FinnGen: Unique genetic insights from combining isolated population and national health register data
FinnGen: Unique genetic insights from combining isolated population and national health register data
ABSTRACT 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.
Soini Sirpa、Metspalu Andres、Salminen Eveliina、Lawless Nathan、Niemi Mari EK.、R¨1eger Sina、Tienari Pentti、Tasanen Kaisa、Toppila-Salmi Sanna、Tukiainen Taru、Turunen Joni A.、Ulirsch Jacob C.、Vaura Felix、Jalanko Anu、Laitinen Tarja、Plenge Robert、Runz Heiko、Daly Mark J.、Palotie Aarno、Virolainen Petri、Reigo Anu、Ding Zhihao、Ehm Margaret G.、Ghazal Awaisa、Graham Robert R.、Green Eric、Hakanen Antti、Hedman ?sa、Huertas-Vazquez Adriana、Jacob Howard、John Sally、Julkunen Valtteri、Jung Marc、Junttila Juhani、Kaarniranta Kai、Kallio Lila、Kurki Mitja I.、Karjalainen Juha、Kristiansson Kati、Reeve Mary P.、Laivuori Hannele、Aavikko Mervi、Kaunisto Mari A.、Loukola Anu、Lahtela Elisa、Della Briotta Parolo Pietro、Lehisto Arto、Kiiskinen Tuomo、Fox Caroline、Ripatti Samuli、Meretoja Tuomo、Mozaffari Sahar V.、Shen Huei-yi、Silander Kaisa、Sul Jae H.、Kerimov Nurlan、Kettunen Johannes、Kilpel?inen Elina、Kilpi Terhi、Kurra Venla、Liu Aoxing、M?kitie Antti、Malarstig Anders、Zhou Wei、Heyne Henrike O.、Ruotsalainen Sanni、P?rn Kalle、Paajanen Teemu、Reis Kadri、Aalto-Set?l? Katriina、Arvas Mikko、Biswas Shameek、Bizaki-Vallaskangas Argyro、Carpen Olli、Chen Chia-Yen、Niemi Marianna、Palom?ki Antti、Partanen Jukka、Pelkonen Margit、Niiranen Teemu、Punkka Eero、Pussinen Pirkko、Raghavan Neha、Rahimov Fedik、Rajpal Deepak、Renaud Nicole A.、Salminen Aino、Salomaa Veikko、Mattsson Hannele、Perola Markus、Koskelainen Sami、Saarentaus Elmo、Rodosthenous Rodosthenis、Riley-Gillis Bridget、Matakidou Athena、M?kel? Johanna、Longerich Simonne、Eklund Kari、McCarthy Mark、Waring Jeffrey、Milani Lili、Alasoo Kaur、Finucane Hilary、Kuopio Teijo、Jensen Jan-Nygaard、Nelis Mari、Siirtola Harri、Hiltunen Mikko、K?lvi?inen Reetta、Veerapen Kumar、Huilaja Laura、Esko T?nu、M?kel? Tomi、Hiekkalinna Tero、Kajanne Risto M.、Pendergrass Rion K.、Platt Adam、K?h?nen Mika、Pulford David、Hu Xinli、Pitk?ranta Anne、Elnahas Abdelrahman G.、Maranville Joseph、Palotie Tuula、O?ˉDonnell Christopher J.、Waterworth Dawn、Tuomi Tiinamaija、Havulinna Aki S.、R?m? Joel、Mars Nina、Hunkapiller Julie、Paul Dirk S.、Kosma Veli-Matti、Ollila Hanna M.、Hovatta Iiris、Gracia-Tabuenca Javier、Hinttala Reetta、Mannermaa Arto、Palta Priit、Sipil? Timo P.、Ganna Andrea、Donner Kati、Serpi Raisa、Joensuu Heikki、Petrovski Slav¨|、F?rkkil? Martti、Siegel Richard、M?gi Reedik、Laukkanen Jari、Klinger Katherine、Yang Robert、Kanai Masahiro、Tachmazidou Ioanna、Kaprio Jaakko、Obeidat Ma?ˉen、Laiho P?ivi、Dada Oluwaseun A.、Soininen Hilkka、Laisk Triin、Schleutker Johanna、Auro Kirsi、Hautalahti Marco、Okafo George、Llorens Vincent、Lemmel? Susanna、Siltanen Sanna
Finnish Institute for Health and Welfare, Helsinki, Finland (THL Biobank (BB) / THL)University of Tartu, Institute of Genomics, Head of the Estonian BiobankUniversity of Helsinki and Helsinki University HospitalBoehringer Ingelheim, Ingelheim am RheinInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiUniversity of Helsinki and Helsinki University HospitalPEDEGO Research Unit, University of Oulu||Department of Dermatology and Medical Research Center Oulu, Oulu University HospitalDepartment of Allergy, Helsinki University Hospital and University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiHelsinki University Hospital and University of Helsinki||Eye Genetics Group, Folkh?lsan Research CenterProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITFinnish Institute for Health and Welfare||University of TurkuInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiFinnish Clinical Biobank Tampere, Tampere University and Tampere University HospitalBristol Myers SquibbBiogenInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITAuria Biobank, University of Turku and Turku University HospitalUniversity of Tartu, Institute of GenomicsBoehringer Ingelheim, Ingelheim am RheinGlaxoSmithKlineInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiMaze TherapeuticsMaze TherapeuticsAuria Biobank, University of Turku and Turku University HospitalPfizer||Karolinska InstituteMerck & Co., Inc.AbbVieBiogenUniversity of Eastern Finland||Kuopio University HospitalBoehringer Ingelheim, Ingelheim am RheinNorthern Finland Biobank Borealis / University of Oulu / Northern Ostrobothnia Hospital DistrictUniversity of Eastern Finland||Kuopio University HospitalAuria Biobank, University of Turku and Turku University HospitalInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Analytic and Translational Genetics Unit, Massachusetts General HospitalInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITFinnish Institute for Health and Welfare (THL)Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital||Department of Obstetrics and Gynecology, Tampere University Hospital and University of Tampere, Faculty of Medicine and Health Technology, Center for Child, Adolescent and Maternal HealthInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinkii Biobank, University of Helsinki and Hospital District of Helsinki and UusimaaInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiMerck & Co., Inc.Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiHelsinki University Hospital and University of HelsinkiMaze TherapeuticsInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiFinnish Institute for Health and Welfare, Helsinki, Finland (THL Biobank (BB) / THL)Merck & Co., Inc.Institute of Computer Science, University of TartuFinnish Institute for Health and Welfare (THL)||Computational Medicine, Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter OuluInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiFinnish Institute for Health and Welfare, Helsinki, Finland (THL Biobank (BB) / THL)Department of Clinical Genetics, Tampere University Hospital and Tampere University, Faculty of Medicine and Health TechnologyInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiDepartment of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and Helsinki University HospitalPfizer||Department of Medical Epidemiology and Biostatistics, Karolinska InstituteProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Analytic and Translational Genetics Unit, Massachusetts General HospitalInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Digital Health Center, Hasso Plattner Institute for Digital Engineering, University of Potsdam Potsdam||Hasso Plattner Institute for Digital Health at Mount Sinai/Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiFinnish Institute for Health and Welfare (THL)Estonian Genome Centre, Institute of Genomics, University of TartuFaculty of Medicine and Health Technology, Tampere UniversityFinnish Red Cross Blood ServiceBristol Myers SquibbTampere University Hospital and Tampere Universityi Biobank, University of Helsinki and Hospital District of Helsinki and UusimaaBiogenFaculty of Medicine and Health Technology, Tampere University||TAUCHI Research CenterTurku University Hospital and University of TurkuFinnish Red Cross Blood Service||Finnish Hematological BiobankDepartment of Pulmonary Diseases, Kuopio University HospitalFinnish Institute for Health and Welfare (THL)||Turku University Hospital and University of Turkui Biobank, University of Helsinki and Hospital District of Helsinki and UusimaaUniversity of Helsinki and Helsinki University HospitalMerck & Co., Inc.AbbVieTranslational Sciences, Sanofi R&DNovartis Institutes for BioMedical ResearchUniversity of Helsinki and