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1. Socio-demographic and genetic risk factors for drug adherence and persistence across 5 common medication classes

Author: Mattia Cordioli, Andrea Corbetta, Hanna Maria Kariis, Sakari Jukarainen, Pekka Vartiainen, Tuomo Kiiskinen, Matteo Ferro, FinnGen, Estonian Biobank Research Team, Markus Perola, Mikko Niemi, Samuli Ripatti, Kelli Lehto, Lili Milani, and Andrea Ganna
Subjects: Science
Abstract: Abstract Low drug adherence is a major obstacle to the benefits of pharmacotherapies and it is therefore important to identify factors associated with discontinuing or being poorly adherent to a prescribed treatment regimen. Using high-quality nationwide health registry data and genome-wide genotyping, we evaluate the impact of socio-demographic and genetic risk factors on adherence and persistence for 5 common medication classes that require long-term, regular therapy (N = 1,814,591 individuals from Finnish nationwide registries, 217,005 with genetic data from Finland and Estonia). Need for social assistance and immigration status show a notable negative effect on persistence and adherence across the examined medications (odd ratios between 0.48 and 0.82 for persistence and between 1.1% to 4.3% decrease in adherence) while demographic and health factors show comparably modest or inconsistent effects. A genome-wide scan does not identify genetic variants associated with the two phenotypes, while some pharmacogenes (i.e. CYP2C9 and SLCO1B1) are modestly associated with persistence, but not with adherence. We observe significant genetic correlations between medication adherence and participation in research studies. Overall, our findings suggest that socio-economically disadvantaged groups would benefit from targeted interventions to improve the dispensing and uptake of pharmacological treatments.
Published: 2024
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2. ALT levels, alcohol use, and metabolic risk factors have prognostic relevance for liver-related outcomes in the general population

Author: Ville Männistö, Veikko Salomaa, Antti Jula, Annamari Lundqvist, Satu Männistö, Markus Perola, and Fredrik Åberg
Subjects: Advanced liver disease, Alcohol-related liver disease, Cirrhosis, Metabolic dysfunction-associated steatotic liver disease, Nomenclature, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: A new nomenclature and subclassification for steatotic liver disease (SLD) was recently introduced. We validated the prognostic value of SLD subclasses in a Finnish population-based cohort and explored the impact of metabolic risk factors and alcohol consumption on liver-related outcomes and death. Methods: The study included 23,910 individuals (47% men, mean age 50.5 ± 14.0 years, BMI 27.0 ± 4.7 kg/m2) from the FINRISK and Health 2000 health examination surveys with healthcare registry linkage for severe liver-related outcomes and deaths. SLD was identified by alanine aminotransferase (ALT) levels >20 U/L in women and >30 U/L in men (primary analysis) or fatty liver index (FLI) ≥60 (sensitivity analysis). Results: The prevalence of ALT-defined SLD was 43% (n = 10,380), with subclass rates of 34.5% for metabolic dysfunction-associated steatotic liver disease (MASLD), 4.2% for coexistent MASLD and alcohol-related liver disease (ALD) (i.e., MetALD), and 1.8% for ALD. During a median 13.3-year follow-up, we observed 129 liver-related events. MetALD and ALD increased the age- and sex-adjusted liver-related outcome risk by fourfold (HR 3.83, 95% CI 2.51–5.84, p
Published: 2024
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3. TWINGEN: protocol for an observational clinical biobank recall and biomarker cohort study to identify Finnish individuals with high risk of Alzheimer’s disease

Author: Tommi Vasankari, Henri Vähä-Ypyä, Oskari Heikinheimo, Athena Matakidou, Jaakko Kaprio, Eero Vuoksimaa, Ying Wu, Kai Kaarniranta, Peeter Karihtala, Wei Zhou, Caroline Fox, Sanna-Kaisa Herukka, Sarah Smith, Apinya Lertratanakul, Katri Kaukinen, Johannes Kettunen, Minna Männikkö, Eeva Sliz, Markus Perola, Veikko Salomaa, Hilkka Soininen, Ilkka Kalliala, Mika Kähönen, Hao Chen, Andrey Loboda, Laure Morin-Papunen, Terhi Piltonen, Anders Mälarstig, Jason Miller, Jussi Hernesniemi, Henrike Heyne, Sirkku Peltonen, Daniel Gordin, Masahiro Kanai, Benjamin Challis, Juha Sinisalo, David Rice, Fredrik Åberg, Aarno Palotie, Samuli Ripatti, Oili Kaipiainen-Seppänen, Aki Havulinna, Satu Strausz, Tuomo Kiiskinen, Sanni Ruotsalainen, Jukka Koskela, Tuula Palotie, Mark Daly, Howard Jacob, Heiko Runz, Sally John, Robert Plenge, Mark McCarthy, Julie Hunkapiller, Dawn Waterworth, Petri Virolainen, Terhi Kilpi, Jukka Partanen, Anne Pitkäranta, Veli-Matti Kosma, Outi Tuovila, Raimo Pakkanen, Shameek Biswas, Xinli Hu, Johanna Schleutker, Mikko Arvas, Olli Carpen, Reetta Hinttala, Arto Mannermaa, Valtteri Julkunen, Anne Remes, Reetta Kälviäinen, Mikko Hiltunen, Jukka Peltola, Pentti Tienari, Juha Rinne, Adam Ziemann, Jeffrey Waring, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Sanni Lahdenperä, Natalie Bowers, Edmond Teng, Fanli Xu, David Pulford, Martti Färkkilä, Sampsa Pikkarainen, Airi Jussila, Timo Blomster, Mikko Kiviniemi, Markku Voutilainen, Fedik Rahimov, Joseph Maranville, Tim Lu, Kirsi Kalpala, Melissa Miller, Linda McCarthy, Kari Eklund, Antti Palomäki, Pia Isomäki, Laura Pirilä, Johanna Huhtakangas, Marla Hochfeld, Nan Bing, Jorge Esparza Gordillo, Nina Mars, Tarja Laitinen, Margit Pelkonen, Paula Kauppi, Hannu Kankaanranta, Terttu Harju, Hubert Chen, Teemu Niiranen, Kaj Metsärinne, Marja-Riitta Taskinen, Tiinamaija Tuomi, Jari Laukkanen, Audrey Chu, Jaakko Parkkinen, Heikki Joensuu, Tuomo Meretoja, Lauri Aaltonen, Annika Auranen, Päivi Auvinen, Klaus Elenius, Relja Popovic, Bridget Riley-Gillis, Jennifer Schutzman, Heli Lehtonen, Stefan McDonough, Diptee Kulkarni, Terhi Ollila, Hannu Uusitalo, Erich Strauss, Kaisa Tasanen, Laura Huilaja, Katariina Hannula-Jouppi, Teea Salmi, Leena Koulu, David Choy, Anu Jalanko, Risto Kajanne, Mari Kaunisto, Chia-Yen Chen, Robert Yang, Kirsi Auro, Clement Chatelain, Mitja Kurki, Juha Karjalainen, Kimmo Palin, Priit Palta, Susanna Lemmelä, Manuel Rivas, Arto Lehisto, Andrea Ganna, Vincent Llorens, Kati Kristiansson, Kati Hyvärinen, Jarmo Ritari, Katri Pylkäs, Minna Karjalainen, Tuomo Mantere, Eeva Kangasniemi, Sami Heikkinen, Eija Laakkonen, Anu Loukola, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Hannele Mattsson, Tero Hiekkalinna, Kati Donner, Kalle Pärn, Elina Kilpeläinen, Hannele Laivuori, Harri Siirtola, Sirpa Soini, Teijo Kuopio, Ioanna Tachmazidou, Katja Kivinen, Pekka Nieminen, Adam Platt, Sanna Toppila-Salmi, Antti Mäkitie, Elmo Saarentaus, Kristiina Aittomäki, Elisabeth Widen, Marja Vääräsmäki, Erkki Isometsä, Laura Addis, Mika Helminen, Taneli Raivio, Mart Kals, Majd Mouded, Hanna Ollila, Vuokko Anttonen, Tarja Kokkola, Robert Graham, Amanda Elliott, Ali Abbasi, Bridget Riley-Gills, Dirk Paul, Katherine Klinger, Deepak Raipal, Antti Hakanen, Raisa Serpi, Johanna Mäkelä, Mengzhen Liu, Neha Raghavan, Adriana Huertas-Vazquez, Nicole Renaud, Roosa Kallionpää, John Eicher, Minna Raivio, Juulia Partanen, Riitta Lahesmaa, Glenda Lassi, Joanna Betts, Rajashree Mishra, Felix Vaura, Joel Rämö, Mary Pat Reeve, Johanna Mattson, Sauli Vuoti, Esa Pitkänen, Joni A Turunen, Stephanie Loomis, Pirkko Pussinen, Aino Salminen, Tuula Salo, Ulla Palotie, Maria Siponen, Liisa Suominen, Päivi Mäntylä, Ulvi Gursoy, Kirsi Sipilä, Venla Kurra, Laura Kotaniemi-Talonen, Outi Uimari, Taru Tukiainen, Niko Välimäki, Janet Kumar, Juha Mehtonen, Shabbeer Hassan, Pietro Della Briotta Parolo, Mutaamba Maasha, Javier Garcia-Tabuenca, Jiwoo Lee, Kristin Tsuo, Nina Pitkänen, Eero Punkka, Huei-Yi Shen, Mervi Aavikko, L. Elisa Lahtela, Timo P. Sipilä, Awaisa Ghazal, Sami Koskelainen, Teemu Paajanen, Shuang Luo, Javier Gracia-Tabuenca, Tiina Luukkaala, Iida Vähätalo, Marco Hautalahti, Tom Southerington, Paula Iso-Markku, Jaana Suvisaari, Zhihao Ding, Qingqin S Li, Amy Hart, Perttu Terho, Alessandro Porello, Anastasia Kytölä, Antti Aarnisalo, Aoxing Liu, Argyro Bizaki-Vallaskangas, Auli Toivola, Debby Ngo, Dermot Reilly, Ekaterina Khramtsova, Elisa Rahikkala, Eric Green, Eveliina Salminen, Fabiana Farias, George Okafo, Heidi Silven, Heli Salminen-Mankonen, Henna Palin, Iiris Hovatta, Jaakko Tyrmi, Jae-Hoon Sul, Jenni Aittokallio, Jyrki Pitkänen, Karen He, Katriina Aalto-Setälä, Maarit Niinimäki, Malla-Maria Linna, Marc Jung, Margaret G. Ehm, Marianna Niemi, Meijian Guan, Mike Mendelson, Minna Brunfeldt, Natalia Pujol, Nathan Lawless, Oluwaseun Alexander Dada, Rigbe Weldatsadik, Riikka Arffman, Rion Pendergrass, Sahar Mozaffari, Samuel Lessard, Sanna Siltanen, Shanmukha Sampath Padmanabhuni, Simonne Longerich, Susanna Savukoski, Thomas Damm Als, Timo Hiltunen, Tomi P. Mäkelä, Triin Laisk, Tytti Willberg, Varpu Jokimaa, Aija Kyttälä, Toni T Saari, Aino Aaltonen, Sari Aaltonen, Sari Kärkkäinen, Hilkka Liedes, Miina Ollikainen, Teemu Palviainen, Ilona Ruotsalainen, Mia Urjansson, Markus M Forsberg, Jaakko Lähteenmäki, Pia Nyberg, Jani Tikkanen, Mari E. Niemi, and Rodos Rodosthenous
Subjects: Medicine
Abstract: Introduction A better understanding of the earliest stages of Alzheimer’s disease (AD) could expedite the development or administration of treatments. Large population biobanks hold the promise to identify individuals at an elevated risk of AD and related dementias based on health registry information. Here, we establish the protocol for an observational clinical recall and biomarker study called TWINGEN with the aim to identify individuals at high risk of AD by assessing cognition, health and AD-related biomarkers. Suitable candidates were identified and invited to participate in the new study among THL Biobank donors according to TWINGEN study criteria.Methods and analysis A multi-centre study (n=800) to obtain blood-based biomarkers, telephone-administered and web-based memory and cognitive parameters, questionnaire information on lifestyle, health and psychological factors, and accelerometer data for measures of physical activity, sedentary behaviour and sleep. A subcohort is being asked to participate in an in-person neuropsychological assessment (n=200) and wear an Oura ring (n=50). All participants in the TWINGEN study have genome-wide genotyping data and up to 48 years of follow-up data from the population-based older Finnish Twin Cohort (FTC) study of the University of Helsinki. The data collected in TWINGEN will be returned to THL Biobank from where it can later be requested for other biobank studies such as FinnGen that supported TWINGEN.Ethics and dissemination This recall study consists of FTC/THL Biobank/FinnGen participants whose data were acquired in accordance with the Finnish Biobank Act. The recruitment protocols followed the biobank protocols approved by Finnish Medicines Agency. The TWINGEN study plan was approved by the Ethics Committee of Hospital District of Helsinki and Uusimaa (number 16831/2022). THL Biobank approved the research plan with the permission no: THLBB2022_83.
Published: 2024
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4. X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

Author: Markus Scholz, Katrin Horn, Janne Pott, Matthias Wuttke, Andreas Kühnapfel, M. Kamal Nasr, Holger Kirsten, Yong Li, Anselm Hoppmann, Mathias Gorski, Sahar Ghasemi, Man Li, Adrienne Tin, Jin-Fang Chai, Massimiliano Cocca, Judy Wang, Teresa Nutile, Masato Akiyama, Bjørn Olav Åsvold, Nisha Bansal, Mary L. Biggs, Thibaud Boutin, Hermann Brenner, Ben Brumpton, Ralph Burkhardt, Jianwen Cai, Archie Campbell, Harry Campbell, John Chalmers, Daniel I. Chasman, Miao Ling Chee, Miao Li Chee, Xu Chen, Ching-Yu Cheng, Renata Cifkova, Martha Daviglus, Graciela Delgado, Katalin Dittrich, Todd L. Edwards, Karlhans Endlich, J. Michael Gaziano, Ayush Giri, Franco Giulianini, Scott D. Gordon, Daniel F. Gudbjartsson, Stein Hallan, Pavel Hamet, Catharina A. Hartman, Caroline Hayward, Iris M. Heid, Jacklyn N. Hellwege, Bernd Holleczek, Hilma Holm, Nina Hutri-Kähönen, Kristian Hveem, Berend Isermann, Jost B. Jonas, Peter K. Joshi, Yoichiro Kamatani, Masahiro Kanai, Mika Kastarinen, Chiea Chuen Khor, Wieland Kiess, Marcus E. Kleber, Antje Körner, Peter Kovacs, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Mikko Kuokkanen, Mika Kähönen, Leslie A. Lange, James P. Lash, Terho Lehtimäki, Hengtong Li, Bridget M. Lin, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Patrik K. E. Magnusson, Nicholas G. Martin, Koichi Matsuda, Yuri Milaneschi, Pashupati P. Mishra, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Winfried März, Matthias Nauck, Kjell Nikus, Ilja M. Nolte, Raymond Noordam, Yukinori Okada, Isleifur Olafsson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Markus Perola, Nicola Pirastu, Ozren Polasek, David J. Porteous, Tanja Poulain, Bruce M. Psaty, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Humaira Rasheed, Dermot F. Reilly, Kenneth M. Rice, Anne Richmond, Paul M. Ridker, Jerome I. Rotter, Igor Rudan, Charumathi Sabanayagam, Veikko Salomaa, Neil Schneiderman, Ben Schöttker, Mario Sims, Harold Snieder, Klaus J. Stark, Kari Stefansson, Hannah Stocker, Michael Stumvoll, Patrick Sulem, Gardar Sveinbjornsson, Per O. Svensson, E-Shyong Tai, Kent D. Taylor, Bamidele O. Tayo, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Laurent F. Thomas, Johanne Tremblay, Anke Tönjes, Peter J. van der Most, Veronique Vitart, Uwe Völker, Ya Xing Wang, Chaolong Wang, Wen Bin Wei, John B. Whitfield, Sarah H. Wild, James F. Wilson, Thomas W. Winkler, Tien-Yin Wong, Mark Woodward, Xueling Sim, Audrey Y. Chu, Mary F. Feitosa, Unnur Thorsteinsdottir, Adriana M. Hung, Alexander Teumer, Nora Franceschini, Afshin Parsa, Anna Köttgen, Pascal Schlosser, and Cristian Pattaro
Subjects: Science
Abstract: Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.
Published: 2024
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5. Waist-hip ratio is superior to BMI in predicting liver-related outcomes and synergizes with harmful alcohol use

Author: Fredrik Åberg, Martti Färkkilä, Veikko Salomaa, Antti Jula, Satu Männistö, Markus Perola, Annamari Lundqvist, and Ville Männistö
Subjects: Medicine
Abstract: Abstract Background: Obesity is associated with liver disease, but the best obesity-related predictor remains undefined. Controversy exists regarding possible synergism between obesity and alcohol use for liver-related outcomes (LRO). We assessed the predictive performance for LROs, and synergism with alcohol use, of abdominal obesity (waist-hip ratio, WHR), and compared it to overall obesity (body mass index, BMI). Methods: Forty-thousand nine-hundred twenty-two adults attending the Finnish health-examination surveys, FINRISK 1992–2012 and Health 2000 studies, were followed through linkage with electronic healthcare registries for LROs (hospitalizations, cancers, and deaths). Predictive performance of obesity measures (WHR, waist circumference [WC], and BMI) were assessed by Fine-Gray models and time-dependent area-under-the-curve (AUC). Results: There are 355 LROs during a median follow-up of 12.9 years (509047.8 person-years). WHR and WC emerge as more powerful predictors of LROs than BMI. WHR shows significantly better 10-year AUC values for LROs (0.714, 95% CI 0.685–0.743) than WC (0.648, 95% CI 0.617–0.679) or BMI (0.550, 95% CI 0.514–0.585) both overall and separately among men and women. WHR is predictive also in BMI strata. Absolute 10-year risks of LROs are more dependent on WHR than BMI. Moreover, WHR shows a significant supra-additive interaction effect with harmful alcohol use for liver-related outcomes (excess 10-year cumulative incidence of 2.8% from the interaction), which is not seen between BMI and harmful alcohol use. Conclusions: WHR is a better predictor than BMI or WC for LROs, and WHR better reflects the synergism with harmful alcohol use. WHR should be included in clinical assessment when evaluating obesity-related risks for liver outcomes.
Published: 2023
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6. A FinnGen pilot clinical recall study for Alzheimer’s disease

