Effect of parental autoimmune diseases on type 1 diabetes in offspring can be partially explained by HLA and non-HLA polymorphisms: a nationwide registry and biobank-based study in 7.2M Finns

Type 1 diabetes (T1D) and other autoimmune diseases (AIDs) co-occur in families. We studied the aggregation of 50 parental AIDs with T1D in offspring and the contribution of a shared genetic background, which was partitioned into HLA and non-HLA variation. Leveraging nationwide registers of 7.2M Finns, including 58,284 family trios, we observed that 15 parental AIDs, such as coeliac disease and rheumatoid arthritis, were associated with an increased risk of T1D in offspring. The identified epidemiological associations were then tested by comprehensive genetic analyses performed on 470K Finns genotyped in the FinnGen study (12,563 trios). The within-family genetic transmission analysis further demonstrated that the aggregation of parental AIDs with offspring T1D could be partially explained by HLA and non-HLA polymorphisms in a disease-dependent manner. For example, the associations with offspring T1D for coeliac disease and psoriasis were mainly driven by HLA while autoimmune hypothyroidism and rheumatoid arthritis also had non-HLA contributors. We, therefore, proposed a novel parental polygenic score (PGS), integrating variations in both HLA and non-HLA genes, to understand the cumulative risk pattern of T1D in offspring. This raises an intriguing possibility of considering parental PGS, in conjunction with clinical diagnoses, to inform individuals about T1D risk in their offspring. ### Competing Interest Statement AG is the founder of Real World Genetics. RO holds a UK Medical Research Council Institutional Confidence in Concept Grant to develop a 10 SNP biochip T1D genetic test in collaboration with Randox. ### Funding Statement FW was funded by the University of Helsinki and the University of Edinburgh joint PhD program in Human Genomics. AG was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [grant number 945733], starting grant AI-Prevent. AG was supported by the Academy of Finland (grant no. 323116). This project also received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 101016775. TT was supported by grants from Folkhalsan Research Foundation, The Academy of Finland (336822, 312072 and 336826), and the University of Helsinki. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: FinRegistry is a collaboration project of the Finnish Institute for Health and Welfare (THL) and the Data Science Genetic Epidemiology research group at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki. The FinRegistry project has received the following approvals for data access from the National Institute of Health and Welfare (THL/1776/6.02.00/2019 and subsequent amendments), DVV (VRK/5722/2019-2), Finnish Center for Pension (ETK/SUTI 22003) and Statistics Finland (TK-53-1451-19). The FinRegistry project has received IRB approval from the National Institute of Health and Welfare (Kokous 7/2019). Patients and control subjects in FinnGen provided informed consent for biobank research, based on the Finnish Biobank Act. Alternatively, separate research cohorts, collected prior the Finnish Biobank Act came into effect (in September 2013) and start of FinnGen (August 2017), were collected based on study-specific consents and later transferred to the Finnish biobanks after approval by Fimea (Finnish Medicines Agency), the National Supervisory Authority for Welfare and Health. Recruitment protocols followed the biobank protocols approved by Fimea. The Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) statement number for the FinnGen study is Nr HUS/990/2017. The FinnGen study is approved by Finnish Institute for Health and Welfare (permit numbers: THL/2031/6.02.00/2017, THL/1101/5.05.00/2017, THL/341/6.02.00/2018, THL/2222/6.02.00/2018, THL/283/6.02.00/2019, THL/1721/5.05.00/2019 and THL/1524/5.05.00/2020), Digital and population data service agency (permit numbers: VRK43431/2017-3, VRK/6909/2018-3, VRK/4415/2019-3), the Social Insurance Institution (permit numbers: KELA 58/522/2017, KELA 131/522/2018, KELA 70/522/2019, KELA 98/522/2019, KELA 134/522/2019, KELA 138/522/2019, KELA 2/522/2020, KELA 16/522/2020), Findata permit numbers THL/2364/14.02/2020, THL/4055/14.06.00/2020, THL/3433/14.06.00/2020, THL/4432/14.06/2020, THL/5189/14.06/2020, THL/5894/14.06.00/2020, THL/6619/14.06.00/2020, THL/209/14.06.00/2021, THL/688/14.06.00/2021, THL/1284/14.06.00/2021, THL/1965/14.06.00/2021, THL/5546/14.02.00/2020, THL/2658/14.06.00/2021, THL/4235/14.06.00/2021, Statistics Finland (permit numbers: TK-53-1041-17 and TK/143/07.03.00/2020 (earlier TK-53-90-20) TK/1735/07.03.00/2021, TK/3112/07.03.00/2021) and Finnish Registry for Kidney Diseases permission/extract from the meeting minutes on 4th July 2019. The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 10 include: THL Biobank BB2017\_55, BB2017\_111, BB2018\_19, BB\_2018\_34, BB\_2018\_67, BB2018\_71, BB2019\_7, BB2019\_8, BB2019\_26, BB2020\_1, BB2021\_65, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS/359/2017, HUS/248/2020, HUS/150/2022 12, 13, 14, 15, 16, 17, 18, and 23, Auria Biobank AB17-5154 and amendment #1 (August 17 2020) and amendments BB\_2021-0140, BB\_2021-0156 (August 26 2021, Feb 2 2022), BB\_2021-0169, BB\_2021-0179, BB\_2021-0161, AB20-5926 and amendment #1 (April 23 2020)and its modification (Sep 22 2021), Biobank Borealis of Northern Finland\_2017\_1013, 2021\_5010, 2021\_5018, 2021\_5015, 2021\_5023, 2021\_5017, 2022\_6001, Biobank of Eastern Finland 1186/2018 and amendment 22 /2020, 53 /2021, 13 /2022, 14 /2022, 15 /2022, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), 8/2021, 9/2022, 10/2022, 12/2022, 20/2022, 21/2022, 22/2022, 23/2022, Central Finland Biobank 1-2017, and Terveystalo Biobank STB 2018001 and amendment 25th Aug 2020, Finnish Hematological Registry and Clinical Biobank decision 18th June 2021, Arctic biobank P0844: ARC\_2021\_1001. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data description for FinRegistry is publicly available on its website (www.finregistry.fi/finnish-registry -data). Access to FinRegistry data at an individual level is possible by submitting a data permit application (https://asiointi.findata.fi). The application includes information on the purpose of data use; the requested data, including the variables, definitions for the target and control groups, and external datasets to be combined with FinRegistry data; the dates of the data needed; and a data utilization plan. The requests will be evaluated on a case-by-case basis. Once approved, the data will be sent to a secure environment Kapseli and can be accessed within the European Economic Area (EEA) and within countries with an adequacy decision from the European Commission. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB.