to promote health (76% (N = 29) strongly agreed and 24% (N = 9) partly agreed) (Fig. 1 D). Most of the participants (82%) had recognized that consenting to receiving information relevant to health, might lead to receiving health related information. All participants, 100%, wished to receive similar information in the future, should it appear. The participants stated that their trust in The Blood Service and their willingness to belong to The Blood Service Biobank had grown (Fig. 1 C). All participants, 100%, reported having discussed about the finding with their first-degree family members. Based on the open field answers, the participants reported the reactions of the family members to have been mainly neutral with minor concern or confusion. Some of the participants reported family history with haemochromatosis in the open fields. Majority of the participants (92%) stated that knowing their genetic risk made them feel motivated to take better care of their health. Eighty-six percent of the participants believe they can affect their predisposition to haemochromatosis with lifestyle choices. Of the participants, 50% (N = 19) reported they plan to continue donating blood as before and 34% (N = 13) thought they would donate more often in the future than currently. Some participants stated they’ll quit blood donation for another reason, but none of the participants reported quitting donation because they had received genetic risk information. Apart from one participant, all participants had sought advice from healthcare, as recommended in the letter. The participants stated their matter was handled fluently in the healthcare (61% (N = 23) strongly agreed, 26% (N = 19), partly agreed) and that they received enough support in the healthcare (strongly agreed 45% (N = 17) and partly agreed 45% (N = 17)). Majority of the participants stated that their questions were answered in healthcare (29% (N = 11) strongly agreed, 39% (N = 15) partly agreed). Self-reported clinical findings Participants’ self-reported results of the clinical endpoints measured in the healthcare are shown in Table 2 . Distribution and median of each measurement are shown in Fig. 2 . The number of responses varied between different clinical endpoints. As it is not known where in Finland the survey participants had their clinical measurements taken, all the reference intervals are reported in accordance with the reference intervals of the Helsinki University Hospital. The reference intervals used areshown in detail in Supplementary information. 63% of the participants reported the confirmatory HFE C282Y (+/+) from a clinical sample had been taken but putatively because of difficulty in interpreting the laboratory result or insufficient question structure in the survey, majority of the participants did not report the outcome of the HFE C282Y (+/+) test. However, no contradictory findings were reported by the donors or could be observed from the survey results. Haemoglobin exceeded the upper bound of reference interval in 29% of females (117–155 g/L) and in 7% of males (134–167 g/L). The target ferritin level for phlebotomy in the induction phase of haemochromatosis is 50 µg/L and 100 µg/L in the maintenance phase 15 . Accordingly, of the participants, 65% reported ferritin levels higher than 50 µg/L and 47% higher than 100 µg/L. Transferrin saturation (TSAT) exceeded the upper bound of reference interval (52%) in 67% of females and 71% of males. Mean red blood cell volume (MCV) was elevated in 4% of females and 7% of males (reference interval 82–98 fl). The alanine aminotransferase (ALT) was within the reference interval in all participants who reported the results (reference interval < 35 U/L in females and < 50 U/L in males). High ALT values can indicate liver cell damage 23 . Altogether 37% of all the participants reported they had received a clinical diagnosis (ICD10: E83.1) for haemochromatosis. Of those who responded either yes or no, 56% reported to have received a clinical haemochromatosis diagnose (Fig. 1 B). Table 2 Results of the clinical laboratory measurements taken in the healthcare. Above column indicates how many participants reported results above the reference interval and respectively below column the results below the reference interval. The reference intervals used are those of Helsinki University Hospital. MAD median absolute deviation. Female Male Statistic Above Below Median MAD Above Below Median MAD Haemoglobin (g/L) 7 0 150 10 < 5 < 5 157 10 Ferritin (µg/L) 7 0 56 40 6 0 194 233 Transferrin Saturation (%) 16 < 5 58 21 10 0 69 32 eMCV (fl) < 5 < 5 94 4 < 5 0 93 3 Alanine aminotransferase (U/L) 0 20 19 9 0 9 33 12 Discussion Overall, the response rate was high; 77% returned the feedback form after receiving genetic risk information from the biobank and 68% participated in the further survey. Surprisingly, only 9.5% of the participants were aware of their genetic predisposition to haemochromatosis or clinical haemochromatosis. The overall experience of the biobank participants receiving genetic risk information from the Biobank was very positive. In participants’ perspective the information they received was useful and 100% stated they’d like to receive similar information in the future should it appear. However, a need for raising awareness was visible; a portion of the participants reported they didn’t know to expect such information, and a portion reported they weren’t aware if they had been set a clinical diagnosis (ICD10: E83.1). In the era of genomic medicine, pilot projects like this are an excellent way to increase the genomic information awareness, which is one of the goals of the National Genome Strategy of Finland 3 and has also been endorsed by the European Society of Human Genetics 12 . Another clear aim of this work was to identify blood donors that would benefit from avoiding iron supplementation in future blood donations. Of the participants who were identified with HFE C282Y (+/+) genotype, 100% gave the permission to record this finding in the blood donation registry. These blood donors will not be offered iron supplementation in future blood donations. The self-reported laboratory results indicate relatively high penetrance 24 but no signs of similar organ level damage than previously reported 25 . We have previously shown a positive genetic correlation (r g = 0.18) between blood donorship and haemoglobin 26 . It could be possible that individuals with high haemoglobin level are more likely to apply to donate blood