Author: Valtteri Julkunen, Claudia Schwarz, Juho Kalapudas, Merja Hallikainen, Aino-Kaisa Piironen, Arto Mannermaa, Hanna Kujala, Timo Laitinen, Veli-Matti Kosma, Teemu I. Paajanen, Reetta Kälviäinen, Mikko Hiltunen, Sanna-Kaisa Herukka, Sari Kärkkäinen, Tarja Kokkola, Mia Urjansson, FinnGen, Markus Perola, Aarno Palotie, Eero Vuoksimaa, and Heiko Runz
Subjects: Medicine, Science
Abstract: Abstract Successful development of novel therapies requires that clinical trials are conducted in patient cohorts with the highest benefit-to-risk ratio. Population-based biobanks with comprehensive health and genetic data from large numbers of individuals hold promise to facilitate identification of trial participants, particularly when interventions need to start while symptoms are still mild, such as for Alzheimer’s disease (AD). This study describes a process for clinical recall studies from FinnGen. We demonstrate the feasibility to systematically ascertain customized clinical data from FinnGen participants with ICD10 diagnosis of AD or mild cognitive disorder (MCD) in a single-center cross-sectional study testing blood-based biomarkers and cognitive functioning in-person, computer-based and remote. As a result, 19% (27/140) of a pre-specified FinnGen subcohort were successfully recalled and completed the study. Hospital records largely validated registry entries. For 8/12 MCD patients, other reasons than AD were identified as underlying diagnosis. Cognitive measures correlated across platforms, with highest consistencies for dementia screening (r = 0.818) and semantic fluency (r = 0.764), respectively, for in-person versus telephone-administered tests. Glial fibrillary acidic protein (GFAP) (p
Published: 2023
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7. Genetic insights into resting heart rate and its role in cardiovascular disease

Author: Yordi J. van de Vegte, Ruben N. Eppinga, M. Yldau van der Ende, Yanick P. Hagemeijer, Yuvaraj Mahendran, Elias Salfati, Albert V. Smith, Vanessa Y. Tan, Dan E. Arking, Ioanna Ntalla, Emil V. Appel, Claudia Schurmann, Jennifer A. Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian’an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U. Jackson, Lawrence F. Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E. Kleber, Xiuqing Guo, Henry J. Lin, Francesca Pavani, Tessel E. Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E. Schraut, Marcel den Hoed, Frauke Degenhardt, Stella Trompet, Marten E. van den Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S. Sim, Hengtong L. Li, Peter J. van der Most, Ilja M. Nolte, Leo-Pekka Lyytikäinen, M. Abdullah Said, Daniel R. Witte, Carlos Iribarren, Lenore Launer, Susan M. Ring, Paul S. de Vries, Peter Sever, Allan Linneberg, Erwin P. Bottinger, Sandosh Padmanabhan, Bruce M. Psaty, Nona Sotoodehnia, Ivana Kolcic, The DCCT/EDIC Research Group, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T. Silva, Christopher H. Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L. Mohlke, Patricia A. Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C. Rao, Marilyn C. Cornelis, Jessica D. Faul, Jennifer A. Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F. Sinner, Konstantin Strauch, Graciela E. Delgado, Kent D. Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline de Graaf, Renée de Mutsert, Eco J. C. de Geus, Åsa Johansson, Peter K. Joshi, Lars Lind, Andre Franke, Peter W. Macfarlane, Kirill V. Tarasov, Nicholas Tan, Stephan B. Felix, E-Shyong Tai, Debra Q. Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P. Morris, Olli T. Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J. Timpson, Alanna C. Morrison, Patricia B. Munroe, David P. Strachan, Niels Grarup, Ruth J. F. Loos, Susan R. Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J. Wareham, Cornelia M. van Duijn, Mary F. Feitosa, Christopher J. O’Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L. R. Kardia, Jeanette Erdmann, Colin N. A. Palmer, Claes Ohlsson, David J. Porteous, Johan G. Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R. Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C. Chambers, Jaspal S. Kooner, Winfried März, Jerome I. Rotter, Andrew A. Hicks, J. Gustav Smith, Lambertus A. L. M. Kiemeney, Dennis O. Mook-Kanamori, Brenda W. J. H. Penninx, Ulf Gyllensten, James F. Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J. Wouter Jukema, Mark Eijgelsheim, Edward L. M. Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J. Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij, and Pim van der Harst
Subjects: Science
Abstract: Abstract Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
Published: 2023
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8. A metabolic profile of xenon and metabolite associations with 6-month mortality after out-of-hospital cardiac arrest: A post-hoc study of the randomised Xe-Hypotheca trial.

Author: Aleksi J Nummela, Harry Scheinin, Markus Perola, Anni Joensuu, Ruut Laitio, Olli Arola, Juha Grönlund, Risto O Roine, Minna Bäcklund, Tero J Vahlberg, Timo Laitio, and Xe-Hypotheca Collaboration Group
Subjects: Medicine, Science
Abstract: PurposeOut-of-hospital cardiac arrest (OHCA) carries a relatively poor prognosis and requires multimodal prognostication to guide clinical decisions. Identification of previously unrecognized metabolic routes associated with patient outcome may contribute to future biomarker discovery. In OHCA, inhaled xenon elicits neuro- and cardioprotection. However, the metabolic effects remain unknown.Materials and methodsIn this post-hoc study of the randomised, 2-group, single-blind, phase 2 Xe-Hypotheca trial, 110 OHCA survivors were randomised 1:1 to receive targeted temperature management (TTM) at 33°C with or without inhaled xenon during 24 h. Blood samples for nuclear magnetic resonance spectroscopy metabolic profiling were drawn upon admission, at 24 and 72 h.ResultsAt 24 h, increased lactate, adjusted hazard-ratio 2.25, 95% CI [1.53; 3.30], pConclusionsIn OHCA patients receiving TTM with or without xenon, high lactate and alanine and decreased BCAAs and S-HDL-CE associated with increased mortality. It remains to be established whether current observations on BCAAs, and possibly alanine and lactate, could reflect neural damage via their roles in the metabolism of the neurotransmitter glutamate. Xenon did not significantly alter the measured metabolic profile, a potentially beneficial attribute in the context of compromised ICU patients.Trial registrationTrial Registry number: ClinicalTrials.gov Identifier: NCT00879892.
Published: 2024
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9. Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Author: Hanna M. Ollila, Eilon Sharon, Ling Lin, Nasa Sinnott-Armstrong, Aditya Ambati, Selina M. Yogeshwar, Ryan P. Hillary, Otto Jolanki, Juliette Faraco, Mali Einen, Guo Luo, Jing Zhang, Fang Han, Han Yan, Xiao Song Dong, Jing Li, Jun Zhang, Seung-Chul Hong, Tae Won Kim, Yves Dauvilliers, Lucie Barateau, Gert Jan Lammers, Rolf Fronczek, Geert Mayer, Joan Santamaria, Isabelle Arnulf, Stine Knudsen-Heier, May Kristin Lyamouri Bredahl, Per Medbøe Thorsby, Giuseppe Plazzi, Fabio Pizza, Monica Moresco, Catherine Crowe, Stephen K. Van den Eeden, Michel Lecendreux, Patrice Bourgin, Takashi Kanbayashi, Francisco J. Martínez-Orozco, Rosa Peraita-Adrados, Antonio Benetó, Jacques Montplaisir, Alex Desautels, Yu-Shu Huang, FinnGen, Poul Jennum, Sona Nevsimalova, David Kemlink, Alex Iranzo, Sebastiaan Overeem, Aleksandra Wierzbicka, Peter Geisler, Karel Sonka, Makoto Honda, Birgit Högl, Ambra Stefani, Fernando Morgadinho Coelho, Vilma Mantovani, Eva Feketeova, Mia Wadelius, Niclas Eriksson, Hans Smedje, Pär Hallberg, Per Egil Hesla, David Rye, Zerrin Pelin, Luigi Ferini-Strambi, Claudio L. Bassetti, Johannes Mathis, Ramin Khatami, Adi Aran, Sheela Nampoothiri, Tomas Olsson, Ingrid Kockum, Markku Partinen, Markus Perola, Birgitte R. Kornum, Sina Rueger, Juliane Winkelmann, Taku Miyagawa, Hiromi Toyoda, Seik-Soon Khor, Mihoko Shimada, Katsushi Tokunaga, Manuel Rivas, Jonathan K. Pritchard, Neil Risch, Zoltan Kutalik, Ruth O’Hara, Joachim Hallmayer, Chun Jimmie Ye, and Emmanuel J. Mignot
Subjects: Science
Abstract: Abstract Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.
Published: 2023
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10. Atlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank

Author: Heli Julkunen, Anna Cichońska, Mika Tiainen, Harri Koskela, Kristian Nybo, Valtteri Mäkelä, Jussi Nokso-Koivisto, Kati Kristiansson, Markus Perola, Veikko Salomaa, Pekka Jousilahti, Annamari Lundqvist, Antti J. Kangas, Pasi Soininen, Jeffrey C. Barrett, and Peter Würtz
Subjects: Science
Abstract: The authors report a systematic analyses of blood biomarkers for metabolism against the whole spectrum of diseases in 100,000 individuals and reveals a prominent role of numerous metabolic biomarkers as risk markers beyond heart disease and diabetes.
Published: 2023
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11. Pharmacoepigenetics of hypertension: genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design

Author: Marja-Liisa Nuotio, Heini Sánez Tähtisalo, Alexandra Lahtinen, Kati Donner, Frej Fyhrquist, Markus Perola, Kimmo K Kontula, and Timo P Hiltunen
Subjects: epigenomics, hypertension, pharmacogenetics, precision medicine, Genetics, QH426-470
Abstract: Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (https://clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://clinicaltrials.gov/ct2/show/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P
Published: 2022
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12. Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

Author: Olli P. O. Nevalainen, Saana Horstia, Sanna Laakkonen, Jarno Rutanen, Jussi M. J. Mustonen, Ilkka E. J. Kalliala, Hanna Ansakorpi, Hanna-Riikka Kreivi, Pauliina Kuutti, Juuso Paajanen, Seppo Parkkila, Erja-Leena Paukkeri, Markus Perola, Negar Pourjamal, Andreas Renner, Tuomas Rosberg, Taija Rutanen, Joni Savolainen, Solidarity Finland Investigators, Jari K. Haukka, Gordon H. Guyatt, and Kari A. O. Tikkinen
Subjects: Science
Abstract: Many survivors of COVID-19 experience persistent symptoms, continuing beyond three months from the onset of infection. In this study, authors investigate the effect of remdesivir on recovery and long-COVID-19 symptoms, as well as quality of life and other symptom outcomes, in the 1-year follow-up of a randomised trial.
Published: 2022
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13. Association between arterial hypertension and liver outcomes using polygenic risk scores: a population-based study

