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