and hence, the haemochromatosis prevalence among frequent blood donors is high but regular blood donation has maintained a relatively symptom free state of the haemochromatosis. As clinical manifestations cause blood donation ineligibility, the lower organ level damage in HFE C282Y (+/+) can also be caused by selection bias. Therefore, the information about genetic predisposability to haemochromatosis can be of particular importance for those blood donors who do no longer fulfill the donation eligibility criteria eg. due to their age. We have previously reported a high first-degree consanguinity among the biobank blood donors 20 . Although the higher consanguinity can explain the high occurrence of HFE C282Y (+/+) genotype in the Blood Service Biobank 20 , no direct conclusion can be drawn about the effect of high consanguinity on the observed penetrance. The low penetrance of the HFE C282Y (+/+) has caused controversy in the past years whether the genotype should require action. Biobank scale cohorts enable new possibilities in understanding the impact of common haemochromatosis causing mutations in the clinical outcome of haemochromatosis, which may raise the need for re-evaluation of HFE C282Y (+/+) screening on population level 24 . As a result of this work, we are in the process of screening the entire Blood Service Biobank data set for the HFE C282Y (+/+) genotype as well as planning to perform a cost effectiveness analysis to understand the impact of early detected haemochromatosis on healthcare and on individual’s quality of life. European citizens have in general reported positive attitude towards biobanking 27,28 . However, returning genetic information from biobank is not a routine practice in many countries, including Finland. Maintaining the trust of the biobank participants is of utmost importance, hence open, justified and consent-based modes of operation should be prerequisites when genetic information is returned from the biobanks as well as existing sufficient intervention and counseling practices. To date, this pilot study is the only one in Finland, where genetic risk information has been returned under the additional consent on willingness to receive information relevant to health given in connection with the biobank consent. The participants’ experience in this work clearly demonstrates the increased trust towards the Finnish Red Cross blood Service as well as willingness to belong to Blood Service Biobank as a result on receiving genetic risk information. However, when compared to other actionable genotypes on ACMG 7 or CDC tier 1 29 list, such as breast cancer related genotypes, HFE C282Y (+/+) can be considered rather “benign” genotype with efficacious interventions. Taken this and the blood donation context into consideration, the broad biobank consent was considered sufficient. It should be noted that this model may not be applicable in all cases, especially in cases with more severe effect of the variant 12 . Moreover, sufficient resourcing for personal counseling when returning genetic information related to more serious conditions, is essential. In this study, few donors contacted Blood Service physician regarding the results. Although the contacts were overall positive, they emphasize the importance of receiving personal advice. Although this study provides valuable insights on blood donors’ perspective on receiving genetic information, the study is limited by the small number of participants and strictly limited genotype as well as by the self-reported clinical laboratory results. This work demonstrates how the genetic information stored in biobank can be used in a precisely defined context, such as blood donation. Returning genetic information from biobanks in Finland is currently based on high impact CDC tier1 variants. High impact variants as well as non-malignant results with lower impact, have previously been returned from Estonian Biobank. The results of this study are consistent with the Estonian study; majority of the participants in the Estonian Biobank found the received information valuable 30 . Controversiality of the HFE C282Y (+/+) genotype, mainly because of the variants’ low penetrance, has caused confusion. In this study we demonstrate a high occurrence of blood donors not being aware of their genetic risk, a relatively high penetrance and a clear acceptance of receiving genetic risk information from the biobank by the participants. Therefore, further comprehensive studies are needed to fully understand the possibilities biobanks may provide in precision-based medicine in the future. Public engagement, wide national ethical conversation and raising awareness are fundamental steps towards maintaining the public trust and therefore enabling the precision medicine related benefits from biobanks in the future 6 . Declarations Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki. Returning the HFE C282Y (+/+) information to the biobank participants, was performed under the broad biobank consent and consent to receive health-relevant information. An informed consent was obtained from all the survey participants. According to Finnish Biobank Act, all survey results were pseudonymized, hence the research team only handled pseudonymized information. The study was conducted in accordance with the informed consent obtained from the survey participants. A study specific ethical permit HUS/1316/2024 was obtained from the Helsinki University Hospital HUS Regional Committee on Medical Research Ethics. A biobank permit 002-2024 was obtained from the Finnish Red Cross Blood Service Biobank ( https://www.veripalvelu.fi/en/biobank/biobank-research/ ). The use of the Biobank material is in accordance with the biobank consent and meets the requirements of the Finnish Biobank Act (688/2012). Consent for publication Not applicable Conflict of interest: Authors Funding Statement This study was partially funded by The Finnish Innovation Fund Sitra (to the Blood Service Biobank). Author Contribution J.Clancy: Conceptualization, Methodology, Formal analysis, Validation, Supervision, Writing – Original Draft. J.F: Project administration, Writing - Review & Editing. E.K: Formal analysis, Visualization, Writing – Original Draft. M.A: Methodology, Visualization, Writing - Review & Editing. F.