Author: Fredrik Åberg, Katri Kantojärvi, Ville Männistö, Anna But, Veikko Salomaa, Teemu Niiranen, Martti Färkkilä, Panu Luukkonen, Satu Männistö, Annamari Lundqvist, Markus Perola, and Antti Jula
Subjects: Medicine, Science
Abstract: Abstract Arterial hypertension (HTA) is associated with liver disease, but causality remains unclear. We investigated whether genetic predisposition to HTA is associated with liver disease in the population, and if antihypertensive medication modifies this association. Participants of the Finnish health-examination surveys, FINRISK 1992–2012 and Health 2000 (n = 33,770), were linked with national electronic healthcare registers for liver-related outcomes (K70-K77, C22.0) and with the drug reimbursement registry for new initiation of antihypertensive medication during follow-up. Genetic predisposition to HTA was defined by polygenic risk scores (PRSs). During a median 12.9-year follow-up (409,268.9 person-years), 441 liver-related outcomes occurred. In the fully-adjusted Cox-regression models, both measured systolic blood pressure and clinically defined HTA were associated with liver-related outcomes. PRSs for systolic and diastolic blood pressure were significantly associated with liver-related outcomes (HR/SD 1.19, 95% CI 1.01–1.24, and 1.12, 95% CI 1.01–1.25, respectively). In the highest quintile of the systolic blood pressure PRS, new initiation of antihypertensive medication was associated with reduced rates of liver-related outcomes (HR 0.55, 95% CI 0.31–0.97). HTA and a genetic predisposition for HTA are associated with liver-related outcomes in the population. New initiation of antihypertensive medication attenuates this association in persons with high genetic risk for HTA.
Published: 2022
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14. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Author: Thomas W. Winkler, Humaira Rasheed, Alexander Teumer, Mathias Gorski, Bryce X. Rowan, Kira J. Stanzick, Laurent F. Thomas, Adrienne Tin, Anselm Hoppmann, Audrey Y. Chu, Bamidele Tayo, Chris H. L. Thio, Daniele Cusi, Jin-Fang Chai, Karsten B. Sieber, Katrin Horn, Man Li, Markus Scholz, Massimiliano Cocca, Matthias Wuttke, Peter J. van der Most, Qiong Yang, Sahar Ghasemi, Teresa Nutile, Yong Li, Giulia Pontali, Felix Günther, Abbas Dehghan, Adolfo Correa, Afshin Parsa, Agnese Feresin, Aiko P. J. de Vries, Alan B. Zonderman, Albert V. Smith, Albertine J. Oldehinkel, Alessandro De Grandi, Alexander R. Rosenkranz, Andre Franke, Andrej Teren, Andres Metspalu, Andrew A. Hicks, Andrew P. Morris, Anke Tönjes, Anna Morgan, Anna I. Podgornaia, Annette Peters, Antje Körner, Anubha Mahajan, Archie Campbell, Barry I. Freedman, Beatrice Spedicati, Belen Ponte, Ben Schöttker, Ben Brumpton, Bernhard Banas, Bernhard K. Krämer, Bettina Jung, Bjørn Olav Åsvold, Blair H. Smith, Boting Ning, Brenda W. J. H. Penninx, Brett R. Vanderwerff, Bruce M. Psaty, Candace M. Kammerer, Carl D. Langefeld, Caroline Hayward, Cassandra N. Spracklen, Cassianne Robinson-Cohen, Catharina A. Hartman, Cecilia M. Lindgren, Chaolong Wang, Charumathi Sabanayagam, Chew-Kiat Heng, Chiara Lanzani, Chiea-Chuen Khor, Ching-Yu Cheng, Christian Fuchsberger, Christian Gieger, Christian M. Shaffer, Christina-Alexandra Schulz, Cristen J. Willer, Daniel I. Chasman, Daniel F. Gudbjartsson, Daniela Ruggiero, Daniela Toniolo, Darina Czamara, David J. Porteous, Dawn M. Waterworth, Deborah Mascalzoni, Dennis O. Mook-Kanamori, Dermot F. Reilly, E. Warwick Daw, Edith Hofer, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, E-Shyong Tai, Eulalia Catamo, Federica Rizzi, Feng Guo, Fernando Rivadeneira, Franco Guilianini, Gardar Sveinbjornsson, Georg Ehret, Gerard Waeber, Ginevra Biino, Giorgia Girotto, Giorgio Pistis, Girish N. Nadkarni, Graciela E. Delgado, Grant W. Montgomery, Harold Snieder, Harry Campbell, Harvey D. White, He Gao, Heather M. Stringham, Helena Schmidt, Hengtong Li, Hermann Brenner, Hilma Holm, Holgen Kirsten, Holly Kramer, Igor Rudan, Ilja M. Nolte, Ioanna Tzoulaki, Isleifur Olafsson, Jade Martins, James P. Cook, James F. Wilson, Jan Halbritter, Janine F. Felix, Jasmin Divers, Jaspal S. Kooner, Jeannette Jen-Mai Lee, Jeffrey O’Connell, Jerome I. Rotter, Jianjun Liu, Jie Xu, Joachim Thiery, Johan Ärnlöv, Johanna Kuusisto, Johanna Jakobsdottir, Johanne Tremblay, John C. Chambers, John B. Whitfield, John M. Gaziano, Jonathan Marten, Josef Coresh, Jost B. Jonas, Josyf C. Mychaleckyj, Kaare Christensen, Kai-Uwe Eckardt, Karen L. Mohlke, Karlhans Endlich, Katalin Dittrich, Kathleen A. Ryan, Kenneth M. Rice, Kent D. Taylor, Kevin Ho, Kjell Nikus, Koichi Matsuda, Konstantin Strauch, Kozeta Miliku, Kristian Hveem, Lars Lind, Lars Wallentin, Laura M. Yerges-Armstrong, Laura M. Raffield, Lawrence S. Phillips, Lenore J. Launer, Leo-Pekka Lyytikäinen, Leslie A. Lange, Lorena Citterio, Lucija Klaric, M. Arfan Ikram, Marcus Ising, Marcus E. Kleber, Margherita Francescatto, Maria Pina Concas, Marina Ciullo, Mario Piratsu, Marju Orho-Melander, Markku Laakso, Markus Loeffler, Markus Perola, Martin H. de Borst, Martin Gögele, Martina La Bianca, Mary Ann Lukas, Mary F. Feitosa, Mary L. Biggs, Mary K. Wojczynski, Maryam Kavousi, Masahiro Kanai, Masato Akiyama, Masayuki Yasuda, Matthias Nauck, Melanie Waldenberger, Miao-Li Chee, Miao-Ling Chee, Michael Boehnke, Michael H. Preuss, Michael Stumvoll, Michael A. Province, Michele K. Evans, Michelle L. O’Donoghue, Michiaki Kubo, Mika Kähönen, Mika Kastarinen, Mike A. Nalls, Mikko Kuokkanen, Mohsen Ghanbari, Murielle Bochud, Navya Shilpa Josyula, Nicholas G. Martin, Nicholas Y. Q. Tan, Nicholette D. Palmer, Nicola Pirastu, Nicole Schupf, Niek Verweij, Nina Hutri-Kähönen, Nina Mononen, Nisha Bansal, Olivier Devuyst, Olle Melander, Olli T. Raitakari, Ozren Polasek, Paolo Manunta, Paolo Gasparini, Pashupati P. Mishra, Patrick Sulem, Patrik K. E. Magnusson, Paul Elliott, Paul M. Ridker, Pavel Hamet, Per O. Svensson, Peter K. Joshi, Peter Kovacs, Peter P. Pramstaller, Peter Rossing, Peter Vollenweider, Pim van der Harst, Rajkumar Dorajoo, Ralene Z. H. Sim, Ralph Burkhardt, Ran Tao, Raymond Noordam, Reedik Mägi, Reinhold Schmidt, Renée de Mutsert, Rico Rueedi, Rob M. van Dam, Robert J. Carroll, Ron T. Gansevoort, Ruth J. F. Loos, Sala Cinzia Felicita, Sanaz Sedaghat, Sandosh Padmanabhan, Sandra Freitag-Wolf, Sarah A. Pendergrass, Sarah E. Graham, Scott D. Gordon, Shih-Jen Hwang, Shona M. Kerr, Simona Vaccargiu, Snehal B. Patil, Stein Hallan, Stephan J. L. Bakker, Su-Chi Lim, Susanne Lucae, Suzanne Vogelezang, Sven Bergmann, Tanguy Corre, Tarunveer S. Ahluwalia, Terho Lehtimäki, Thibaud S. Boutin, Thomas Meitinger, Tien-Yin Wong, Tobias Bergler, Ton J. Rabelink, Tõnu Esko, Toomas Haller, Unnur Thorsteinsdottir, Uwe Völker, Valencia Hui Xian Foo, Veikko Salomaa, Veronique Vitart, Vilmantas Giedraitis, Vilmundur Gudnason, Vincent W. V. Jaddoe, Wei Huang, Weihua Zhang, Wen Bin Wei, Wieland Kiess, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Xin Gao, Xueling Sim, Ya Xing Wang, Yechiel Friedlander, Yih-Chung Tham, Yoichiro Kamatani, Yukinori Okada, Yuri Milaneschi, Zhi Yu, Lifelines cohort study, DiscovEHR/MyCode study, VA Million Veteran Program, Klaus J. Stark, Kari Stefansson, Carsten A. Böger, Adriana M. Hung, Florian Kronenberg, Anna Köttgen, Cristian Pattaro, and Iris M. Heid
Subjects: Biology (General), QH301-705.5
Abstract: A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.
Published: 2022
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15. Association between mitochondrial DNA haplogroups J and K, serum branched-chain amino acids and lowered capability for endurance exercise