Helsinki University HospitalFinnish Institute for Health and Welfare (THL)Finnish Institute for Health and Welfare (THL)Finnish Institute for Health and Welfare (THL)Finnish Institute for Health and Welfare (THL)Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiAbbVieCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&DFinBB, Finnish Biobank CooperativeMerck & Co., Inc.University of Helsinki and Helsinki University Hospital||Orton orthopedic hospitalGenentechAbbVieEstonian Genome Centre, Institute of Genomics, University of TartuInstitute of Computer Science, University of TartuAnalytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITCentral Finland Biobank, Central Finland Health Care DistrictBoehringer Ingelheim, Ingelheim am RheinUniversity of Tartu, Institute of Genomics, Genomics Core FacilityTAUCHI Research Center, Faculty of Information Technology and Communication Sciences, Tampere UniversityUniversity of Eastern FinlandKuopio University Hospital||University of EasternInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITPEDEGO Research Unit, University of Oulu||Department of Dermatology and Medical Research Center Oulu, Oulu University HospitalEstonian Genome Centre, Institute of Genomics, University of TartuHelsinki Institute of Life Sciences (HiLIFE), University of HelsinkiFinnish Institute for Health and Welfare (THL)Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiGenentechTranslational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&DFaculty of Medicine and Health Technology, Tampere University||Department of Clinical Physiology, Tampere University HospitalGlaxoSmithKlinePfizerUniversity of Helsinki and Helsinki University HospitalEstonian Genome Centre, Institute of Genomics, University of TartuBristol Myers SquibbOrthodontics, University of Helsinki, Department of Oral and Maxillofacial Diseases, Helsinki University HospitalNovartis Institutes for BioMedical ResearchJanssen Research & Development, LLCInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Helsinki University Hospital, Abdominal Center, Endocrinology||Folkhalsan Research Center||Research Program of Clinical and Molecular Metabolism, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Finnish Institute for Health and Welfare (THL)Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiGenentechCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&DBiobank of Eastern Finland, University of Eastern Finland and Kuopio University HospitalInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Anesthesia, Critical Care, and Pain Medicine, Massachusetts General HospitalDepartment of Psychology and Logopedics, Faculty of Medicine, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of HelsinkiTAUCHI Research Center, Faculty of Information Technology and Communication Sciences, Tampere UniversityMedical Research Center Oulu and PEDEGO Research Unit, University of Oulu and Oulu University Hospital||Biocenter Oulu, University of OuluBiobank of Eastern Finland, University of Eastern Finland and Kuopio University HospitalInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Estonian Genome Centre, Institute of Genomics, University of TartuInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MITInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiNorthern Finland Biobank Borealis, University of Oulu and Northern Ostrobothnia Hospital DistrictHelsinki University Hospital and University of HelsinkiCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&DUniversity of Helsinki and Helsinki University HospitalNovartis Institutes for BioMedical ResearchEstonian Genome Centre, Institute of Genomics, University of TartuUniversity of Eastern Finland||Central Finland Biobank, Central Finland Health Care DistrictTranslational