Å: Project administration, Writing - Review & Editing. K.P: Conceptualization, Funding acquisition, Writing - Review & Editing. J.Castrén: Conceptualization, Writing - Review & Editing. Acknowledgement We acknowledge the kind and professional help of the personnel of The Finnish Red Cross Blood Service Biobank and Synlab. Data Availability Aggregate level survey data is available in the article and in the Supplementary information. Analysis scripts are available at https://github.com/FRCBS/hemochromatosis_questionaire. References Al, S. et. Lifetime Cost-Effectiveness of Hereditary Breast and Ovarian Cancer Prevention Based on FinnGen and Biobank Data, Data Returning Process, and Prophylaxis. https://www.ispor.org/heor-resources/presentations-database/presentation/intl2024-3898/138057 (2024). Zimani, A. N., Peterlin, B. & Kovanda, A. Increasing Genomic Literacy Through National Genomic Projects. Front. Genet. 12 , 693253 (2021). Genome Strategy - Finland . https://stm.fi/documents/1271139/2013549/UK-Genomistrategia-final-verkko+(1).pdf/c079fdae-94ea-4869-91df-02603c9b44ed/UK-Genomistrategia-final-verkko+(1).pdf?t=1678281581906. Paskal, W., Paskal, A. 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Supplementary Files JulkaisuSupplementaryinformationID156632.docx Cite Share Download PDF Status: Published Journal Publication published 17 Dec, 2025 Read the published version in BMC Medical Genomics → Version 1 posted Editorial decision: Revision requested 17 Sep, 2025 Reviews received at journal 12 Sep, 2025 Reviews received at journal 12 Sep, 2025 Reviews received at journal 04 Sep, 2025 Reviewers agreed at journal 04 Sep, 2025 Reviewers agreed at journal 02 Sep, 2025 Reviewers agreed at journal 31 Aug, 2025 Reviewers agreed at journal 30 Aug, 2025 Reviewers agreed at journal 28 Aug, 2025 Reviewers invited by journal 22 Aug, 2025 Editor invited by journal 09 Jul, 2025 Editor assigned by journal 23 Jun, 2025 Submission checks completed at journal 23 Jun, 2025 First submitted to journal 23 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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The unit scale corresponding to each laboratory parameter is depicted on the y-axis. Reference intervals are stated in accordance with the reference intervals of the Helsinki University Hospital.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6927867/v1/c2fbaf045bd700eff2aa084a.jpeg"},{"id":98813957,"identity":"2b968da4-0225-4223-8654-256bc1e8632b","added_by":"auto","created_at":"2025-12-22 16:08:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1252620,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6927867/v1/d83d91a7-a7f2-4062-83a6-9283afbe8426.pdf"},{"id":90318829,"identity":"cdc5836b-91b7-44e8-aac0-9164508cdccc","added_by":"auto","created_at":"2025-09-01 10:37:16","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":438011,"visible":true,"origin":"","legend":"","description":"","filename":"JulkaisuSupplementaryinformationID156632.docx","url":"https://assets-eu.researchsquare.com/files/rs-6927867/v1/26444162085a7cac7ee50d9b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Biobank Participants’ Perspectives on Receiving Genetic Risk Information from a Biobank – The case of Haemochromatosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrecision medicine has become attractive in past years, due to its potential in enabling more efficient treatment, increasing the quality of life and providing significant cost efficiency\u003csup\u003e1\u003c/sup\u003e. Especially in the field of pharmacogenomics and oncology, genetic based precision medicine is widely used. Several countries have established national genome projects to enhance the usage of genome data to promote health\u003csup\u003e2\u003c/sup\u003e, including Finland\u003csup\u003e3\u003c/sup\u003e. Large population-based biobanks in professional, standardized and legislated operating environment, can serve as an excellent basis for piloting and implementing the use of genetic information in personalized health care\u003csup\u003e4,5\u003c/sup\u003e. Prerequisites for returning genetic information to sample donors are evidence-based scientific results. Only genetic variants for which the potential morbidity penetrance threshold is met and for which efficacious intervention measures exist should be returned\u003csup\u003e6,7\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAccording to the Finnish Biobank Act, biobank participants\u0026rsquo; have the right, upon request, to receive information about health-related factors determined from their biobank sample\u003csup\u003e8,9\u003c/sup\u003e. In addition, when consenting for biobank in Finland, the sample donors are also asked for a consent to receive health-relevant information. Of the biobank participants in the Finnish Red Cross Blood Service, \u0026gt;99% have consented for receiving health-related information. Real life examples of actively returning genetic information from biobanks exist; genetic risk information related to several disease-associated genetic variants such as ovarian and breast cancer\u003csup\u003e10\u003c/sup\u003e and familial hypercholesterolemia\u003csup\u003e11\u003c/sup\u003e has previously been returned from the Estonian biobank\u003csup\u003e5\u003c/sup\u003e. In Finland, breast cancer related genetic risk information has been returned to sample donors from all hospital biobanks (unpublished data). To date, the European Society of Human Genetics (ESHG) recommends screening of actionable genotypes to be performed as pilot studies rather than routine screening to gain understanding on several uncertainties\u003csup\u003e12\u003c/sup\u003e, while the American College of Medical Genetics (ACMG) recommends active screening on several identified genetic variants in along with clinical exome sequencing in health care\u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eHereditary haemochromatosis is an iron accumulation disease caused by mainly founder mutations C282Y and H63D in the \u003cem\u003eHFE\u003c/em\u003e gene\u003csup\u003e13,14\u003c/sup\u003e that are common in Northern European populations\u003csup\u003e15\u003c/sup\u003e. According to ACMG recommendation, \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) is as an actionable finding as potential morbidity meets the penetrance threshold and efficacious interventions exist\u003csup\u003e7\u003c/sup\u003e. Despite of the ACMG recommendation, the low penetrance of the \u003cem\u003eHFE\u003c/em\u003e C282Y variant raises questions. In Finland, post donation iron supplementation is supplied for all frequently donating blood donors and all women under 50 years of age, to help to replenish the iron deficit caused by the blood loss. However, individuals with \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype probably should avoid iron supplementation in this context\u003csup\u003e16\u003c/sup\u003e. In this work, we identified biobank participants with genetic predisposition for haemochromatosis, informed them about the finding and provided a recommendation to seek further advice from health care with information enclosed for the health care professional. The aim was to improve blood donor health by not providing futile and potentially harmful iron supplementation in future donations for donors with \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype. Furthermore, we conducted a survey to understand the biobank participants\u0026rsquo; perspectives of receiving genetic risk information and if the primary finding resulted in clinical endpoints, such as clinical haemochromatosis diagnose (ICD10: E83.1).