FinnGen: Unique genetic insights from combining isolated population and national health register data

Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AF<10%) of which 62 were over two-fold enriched in Finland. We studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia. These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery. ### Competing Interest Statement Mervi Aavikko: Lecturing fee and congress trip reimbursement from Ipsen and Novartis (unrelated to this work); Abdelrahman G. Elnahas: Employee of University of Tartu; Kirsi Auro: Employee of GlaxoSmithKline; Shameek Biswas: Employee of Bristol Myers Squibb; Chia-Yen Chen: Employee of Biogen; Zhihao Ding: Employee of Boehringer Ingelheim; Margaret G. Ehm: Employee of GlaxoSmithKline; Kari Eklund: Consultation fees from Sobi, and Orion corporation; Robert R. Graham: Employee of Maze Therapeutics; Eric M. Green: Employee of Maze Therapeutics; Asa K. Hedman: Employee of Pfizer Inc.; Xinli Hu: Employee of Pfizer Inc.; Adriana Huertas-Vazquez: Employee of Merck; Julie Hunkapiller: Employee of Genentech; Howard Jacob: Employee of AbbVie Inc.; Jan-Nygaard Jensen: Employee of Boehringer Ingelheim; Heikki Joensuu: Senior consultant; Orion Pharma Orion Corporation; Chairman of the Scientific Advisory Board, Neutron Therapeutics; Deciphera Pharmaceuticals, a fee for acting as the Chair of an ESMO meeting; stock ownership: Orion Pharma, Sartar Therapeutics.; Sally John: Employee of Biogen; Marc Jung: Employee of Boehringer Ingelheim; Katherine Klinger: Employee of Sanofi; Teijo Kuopio: Lecture fee from Amgen, Roche and MSD; Nathan Lawless: Employee of Boehringer Ingelheim; Simonne Longerich: Employee of Merck; Anders Malarstig: Employee of Pfizer Inc.; Joseph Maranville: Employee of Bristol Myers Squibb; Athena Matakidou: Employee of AstraZeneca; Sahar V. Mozaffari: Employee of Maze Therapeutics; Mari EK. Niemi: Employee of Novartis; Christopher J. O'Donnell: Employee of Novartis; Ma'en Obeidat: Employee of Novartis; George Okafo: Employee of Boehringer Ingelheim; Antti Palomaki: Consulting fee from Abbvie, Amgen and Pfizer, lecture free from Pfizer and Sanofi.; Jukka Partanen: Employee of the Finnish Red Cross Blood Service; Dirk S. Paul: Employee of AstraZeneca; Rion K. Pendergrass: Employee of Genentech; Slave Petrovski: Employee of AstraZeneca; Adam Platt: Employee of AstraZeneca; David Pulford: Employee of GlaxoSmithKline; Neha Raghavan: Employee of Merck; Fedik Rahimov: Employee of AbbVie Inc.; Deepak Rajpal: Employee of Sanofi; Nicole A. Renaud: Employee of Novartis; Bridget Riley-Gillis: Employee of AbbVie Inc.; Veikko Salomaa: Received a honorarium from Sanofi for consulting. Ongoing research collaboration with Bayer Ltd. (All unrelated to the present study).; Richard Siegel: Employee of Novartis; Jae Hoon Sul: Employee of Merck; Ioanna Tachmazidou: Employee of AstraZeneca; Pentti Tienari: Lecture or consulting fee from Alexion, Roche, Merck, Janssen-Cilag, Novartis, Biogen (unrelated to this work); Joni A. Turunen: Lecture fee from Blueprint Genetics Finland, and the advisory board of Novartis Finland (unrelated this work); Jacob C. Ulirsch: J.C.U. has received compensation for consulting from Goldfinch Bio and is an employee of Patch Biosciences.; Jeffrey Waring: Employee of AbbVie Inc.; Dawn Waterworth: Employee of Janssen Research & Development; Robert Yang: Employee of Janssen Biotech; Caroline Fox: Employee of Merck; Robert Plenge: Employee of Bristol Myers Squibb; Mark McCarthy: Employee of Genentech; Heiko Runz: Employee of Biogen; Mark J. Daly: Founder of Maze Therapeutics; Aarno Palotie: Member of the Pfizer Genetics Scientific Advisory Panel ### Funding Statement 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 Sarl), Genentech Inc., Merck Sharp & Dohme Corp., Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. ### 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: 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, 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) approved the FinnGen study protocol Nr HUS/990/2017. The FinnGen study is approved by Finnish Institute for Health and Welfare (THL), approval number THL/2031/6.02.00/2017, amendments 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, Digital and population data service agency VRK43431/2017-3, VRK/6909/2018-3, VRK/4415/2019-3 the Social Insurance Institution (KELA) KELA 58/522/2017, KELA 131/522/2018, KELA 70/522/2019, KELA 98/522/2019, and Statistics Finland TK-53-1041-17. The Biobank Access Decisions for FinnGen samples and data utilized in FinnGen Data Freeze 5 include: THL Biobank BB2017\_55, BB2017\_111, BB2018\_19, BB\_2018\_34, BB\_2018\_67, BB2018\_71, BB2019\_7, BB2019\_8, BB2019\_26, Finnish Red Cross Blood Service Biobank 7.12.2017, Helsinki Biobank HUS/359/2017, Auria Biobank AB17-5154, Biobank Borealis of Northern Finland\_2017_1013, Biobank of Eastern Finland 1186/2018, Finnish Clinical Biobank Tampere MH0004, Central Finland Biobank 1-2017, and Terveystalo Biobank STB 2018001. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes all summary statistics described here are freely available.(www.finngen.fi/en/access_results).