Both socioeconomic circumstances and genetic predisposition shape disease risk, yet their joint contribution across diseases has not been systematically examined. We studied 19 high-burden diseases in 743,194 participants (729,928 European; 13,266 non-European ancestry) from FinnGen, the UK Biobank, and Generation Scotland. Higher educational attainment was associated with lower risk of most conditions, but with higher risk of most common cancers. These associations were largely independent of disease-specific polygenic scores (PGSs). For seven out of 19 diseases, PGSs showed stronger effects among individuals with high education. Joint inclusion of education and PGSs modestly improved prediction for 14 and 10 out of 19 diseases in FinnGen and the UK Biobank, respectively. PGS associations were consistent across ancestries, whereas education effects were less stable; results using an alternative socioeconomic measure were directionally similar but smaller. Our findings highlight the distinct and partly interacting contributions of socioeconomic and genetic factors to disease risk.

A.G. is CEO and founder of Real World Genetics OY. D.L.M. is an employee of Optima Partners Ltd. No other authors have competing interests to declare.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements No 101016775 and No 101060011. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. GS received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL) Reference 104036/Z/14/Z). M.T. was supported by the Doctoral Programme in Population Health, University of Helsinki. P.M. was supported by the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement No 101019329), the Strategic Research Council (SRC) within the Academy of Finland grants for ACElife (#352543-352572) and LIFECON (# 345219), and grants to the Max Planck - University of Helsinki Center from the Jane and Aatos Erkko Foundation (#210046), the Max Planck Society (# 5714240218), University of Helsinki (#77204227), and Cities of Helsinki, Vantaa and Espoo. N.M. is the recipient of funding by the Academy of Finland (grant numbers 331671 and 355567), the University of Helsinki HiLIFE Fellows Grant 2023-2025 and Finska Läkaresällskapet. A.G. was supported by the Academy of Finland Fellowship (no. 323116). The study does not necessarily reflect the Commission's views and in no way anticipates the Commission's future policy in this area. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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:

Study subjects in FinnGen provided (written) 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 11 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/430/2021 28, 29, HUS/150/2022 12, 13, 14, 15, 16, 17, 18, 23, 58, 59, HUS/128/2023 18, 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 it's modifications (Sep 22 2021), BB_2022-0262, BB_2022-0256, Biobank Borealis of Northern Finland_2017_1013, 2021_5010, 2021_5010 Amendment, 2021_5018, 2021_5018 Amendment, 2021_5015, 2021_5015 Amendment, 2021_5015 Amendment_2, 2021_5023, 2021_5023 Amendment, 2021_5023 Amendment_2, 2021_5017, 2021_5017 Amendment, 2022_6001, 2022_6001 Amendment, 2022_6006 Amendment, 2022_6006 Amendment, 2022_6006 Amendment_2, BB22-0067, 2022_0262, 2022_0262 Amendment, Biobank of Eastern Finland 1186/2018 and amendment 22/2020, 53/2021, 13/2022, 14/2022, 15/2022, 27/2022, 28/2022, 29/2022, 33/2022, 35/2022, 36/2022, 37/2022, 39/2022, 7/2023, 32/2023, 33/2023, 34/2023, 35/2023, 36/2023, 37/2023, 38/2023, 39/2023, 40/2023, 41/2023, Finnish Clinical Biobank Tampere MH0004 and amendments (21.02.2020 & 06.10.2020), BB2021-0140 8/2021, 9/2021, 9/2022, 10/2022, 12/2022, 13/2022, 20/2022, 21/2022, 22/2022, 23/2022, 28/2022, 29/2022, 30/2022, 31/2022, 32/2022, 38/2022, 40/2022, 42/2022, 1/2023, Central Finland Biobank 1-2017, BB_2021-0161, BB_2021-0169, BB_2021-0179, BB_2021-0170, BB_2022-0256, BB_2022-0262, BB22-0067, Decision allowing to continue data processing until 31st Aug 2024 for projects: BB_2021-0179, BB22-0067,BB_2022-0262, BB_2021-0170, BB_2021-0164, BB_2021-0161, and BB_2021-0169, 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. Ethics approval for the UK Biobank study was obtained from the North West Centre for Research Ethics Committee (11/NW/0382). UK Biobank data used in this study were obtained under approved application 78537. Ethical approval for the GS:SFHS study was obtained from the Tayside Committee on Medical Research Ethics (on behalf of the National Health Service; REC Reference Number: 05/S1401/89).

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