\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003eIdentification of \u003cem\u003eHFE\u003c/em\u003e C282Y homozygotes\u003c/p\u003e\u003cp\u003eThe Blood Service Biobank data, N\u0026thinsp;=\u0026thinsp;43,868, previously produced in the FinnGen project, was screened for \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) (NM_000410.4:c.845G\u0026thinsp;\u0026gt;\u0026thinsp;A, rs1800562). In brief, the biobank samples were genotyped as part of the FinnGen project with the FinnGen ThermoFisher Axiom custom array v1 or v2. Genotyping, quality control, and genome imputation protocols, R11, are described in detail in FinnGen Gitbook\u003csup\u003e17\u003c/sup\u003e. Shortly, genotype calling was performed with AxiomGT1 algorithm. Prior the imputation, genotyped samples were pre-phased with Eagle 2.3.5 with the default parameters, except the number of conditioning haplotypes was set to 20,000. Genotype imputation was performed using the population-specific imputation reference panel SISu v3 including 3775 high coverage (25\u0026ndash;30x) whole genome sequence data, with Beagle 4.1 (version 08Jun17.d8b).\u003c/p\u003e\u003cp\u003eGenotypes were called from VCF files under the following conditions: when imputed dosage score was \u0026ge;\u0026thinsp;0 and \u0026le;\u0026thinsp;0.1, dosage value was considered as 0, when imputed dosage score was \u0026ge;\u0026thinsp;0.9 and \u0026le;\u0026thinsp;1.1, dosage value was considered as 1 and finally when imputed dosage score was \u0026ge;\u0026thinsp;1.9 and \u0026le;\u0026thinsp;2.0, dosage value was considered as 2. \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) screening was performed in R\u003csup\u003e18\u003c/sup\u003e version 3.6.1 or later, with R Studio\u003csup\u003e19\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eClinical validation of the preliminary finding\u003c/p\u003e\u003cp\u003eThe preliminary \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) findings were validated in an external EAK (Estonian Accreditation Centre, EA MLA member) accredited laboratory (EVS-EN ISO 15189) in SynLab Tallinn, SynLab (synlab.fi). The clinical grade confirmation of \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype was performed with accredited Taqman based genotyping method (B -Hemok-D KL 1858).\u003c/p\u003e\u003cp\u003eInforming biobank participants\u003c/p\u003e\u003cp\u003eBiobank participants with confirmed \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype were contacted via letter. The letter provided information about haemochromatosis, a recommendation to contact healthcare for further information and information about haemochromatosis for a physician. A recommendation of laboratory tests to be measured in the healthcare; basic blood count, ferritin, transferrin saturation, alanine aminotransferase and, due to the nature of biobank samples as research sample, a confirmatory clinical sample taken for validating the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype, was included in the letter. The participants were given a possibility to contact a physician in The Finnish Red Cross Blood Service for any questions related to the information they had received.\u003c/p\u003e\u003cp\u003eAlong with the information letter, the biobank participants were asked to return a feedback form asking three questions: 1) Were you aware of your genetic predisposition to haemochromatosis?, 2) Can the finding be recorded to blood donation registry to avoid the iron supplementation in future blood donations? and 3) Are you willing to take part on survey regarding receiving genetic risk information from biobank?\u003c/p\u003e\u003cp\u003eSurvey\u003c/p\u003e\u003cp\u003eA survey was sent to all those biobank participants, who agreed in the feedback form to participate in the survey, with an informed consent enclosed. The survey consisted of a total of 26 questions, which covered the participants\u0026rsquo; experiences on receiving genetic risk information from the biobank, participants\u0026rsquo; experiences on how their matter was handled among the health care providers, participants\u0026rsquo; perspectives on the impact of the information received has on their lifestyle behavior and participants\u0026rsquo; experiences on sharing the information with first degree family members. The survey form is available in the Supplementary File 1.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAltogether 94 (0.2%) biobank participants were identified as \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) and all these participants had consented for receiving information relevant to their health. Of these participants, 89 had DNA sample available in biobank for the confirmatory testing. All the preliminary \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) findings, N\u0026thinsp;=\u0026thinsp;89, were confirmed as \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) in the external laboratory with accredited clinical grade method. Due to technical reasons (two participants with missing contact information, five participants with difficulty to interpret the biobank consent for recontacting), 82 biobank participants were contacted in the first phase (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). (Since that, the genetic risk information has been returned to all seven biobank participants but due to the delay in informing, the participants are not included in this study) Of the 82 biobank participants, 63 returned the feedback form, resulting in response rate of 77%. Of the biobank participants 98% (N\u0026thinsp;=\u0026thinsp;62) were willing to participate in the survey and 100% (N\u0026thinsp;=\u0026thinsp;63) gave a permission to record the finding to blood donation registry. Seven biobank participants, 8.5%, contacted a physician in Blood Service after receiving the letter. Of the 82 biobank participants, only 13.4% (N\u0026thinsp;=\u0026thinsp;11) were aware of their predisposition to haemochromatosis.