Author: Jukka M. Kiiskilä, Ilmo E. Hassinen, Johannes Kettunen, Laura Kytövuori, Ilona Mikkola, Pirjo Härkönen, Jari J. Jokelainen, Sirkka Keinänen-Kiukaanniemi, Markus Perola, and Kari Majamaa
Subjects: mtDNA haplogroup, Branched-chain amino acid, Trainability, Low-responder, Military conscript, Sports medicine, RC1200-1245
Abstract: Abstract Background Endurance exercise training promotes the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles. We have previously shown that mitochondrial DNA (mtDNA) haplogroups J and K are markers of low responders in endurance training. In this paper, we hypothesize that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups. We evaluated whether exercise-induced changes in amino acid concentrations differ between subjects harbouring mtDNA haplogroups J or K and those with non-JK haplogroups. Methods Finnish male conscripts (N = 633) undertook the 12-min Cooper running test at the beginning and end of their military service. The intervention during the service mainly included endurance aerobic exercise and sports-related muscle training. Concentrations of seven amino acids were analysed in the serum using a high-throughput 1H NMR metabolomics platform. Total DNA was extracted from whole blood, and restriction fragment analysis was used to determine mtDNA haplogroups J and K. Results The concentrations of the seven amino acids were higher following the intervention, with the exception of phenylalanine; interestingly, the increase in the concentrations of three BCAAs was larger in subjects with haplogroup J or K than in subjects with non-JK haplogroups (p = 0.029). MtDNA haplogroups J and K share two common nonsynonymous variants. Structural analysis based on crystallographic data on bovine complexes I and III revealed that the Leu18 variant in cytochrome b encoded by m.14798T > C may interfere with ubiquinone binding at the Qi site in complex III. Conclusions The increase in the concentrations of serum BCAAs following exercise intervention differs between subjects harbouring mtDNA haplogroup J or K and those harbouring non-JK haplogroups. Lower response in endurance training and difference in exercise-induced increase in the concentrations of serum BCAAs suggest decreased respiratory chain activity. Haplogroups J and K share m.14798T > C in MT-CYB, which may hamper the function of complex III.
Published: 2022
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16. The genomics of heart failure: design and rationale of the HERMES consortium

Author: R. Thomas Lumbers, Sonia Shah, Honghuang Lin, Tomasz Czuba, Albert Henry, Daniel I. Swerdlow, Anders Mälarstig, Charlotte Andersson, Niek Verweij, Michael V. Holmes, Johan Ärnlöv, Per Svensson, Harry Hemingway, Neneh Sallah, Peter Almgren, Krishna G. Aragam, Geraldine Asselin, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Eric Boersma, Jeffrey Brandimarto, Michael R. Brown, Hans‐Peter Brunner‐La Rocca, David J. Carey, Mark D. Chaffin, Daniel I. Chasman, Olympe Chazara, Xing Chen, Xu Chen, Jonathan H. Chung, William Chutkow, John G.F. Cleland, James P. Cook, Simon deDenus, Abbas Dehghan, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Gunnar Engström, Tõnu Esko, Ghazaleh Fatemifar, Stephan B. Felix, Chris Finan, Ian Ford, Francoise Fougerousse, René Fouodjio, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Hongsheng Gui, Rebecca Gutmann, Christopher M. Haggerty, Pim van derHarst, Åsa K. Hedman, Anna Helgadottir, Hans Hillege, Craig L. Hyde, Jaison Jacob, J. Wouter Jukema, Frederick Kamanu, Isabella Kardys, Maryam Kavousi, Kay‐Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Bill Kraus, Karoline Kuchenbaecker, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian'an Luan, Patrik Magnusson, Anubha Mahajan, Douglas Mann, Kenneth B. Margulies, Nicholas A. Marston, Winfried März, John J.V. McMurray, Olle Melander, Giorgio Melloni, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Christopher Newton‐Cheh, Alexander Niessner, Teemu Niiranen, Christoph Nowak, Michelle L. O'Donoghue, Anjali T. Owens, Colin N.A. Palmer, Guillaume Paré, Markus Perola, Louis‐Philippe Lemieux Perreault, Eliana Portilla‐Fernandez, Bruce M. Psaty, Kenneth M. Rice, Paul M. Ridker, Simon P.R. Romaine, Carolina Roselli, Jerome I. Rotter, Christian T. Ruff, Marc S. Sabatine, Perttu Salo, Veikko Salomaa, Jessica vanSetten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Kari Stefansson, Steen Stender, David J. Stott, Garðar Sveinbjörnsson, Mari‐Liis Tammesoo, Jean‐Claude Tardif, Kent D. Taylor, Maris Teder‐Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp‐Pedersen, Stella Trompet, Danny Tuckwell, Benoit Tyl, Andre G. Uitterlinden, Felix Vaura, Abirami Veluchamy, Peter M. Visscher, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Peter E. Weeke, Raul Weiss, Harvey D. White, Kerri L. Wiggins, Heming Xing, Jian Yang, Yifan Yang, Laura M. Yerges‐Armstrong, Bing Yu, Faiez Zannad, Faye Zhao, Regeneron Genetics Center, Jemma B. Wilk, Hilma Holm, Naveed Sattar, Steven A. Lubitz, David E. Lanfear, Svati Shah, Michael E. Dunn, Quinn S. Wells, Folkert W. Asselbergs, Aroon D. Hingorani, Marie‐Pierre Dubé, Nilesh J. Samani, Chim C. Lang, Thomas P. Cappola, Patrick T. Ellinor, Ramachandran S. Vasan, and J. Gustav Smith
Subjects: Heart failure, Cardiomyopathy, Genetics, Biomarkers, Association studies, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P
Published: 2021
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17. Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine: a randomised controlled trial using tandem mass spectrometry