Sciences, Sanofi R&DJanssen BiotechInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Analytic and Translational Genetics Unit, Massachusetts General Hospital||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT||Harvard Medical SchoolCentre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&DInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||University of Helsinki and Helsinki University HospitalNovartis Institutes for BioMedical ResearchFinnish Institute for Health and Welfare (THL)Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiUniversity of Eastern FinlandEstonian Genome Centre, Institute of Genomics, University of TartuAuria Biobank, University of Turku and Turku University HospitalGlaxoSmithKlineFinBB, Finnish Biobank CooperativeBoehringer Ingelheim, Ingelheim am RheinInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki||Finnish institute for heath and wellfare (THL)Finnish Clinical Biobank Tampere, Tampere University and Tampere University Hospital
医学研究方法遗传学基础医学
Soini Sirpa,Metspalu Andres,Salminen Eveliina,Lawless Nathan,Niemi Mari EK.,R¨1eger Sina,Tienari Pentti,Tasanen Kaisa,Toppila-Salmi Sanna,Tukiainen Taru,Turunen Joni A.,Ulirsch Jacob C.,Vaura Felix,Jalanko Anu,Laitinen Tarja,Plenge Robert,Runz Heiko,Daly Mark J.,Palotie Aarno,Virolainen Petri,Reigo Anu,Ding Zhihao,Ehm Margaret G.,Ghazal Awaisa,Graham Robert R.,Green Eric,Hakanen Antti,Hedman ?sa,Huertas-Vazquez Adriana,Jacob Howard,John Sally,Julkunen Valtteri,Jung Marc,Junttila Juhani,Kaarniranta Kai,Kallio Lila,Kurki Mitja I.,Karjalainen Juha,Kristiansson Kati,Reeve Mary P.,Laivuori Hannele,Aavikko Mervi,Kaunisto Mari A.,Loukola Anu,Lahtela Elisa,Della Briotta Parolo Pietro,Lehisto Arto,Kiiskinen Tuomo,Fox Caroline,Ripatti Samuli,Meretoja Tuomo,Mozaffari Sahar V.,Shen Huei-yi,Silander Kaisa,Sul Jae H.,Kerimov Nurlan,Kettunen Johannes,Kilpel?inen Elina,Kilpi Terhi,Kurra Venla,Liu Aoxing,M?kitie Antti,Malarstig Anders,Zhou Wei,Heyne Henrike O.,Ruotsalainen Sanni,P?rn Kalle,Paajanen Teemu,Reis Kadri,Aalto-Set?l? Katriina,Arvas Mikko,Biswas Shameek,Bizaki-Vallaskangas Argyro,Carpen Olli,Chen Chia-Yen,Niemi Marianna,Palom?ki Antti,Partanen Jukka,Pelkonen Margit,Niiranen Teemu,Punkka Eero,Pussinen Pirkko,Raghavan Neha,Rahimov Fedik,Rajpal Deepak,Renaud Nicole A.,Salminen Aino,Salomaa Veikko,Mattsson Hannele,Perola Markus,Koskelainen Sami,Saarentaus Elmo,Rodosthenous Rodosthenis,Riley-Gillis Bridget,Matakidou Athena,M?kel? Johanna,Longerich Simonne,Eklund Kari,McCarthy Mark,Waring Jeffrey,Milani Lili,Alasoo Kaur,Finucane Hilary,Kuopio Teijo,Jensen Jan-Nygaard,Nelis Mari,Siirtola Harri,Hiltunen Mikko,K?lvi?inen Reetta,Veerapen Kumar,Huilaja Laura,Esko T?nu,M?kel? Tomi,Hiekkalinna Tero,Kajanne Risto M.,Pendergrass Rion K.,Platt Adam,K?h?nen Mika,Pulford David,Hu Xinli,Pitk?ranta Anne,Elnahas Abdelrahman G.,Maranville Joseph,Palotie Tuula,O?ˉDonnell Christopher J.,Waterworth Dawn,Tuomi Tiinamaija,Havulinna Aki S.,R?m? Joel,Mars Nina,Hunkapiller Julie,Paul Dirk S.,Kosma Veli-Matti,Ollila Hanna M.,Hovatta Iiris,Gracia-Tabuenca Javier,Hinttala Reetta,Mannermaa Arto,Palta Priit,Sipil? Timo P.,Ganna Andrea,Donner Kati,Serpi Raisa,Joensuu Heikki,Petrovski Slav¨|,F?rkkil? Martti,Siegel Richard,M?gi Reedik,Laukkanen Jari,Klinger Katherine,Yang Robert,Kanai Masahiro,Tachmazidou Ioanna,Kaprio Jaakko,Obeidat Ma?ˉen,Laiho P?ivi,Dada Oluwaseun A.,Soininen Hilkka,Laisk Triin,Schleutker Johanna,Auro Kirsi,Hautalahti Marco,Okafo George,Llorens Vincent,Lemmel? Susanna,Siltanen Sanna.FinnGen: Unique genetic insights from combining isolated population and national health register data[EB/OL].(2025-03-28)[2025-04-27].https://www.medrxiv.org/content/10.1101/2022.03.03.22271360.点此复制
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