\u003c/p\u003e\u003cp\u003eThe response rate in the survey was 68% (N\u0026thinsp;=\u0026thinsp;38) among biobank participants who weren\u0026rsquo;t aware of their genetic tendency to haemochromatosis previously (N\u0026thinsp;=\u0026thinsp;56). All survey results, including the clinical results, are self-reported.\u003c/p\u003e\u003cp\u003eDemographic information of the survey participants is available in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The sex distribution of the participants reflects to the overall sex distribution of the blood donors; female donors represented majority of the donors participating in the survey. The donation activity reflects well on the overall high donation activity of the biobank donors\u003csup\u003e20\u003c/sup\u003e: majority of the respondents, 79% of the females and males, had donated blood at least 21 times. The survey results are shown in more detail in Supplementary information.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic characteristics of the participants. YearStarted refers to the year a participant started donating blood. DonationCount refers to the overall times the participant has donated blood.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale N\u0026thinsp;=\u0026thinsp;24\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMale N\u0026thinsp;=\u0026thinsp;14\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52 (43, 62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50 (42, 60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYearStarted\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2000 (1990, 2007)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1997 (1982, 2002)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDonationCount\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u0026ndash;20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (21%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (21%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21\u0026ndash;40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (46%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (43%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e41\u0026ndash;100+\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (33%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (36%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003csup\u003e\u003cem\u003e1\u003c/em\u003e\u003c/sup\u003eMedian (Q1, Q3); N (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBlood donors\u0026rsquo; experiences on receiving genetic risk information\u003c/p\u003e\u003cp\u003eOverall, the participants reported positive attitude towards receiving genetic results\u003csup\u003e21,22\u003c/sup\u003e. Most of the participants found the received information useful (89% strongly agreed and 8% partly agreed). Of the participants, 45% (N\u0026thinsp;=\u0026thinsp;17) felt that receiving genetic information had caused worry in them. In participants\u0026rsquo; opinion, the genetic information in biobanks should be used more to promote health (76% (N\u0026thinsp;=\u0026thinsp;29) strongly agreed and 24% (N\u0026thinsp;=\u0026thinsp;9) partly agreed) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Most of the participants (82%) had recognized that consenting to receiving information relevant to health, might lead to receiving health related information. All participants, 100%, wished to receive similar information in the future, should it appear. The participants stated that their trust in The Blood Service and their willingness to belong to The Blood Service Biobank had grown (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003eAll participants, 100%, reported having discussed about the finding with their first-degree family members. Based on the open field answers, the participants reported the reactions of the family members to have been mainly neutral with minor concern or confusion. Some of the participants reported family history with haemochromatosis in the open fields.\u003c/p\u003e\u003cp\u003eMajority of the participants (92%) stated that knowing their genetic risk made them feel motivated to take better care of their health. Eighty-six percent of the participants believe they can affect their predisposition to haemochromatosis with lifestyle choices. Of the participants, 50% (N\u0026thinsp;=\u0026thinsp;19) reported they plan to continue donating blood as before and 34% (N\u0026thinsp;=\u0026thinsp;13) thought they would donate more often in the future than currently. Some participants stated they\u0026rsquo;ll quit blood donation for another reason, but none of the participants reported quitting donation because they had received genetic risk information.\u003c/p\u003e\u003cp\u003eApart from one participant, all participants had sought advice from healthcare, as recommended in the letter. The participants stated their matter was handled fluently in the healthcare (61% (N\u0026thinsp;=\u0026thinsp;23) strongly agreed, 26% (N\u0026thinsp;=\u0026thinsp;19), partly agreed) and that they received enough support in the healthcare (strongly agreed 45% (N\u0026thinsp;=\u0026thinsp;17) and partly agreed 45% (N\u0026thinsp;=\u0026thinsp;17)). Majority of the participants stated that their questions were answered in healthcare (29% (N\u0026thinsp;=\u0026thinsp;11) strongly agreed, 39% (N\u0026thinsp;=\u0026thinsp;15) partly agreed).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSelf-reported clinical findings\u003c/p\u003e\u003cp\u003eParticipants\u0026rsquo; self-reported results of the clinical endpoints measured in the healthcare are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Distribution and median of each measurement are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The number of responses varied between different clinical endpoints. As it is not known where in Finland the survey participants had their clinical measurements taken, all the reference intervals are reported in accordance with the reference intervals of the Helsinki University Hospital. The reference intervals used areshown in detail in Supplementary information.