FinnGen: Unique genetic insights from combining isolated population and national health register data
Authors: Kurki Mitja I. , Karjalainen Juha , Palta Priit , Sipilä Timo P. , Kristiansson Kati , Donner Kati , Reeve Mary P. , Laivuori Hannele , Aavikko Mervi , Kaunisto Mari A. , Loukola Anu , Lahtela Elisa , Mattsson Hannele , Laiho Päivi , Della Briotta Parolo Pietro , Lehisto Arto , Kanai Masahiro , Mars Nina , Rämö Joel , Kiiskinen Tuomo , Heyne Henrike O. , Veerapen Kumar , Rüeger Sina , Lemmelä Susanna , Zhou Wei , Ruotsalainen Sanni , Pärn Kalle , Hiekkalinna Tero , Koskelainen Sami , Paajanen Teemu , Llorens Vincent , Gracia-Tabuenca Javier , Siirtola Harri , Reis Kadri , Elnahas Abdelrahman G. , Aalto-Setälä Katriina , Alasoo Kaur , Arvas Mikko , Auro Kirsi , Biswas Shameek , Bizaki-Vallaskangas Argyro , Carpen Olli , Chen Chia-Yen , Dada Oluwaseun A. , Ding Zhihao , Ehm Margaret G. , Eklund Kari , Färkkilä Martti , Finucane Hilary , Ganna Andrea , Ghazal Awaisa , Graham Robert R. , Green Eric , Hakanen Antti , Hautalahti Marco , Hedman Åsa , Hiltunen Mikko , Hinttala Reetta , Hovatta Iiris , Hu Xinli , Huertas-Vazquez Adriana , Huilaja Laura , Hunkapiller Julie , Jacob Howard , Jensen Jan-Nygaard , Joensuu Heikki , John Sally , Julkunen Valtteri , Jung Marc , Junttila Juhani , Kaarniranta Kai , Kähönen Mika , Kajanne Risto M. , Kallio Lila , Kälviäinen Reetta , Kaprio Jaakko , Kerimov Nurlan , Kettunen Johannes , Kilpeläinen Elina , Kilpi Terhi , Klinger Katherine , Kosma Veli-Matti , Kuopio Teijo , Kurra Venla , Laisk Triin , Laukkanen Jari , Lawless Nathan , Liu Aoxing , Longerich Simonne , Mägi Reedik , Mäkelä Johanna , Mäkitie Antti , Malarstig Anders , Mannermaa Arto , Maranville Joseph , Matakidou Athena , Meretoja Tuomo , Mozaffari Sahar V. , Niemi Mari EK. , Niemi Marianna , Niiranen Teemu , O’Donnell Christopher J. , Obeidat Ma’en , Okafo George , Ollila Hanna M. , Palomäki Antti , Palotie Tuula , Partanen Jukka , Paul Dirk S. , Pelkonen Margit , Pendergrass Rion K. , Petrovski Slavé , Pitkäranta Anne , Platt Adam , Pulford David , Punkka Eero , Pussinen Pirkko , Raghavan Neha , Rahimov Fedik , Rajpal Deepak , Renaud Nicole A. , Riley-Gillis Bridget , Rodosthenous Rodosthenis , Saarentaus Elmo , Salminen Aino , Salminen Eveliina , Salomaa Veikko , Schleutker Johanna , Serpi Raisa , Shen Huei-yi , Siegel Richard , Silander Kaisa , Siltanen Sanna , Soini Sirpa , Soininen Hilkka , Sul Jae H. , Tachmazidou Ioanna , Tasanen Kaisa , Tienari Pentti , Toppila-Salmi Sanna , Tukiainen Taru , Tuomi Tiinamaija , Turunen Joni A. , Ulirsch Jacob C. , Vaura Felix , Virolainen Petri , Waring Jeffrey , Waterworth Dawn , Yang Robert , Nelis Mari , Reigo Anu , Metspalu Andres , Milani Lili , Esko Tõnu , Fox Caroline , Havulinna Aki S. , Perola Markus , Ripatti Samuli , Jalanko Anu , Laitinen Tarja , Mäkelä Tomi , Plenge Robert , McCarthy Mark , Runz Heiko , Daly Mark J. , Palotie Aarno 
Published: March 2022

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.