FinnGen provides genetic insights from a well-phenotyped isolated population.
FinnGen provides genetic insights from a well-phenotyped isolated population.
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DOI：
10.1038/s41586-022-05473-8
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发表时间：
2023-01
期刊：
影响因子：
64.8
通讯作者：
Palotie, Aarno
中科院分区：
文献类型：
--
作者：
Kurki, Mitja, I;Karjalainen, Juha;Palta, Priit;Sipila, Timo P.;Kristiansson, Kati;Donner, Kati M.;Reeve, Mary P.;Laivuori, Hannele;Aavikko, Mervi;Kaunisto, Mari A.;Loukola, Anu;Lahtela, Elisa;Mattsson, Hannele;Laiho, Paivi;Parolo, Pietro Della Briotta;Lehisto, Arto A.;Kanai, Masahiro;Mars, Nina;Ramo, Joel;Kiiskinen, Tuomo;Heyne, Henrike O.;Veerapen, Kumar;Rueger, Sina;Lemmela, Susanna;Zhou, Wei;Ruotsalainen, Sanni;Parn, Kalle;Hiekkalinna, Tero;Koskelainen, Sami;Paajanen, Teemu;Llorens, Vincent;Gracia-Tabuenca, Javier;Siirtola, Harri;Reis, Kadri;Elnahas, Abdelrahman G.;Sun, Benjamin;Foley, Christopher N.;Aalto-Setala, 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;Farkkila, Martti;Finucane, Hilary;Ganna, Andrea;Ghazal, Awaisa;Graham, Robert R.;Green, Eric M.;Hakanen, Antti;Hautalahti, Marco;Hedman, Asa K.;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;Kahonen, Mika;Kajanne, Risto;Kallio, Lila;Kalviainen, Reetta;Kaprio, Jaakko;Kerimov, Nurlan;Kettunen, Johannes;Kilpelainen, Elina;Kilpi, Terhi;Klinger, Katherine;Kosma, Veli-Matti;Kuopio, Teijo;Kurra, Venla;Laisk, Triin;Laukkanen, Jari;Lawless, Nathan;Liu, Aoxing;Longerich, Simonne;Magi, Reedik;Makela, Johanna;Makitie, Antti;Malarstig, Anders;Mannermaa, Arto;Maranville, Joseph;Matakidou, Athena;Meretoja, Tuomo;Mozaffari, Sahar, V;Niemi, Mari E. K.;Niemi, Marianna;Niiranen, Teemu;Okafo, George;Ollila, Hanna M.;Palomaki, Antti;Palotie, Tuula;Partanen, Jukka;Paul, Dirk S.;Pelkonen, Margit;Pendergrass, Rion K.;Petrovski, Slave;Pitkaranta, 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 Hoon;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, Tonu;Fox, Caroline;Havulinna, Aki S.;Perola, Markus;Ripatti, Samuli;Jalanko, Anu;Laitinen, Tarja;Makela, Tomi P.;Plenge, Robert;McCarthy, Mark;Runz, Heiko;Daly, Mark J.;Palotie, Aarno
群体分离株（如芬兰的分离株）有利于遗传研究，因为有害等位基因通常集中在少数低频变异（0.1% ≤次要等位基因频率< 5%）上。这些变体在创始瓶颈中幸存下来，而不是分布在大量的超稀有变体中。虽然这种效应在孟德尔遗传学中得到了很好的证实，但它在常见疾病遗传学中的价值却很少被探索。FinnGen的目标是研究50万芬兰人的基因组和国家健康登记数据。考虑到参与者的中位年龄相对较高（63岁）和基于医院的招募的相当大一部分，FinnGen丰富了疾病终点。在这里，我们分析了来自FinnGen的224，737名参与者的数据，并研究了以前在大型全基因组关联研究（GWAS）中研究过的15种疾病。我们还包括来自爱沙尼亚和英国的生物银行数据的荟萃分析。我们确定了30个新的关联，主要是低频变异，在芬兰人群中富集。对1，932种疾病的GWAS还在2，496个（771个PWS）独立位点和807个（247个PWS）终点确定了2，733个全基因组显著关联（893个全表型显著（PWS），P < 2.6 × 10-11）。其中，精细定位涉及与83个（42个PWS）终点相关的148个（73个PWS）编码变体。此外，在非芬兰的欧洲个体中，91个（47个PWS）的等位基因频率<5%，其中62个（32个PWS）在芬兰富集超过两倍。这些发现表明，通过低频率、高影响力的变异，被检查的人群有能力找到进入常见疾病生物学的切入点。来自孤立人群的个体的全基因组关联研究（来自芬兰生物库研究FinnGen的数据）和随后的荟萃分析有助于识别以前未知的编码变异与罕见和常见疾病的关联。
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants. Genome-wide association studies of individuals from an isolated population (data from the Finnish biobank study FinnGen) and consequent meta-analyses facilitate the identification of previously unknown coding variant associations for both rare and common diseases.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
30.8
作者：
Kerimov N;Hayhurst JD;Peikova K;Manning JR;Walter P;Kolberg L;Samoviča M;Sakthivel MP;Kuzmin I;Trevanion SJ;Burdett T;Jupp S;Parkinson H;Papatheodorou I;Yates AD;Zerbino DR;Alasoo K
通讯作者：
Alasoo K
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G