\u003c/p\u003e\u003cp\u003e63% of the participants reported the confirmatory \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) from a clinical sample had been taken but putatively because of difficulty in interpreting the laboratory result or insufficient question structure in the survey, majority of the participants did not report the outcome of the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) test. However, no contradictory findings were reported by the donors or could be observed from the survey results.\u003c/p\u003e\u003cp\u003eHaemoglobin exceeded the upper bound of reference interval in 29% of females (117\u0026ndash;155 g/L) and in 7% of males (134\u0026ndash;167 g/L). The target ferritin level for phlebotomy in the induction phase of haemochromatosis is 50 \u0026micro;g/L and 100 \u0026micro;g/L in the maintenance phase\u003csup\u003e15\u003c/sup\u003e. Accordingly, of the participants, 65% reported ferritin levels higher than 50 \u0026micro;g/L and 47% higher than 100 \u0026micro;g/L. Transferrin saturation (TSAT) exceeded the upper bound of reference interval (52%) in 67% of females and 71% of males. Mean red blood cell volume (MCV) was elevated in 4% of females and 7% of males (reference interval 82\u0026ndash;98 fl). The alanine aminotransferase (ALT) was within the reference interval in all participants who reported the results (reference interval\u0026thinsp;\u0026lt;\u0026thinsp;35 U/L in females and \u0026lt;\u0026thinsp;50 U/L in males). High ALT values can indicate liver cell damage\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAltogether 37% of all the participants reported they had received a clinical diagnosis (ICD10: E83.1) for haemochromatosis. Of those who responded either yes or no, 56% reported to have received a clinical haemochromatosis diagnose (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eResults of the clinical laboratory measurements taken in the healthcare. Above column indicates how many participants reported results above the reference interval and respectively below column the results below the reference interval. The reference intervals used are those of Helsinki University Hospital. MAD median absolute deviation.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStatistic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eAbove\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003eBelow\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eMedian\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eMAD\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eAbove\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003eBelow\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eMedian\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003eMAD\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaemoglobin (g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e157\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFerritin (\u0026micro;g/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e194\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e233\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTransferrin Saturation (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeMCV (fl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlanine aminotransferase (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOverall, the response rate was high; 77% returned the feedback form after receiving genetic risk information from the biobank and 68% participated in the further survey. Surprisingly, only 9.5% of the participants were aware of their genetic predisposition to haemochromatosis or clinical haemochromatosis. The overall experience of the biobank participants receiving genetic risk information from the Biobank was very positive. In participants\u0026rsquo; perspective the information they received was useful and 100% stated they\u0026rsquo;d like to receive similar information in the future should it appear. However, a need for raising awareness was visible; a portion of the participants reported they didn\u0026rsquo;t know to expect such information, and a portion reported they weren\u0026rsquo;t aware if they had been set a clinical diagnosis (ICD10: E83.1). In the era of genomic medicine, pilot projects like this are an excellent way to increase the genomic information awareness, which is one of the goals of the National Genome Strategy of Finland\u003csup\u003e3\u003c/sup\u003e and has also been endorsed by the European Society of Human Genetics\u003csup\u003e12\u003c/sup\u003e. Another clear aim of this work was to identify blood donors that would benefit from avoiding iron supplementation in future blood donations. Of the participants who were identified with \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype, 100% gave the permission to record this finding in the blood donation registry. These blood donors will not be offered iron supplementation in future blood donations.\u003c/p\u003e\u003cp\u003eThe self-reported laboratory results indicate relatively high penetrance\u003csup\u003e24\u003c/sup\u003e but no signs of similar organ level damage than previously reported\u003csup\u003e25\u003c/sup\u003e. We have previously shown a positive genetic correlation (r\u003csub\u003eg\u003c/sub\u003e = 0.18) between blood donorship and haemoglobin\u003csup\u003e26\u003c/sup\u003e. It could be possible that individuals with high haemoglobin level are more likely to apply to donate blood and hence, the haemochromatosis prevalence among frequent blood donors is high but regular blood donation has maintained a relatively symptom free state of the haemochromatosis. As clinical manifestations cause blood donation ineligibility, the lower organ level damage in \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) can also be caused by selection bias. Therefore, the information about genetic predisposability to haemochromatosis can be of particular importance for those blood donors who do no longer fulfill the donation eligibility criteria eg. due to their age. We have previously reported a high first-degree consanguinity among the biobank blood donors\u003csup\u003e20\u003c/sup\u003e. Although the higher consanguinity can explain the high occurrence of \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype in the Blood Service Biobank\u003csup\u003e20\u003c/sup\u003e, no direct conclusion can be drawn about the effect of high consanguinity on the observed penetrance.\u003c/p\u003e\u003cp\u003eThe low penetrance of the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) has caused controversy in the past years whether the genotype should require action. Biobank scale cohorts enable new possibilities in understanding the impact of common haemochromatosis causing mutations in the clinical outcome of haemochromatosis, which may raise the need for re-evaluation of \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) screening on population level\u003csup\u003e24\u003c/sup\u003e. As a result of this work, we are in the process of screening the entire Blood Service Biobank data set for the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype as well as planning to perform a cost effectiveness analysis to understand the impact of early detected haemochromatosis on healthcare and on individual\u0026rsquo;s quality of life.\u003c/p\u003e\u003cp\u003eEuropean citizens have in general reported positive attitude towards biobanking\u003csup\u003e27,28\u003c/sup\u003e. However, returning genetic information from biobank is not a routine practice in many countries, including Finland. Maintaining the trust of the biobank participants is of utmost importance, hence open, justified and consent-based modes of operation should be prerequisites when genetic information is returned from the biobanks as well as existing sufficient intervention and counseling practices. To date, this pilot study is the only one in Finland, where genetic risk information has been returned under the additional consent on willingness to receive information relevant to health given in connection with the biobank consent. The participants\u0026rsquo; experience in this work clearly demonstrates the increased trust towards the Finnish Red Cross blood Service as well as willingness to belong to Blood Service Biobank as a result on receiving genetic risk information. However, when compared to other actionable genotypes on ACMG\u003csup\u003e7\u003c/sup\u003e or CDC tier 1\u003csup\u003e29\u003c/sup\u003e list, such as breast cancer related genotypes, \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) can be considered rather \u0026ldquo;benign\u0026rdquo; genotype with efficacious interventions. Taken this and the blood donation context into consideration, the broad biobank consent was considered sufficient. It should be noted that this model may not be applicable in all cases, especially in cases with more severe effect of the variant\u003csup\u003e12\u003c/sup\u003e. Moreover, sufficient resourcing for personal counseling when returning genetic information related to more serious conditions, is essential. In this study, few donors contacted Blood Service physician regarding the results. Although the contacts were overall positive, they emphasize the importance of receiving personal advice.\u003c/p\u003e\u003cp\u003e Although this study provides valuable insights on blood donors\u0026rsquo; perspective on receiving genetic information, the study is limited by the small number of participants and strictly limited genotype as well as by the self-reported clinical laboratory results.\u003c/p\u003e\u003cp\u003eThis work demonstrates how the genetic information stored in biobank can be used in a precisely defined context, such as blood donation. Returning genetic information from biobanks in Finland is currently based on high impact CDC tier1 variants. High impact variants as well as non-malignant results with lower impact, have previously been returned from Estonian Biobank. The results of this study are consistent with the Estonian study; majority of the participants in the Estonian Biobank found the received information valuable\u003csup\u003e30\u003c/sup\u003e. Controversiality of the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) genotype, mainly because of the variants\u0026rsquo; low penetrance, has caused confusion. In this study we demonstrate a high occurrence of blood donors not being aware of their genetic risk, a relatively high penetrance and a clear acceptance of receiving genetic risk information from the biobank by the participants. Therefore, further comprehensive studies are needed to fully understand the possibilities biobanks may provide in precision-based medicine in the future. Public engagement, wide national ethical conversation and raising awareness are fundamental steps towards maintaining the public trust and therefore enabling the precision medicine related benefits from biobanks in the future\u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki. Returning the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) information to the biobank participants, was performed under the broad biobank consent and consent to receive health-relevant information. An informed consent was obtained from all the survey participants. According to Finnish Biobank Act, all survey results were pseudonymized, hence the research team only handled pseudonymized information. The study was conducted in accordance with the informed consent obtained from the survey participants. A study specific ethical permit HUS/1316/2024 was obtained from the Helsinki University Hospital HUS Regional Committee on Medical Research Ethics. A biobank permit 002-2024 was obtained from the Finnish Red Cross Blood Service Biobank (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.veripalvelu.fi/en/biobank/biobank-research/\u003c/span\u003e\u003cspan address=\"https://www.veripalvelu.fi/en/biobank/biobank-research/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The use of the Biobank material is in accordance with the biobank consent and meets the requirements of the Finnish Biobank Act (688/2012).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e\u003cp\u003eAuthors\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding Statement\u003c/h2\u003e\u003cp\u003eThis study was partially funded by The Finnish Innovation Fund Sitra (to the Blood Service Biobank).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.Clancy: Conceptualization, Methodology, Formal analysis, Validation, Supervision, Writing \u0026ndash; Original Draft. J.F: Project administration, Writing - Review \u0026amp; Editing. E.K: Formal analysis, Visualization, Writing \u0026ndash; Original Draft. M.A: Methodology, Visualization, Writing - Review \u0026amp; Editing. F.\u0026Aring;: Project administration, Writing - Review \u0026amp; Editing. K.P: Conceptualization, Funding acquisition, Writing - Review \u0026amp; Editing. J.Castr\u0026eacute;n: Conceptualization, Writing - Review \u0026amp; Editing.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe acknowledge the kind and professional help of the personnel of The Finnish Red Cross Blood Service Biobank and Synlab.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAggregate level survey data is available in the article and in the Supplementary information. Analysis scripts are available at https://github.com/FRCBS/hemochromatosis_questionaire.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAl, S. et. 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Blood Med.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 775\u0026ndash;786 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFinnGen gitbook. https://github.com/FINNGEN/.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eR Core Team. https://www.r-project.org/.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eR studio. https://www.rstudio.com/.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eClancy, J. \u003cem\u003eet al.\u003c/em\u003e Blood donor biobank as a resource in personalised biomedical genetic research. \u003cem\u003eEur. J. Hum. Genet.\u003c/em\u003e (2024) doi:10.1038/s41431-023-01528-0.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoskinen, E. Blood donors\u0026rsquo; perceptions of receiving genetic results from Blood Service Biobank. (University of Eastern Finland, 2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eP155 Forst\u0026eacute;n et al. 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Ethics\u003c/em\u003e \u003cb\u003e15\u003c/b\u003e, 81 (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCDC Tier 1 Genomics Applications and their Importance to Public Health. https://www.cdc.gov/genomics/implementation/toolkit/tier1.htm.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeitsalu, L. \u003cem\u003eet al.\u003c/em\u003e Lessons learned during the process of reporting individual genomic results to participants of a population-based biobank. \u003cem\u003eEur. J. Hum. Genet.\u003c/em\u003e \u003cb\u003e31\u003c/b\u003e, 1048\u0026ndash;1056 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-genomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mgnm","sideBox":"Learn more about [BMC Medical Genomics](http://bmcmedgenomics.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mgnm/default.aspx","title":"BMC Medical Genomics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HFE C282Y, haemochromatosis, biobank, blood donor, genetic information, actionable genotype","lastPublishedDoi":"10.21203/rs.3.rs-6927867/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6927867/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn the era of genomic medicine, utilizing genetic information in the concept of personalized medicine has become widely attractive. In addition to the large-scale population level data sets, the professional, standardized and legislated operating environment of the biobanks has enabled their growing footprint in the field of personalized medicine. Moreover, the biobank participants in The Finnish Red Cross Blood Service (FRCBS) Biobank have expressed high willingness to receive information relevant to their health. In this study we screened the FRCBS Biobank genome data, N\u0026thinsp;=\u0026thinsp;43,868, for \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) and returned the clinically verified results to 82 biobank participants. In addition, we conducted a survey on their experience on receiving genetic risk information from a biobank. We demonstrate a high occurrence of blood donors not being aware of their genetic risk, a relatively high penetrance of the \u003cem\u003eHFE\u003c/em\u003e C282Y (+/+) and a clear acceptance of receiving genetic risk information from the biobank by the participants. We show how genetic information stored in a biobank can be used in a precisely defined context, such as blood donation. Further comprehensive studies are needed to fully understand the possibilities biobanks could offer in personalized medicine.\u003c/p\u003e","manuscriptTitle":"Biobank Participants’ Perspectives on Receiving Genetic Risk Information from a Biobank – The case of Haemochromatosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 10:21:12","doi":"10.21203/rs.3.rs-6927867/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-17T17:35:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-12T20:34:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-12T17:06:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-04T16:32:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"247681774717751983859875230727641399215","date":"2025-09-04T12:55:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"199475433579281969765511646599280783558","date":"2025-09-02T11:51:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230947012636913480035970839773707106741","date":"2025-08-31T12:13:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"245976261285877764572461701134204261432","date":"2025-08-30T13:32:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"230642185491104651327938204128652647620","date":"2025-08-28T20:54:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-22T10:24:18+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-09T06:18:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-23T12:13:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-23T10:58:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medical Genomics","date":"2025-06-23T10:55:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-genomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mgnm","sideBox":"Learn more about [BMC Medical Genomics](http://bmcmedgenomics.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mgnm/default.aspx","title":"BMC Medical Genomics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"83a4576a-942f-4114-a475-d043785eda97","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-22T16:02:25+00:00","versionOfRecord":{"articleIdentity":"rs-6927867","link":"https://doi.org/10.1186/s12920-025-02285-3","journal":{"identity":"bmc-medical-genomics","isVorOnly":false,"title":"BMC Medical Genomics"},"publishedOn":"2025-12-17 15:58:10","publishedOnDateReadable":"December 17th, 2025"},"versionCreatedAt":"2025-09-01 10:21:12","video":"","vorDoi":"10.1186/s12920-025-02285-3","vorDoiUrl":"https://doi.org/10.1186/s12920-025-02285-3","workflowStages":[]},"version":"v1","identity":"rs-6927867","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6927867","identity":"rs-6927867","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}