Author: Aleksi Nummela, Lauri Laaksonen, Annalotta Scheinin, Kaike Kaisti, Tero Vahlberg, Mikko Neuvonen, Katja Valli, Antti Revonsuo, Markus Perola, Mikko Niemi, Harry Scheinin, and Timo Laitio
Subjects: bile acids, dexmedetomidine, lipidomics, oxylipins, propofol, sevoflurane, Anesthesiology, RD78.3-87.3
Abstract: Background: This exploratory study aimed to investigate whether dexmedetomidine, propofol, sevoflurane, and S-ketamine affect oxylipins and bile acids, which are functionally diverse molecules with possible connections to cellular bioenergetics, immune modulation, and organ protection. Methods: In this randomised, open-label, controlled, parallel group, Phase IV clinical drug trial, healthy male subjects (n=160) received equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml−1; n=40), propofol (1.7 μg ml−1; n=40), sevoflurane (0.9% end-tidal; n=40), S-ketamine (0.75 μg ml−1; n=20), or placebo (n=20). Blood samples for tandem mass spectrometry were obtained at baseline, after study drug administration at 60 and 130 min from baseline; 40 metabolites were analysed. Results: Statistically significant changes vs placebo were observed in 62.5%, 12.5%, 5.0%, and 2.5% of analytes in dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively. Data are presented as standard deviation score, 95% confidence interval, and P-value. Dexmedetomidine induced wide-ranging decreases in oxylipins and bile acids. Amongst others, 9,10-dihydroxyoctadecenoic acid (DiHOME) –1.19 (–1.6; –0.78), P
Published: 2022
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18. Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires: lessons from a pilot study within FinnGen

Author: Oskari Heikinheimo, Athena Matakidou, Jaakko Kaprio, Ying Wu, Kai Kaarniranta, Peeter Karihtala, Wei Zhou, Caroline Fox, Sarah Smith, Apinya Lertratanakul, Katri Kaukinen, Johannes Kettunen, Eeva Sliz, Markus Perola, Veikko Salomaa, Hilkka Soininen, Ilkka Kalliala, Mika Kähönen, Hao Chen, Andrey Loboda, Laure Morin-Papunen, Terhi Piltonen, Anders Mälarstig, Jason Miller, Jussi Hernesniemi, Henrike Heyne, Sirkku Peltonen, Daniel Gordin, Masahiro Kanai, Benjamin Challis, Juha Sinisalo, David Rice, Fredrik Åberg, Aarno Palotie, Samuli Ripatti, Oili Kaipiainen-Seppänen, Aki Havulinna, Satu Strausz, Tuomo Kiiskinen, Sanni Ruotsalainen, Jukka Koskela, Tuula Palotie, Mark Daly, Howard Jacob, Heiko Runz, Sally John, Robert Plenge, Mark McCarthy, Julie Hunkapiller, Dawn Waterworth, Petri Virolainen, Terhi Kilpi, Jukka Partanen, Anne Pitkäranta, Veli-Matti Kosma, Outi Tuovila, Raimo Pakkanen, Shameek Biswas, Xinli Hu, Johanna Schleutker, Mikko Arvas, Olli Carpen, Reetta Hinttala, Arto Mannermaa, Valtteri Julkunen, Anne Remes, Reetta Kälviäinen, Mikko Hiltunen, Jukka Peltola, Pentti Tienari, Juha Rinne, Adam Ziemann, Jeffrey Waring, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Sanni Lahdenperä, Natalie Bowers, Edmond Teng, Fanli Xu, David Pulford, Martti Färkkilä, Sampsa Pikkarainen, Airi Jussila, Timo Blomster, Mikko Kiviniemi, Markku Voutilainen, Fedik Rahimov, Joseph Maranville, Tim Lu, Kirsi Kalpala, Melissa Miller, Linda McCarthy, Kari Eklund, Antti Palomäki, Pia Isomäki, Laura Pirilä, Johanna Huhtakangas, Marla Hochfeld, Nan Bing, Jorge Esparza Gordillo, Nina Mars, Tarja Laitinen, Margit Pelkonen, Paula Kauppi, Hannu Kankaanranta, Terttu Harju, Hubert Chen, Teemu Niiranen, Kaj Metsärinne, Marja-Riitta Taskinen, Tiinamaija Tuomi, Jari Laukkanen, Audrey Chu, Jaakko Parkkinen, Heikki Joensuu, Tuomo Meretoja, Lauri Aaltonen, Annika Auranen, Päivi Auvinen, Klaus Elenius, Relja Popovic, Jennifer Schutzman, Heli Lehtonen, Stefan McDonough, Diptee Kulkarni, Terhi Ollila, Hannu Uusitalo, Erich Strauss, Kaisa Tasanen, Laura Huilaja, Katariina Hannula-Jouppi, Teea Salmi, Leena Koulu, David Choy, Anu Jalanko, Risto Kajanne, Mari Kaunisto, Chia-Yen Chen, Robert Yang, Kirsi Auro, Clement Chatelain, Mitja Kurki, Juha Karjalainen, Kimmo Palin, Priit Palta, Susanna Lemmelä, Manuel Rivas, Arto Lehisto, Andrea Ganna, Vincent Llorens, Kati Kristiansson, Kati Hyvärinen, Jarmo Ritari, Katri Pylkäs, Minna Karjalainen, Tuomo Mantere, Eeva Kangasniemi, Sami Heikkinen, Eija Laakkonen, Anu Loukola, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Hannele Mattsson, Kati Donner, Kalle Pärn, Elina Kilpeläinen, Hannele Laivuori, Harri Siirtola, Lila Kallio, Sirpa Soini, Teijo Kuopio, Ioanna Tachmazidou, Katja Kivinen, Pekka Nieminen, Adam Platt, Sanna Toppila-Salmi, Antti Mäkitie, Elmo Saarentaus, Kristiina Aittomäki, Elisabeth Widen, Marja Vääräsmäki, Erkki Isometsä, Jari Lahti, Laura Addis, Taneli Raivio, Mart Kals, Majd Mouded, Hanna Ollila, Vuokko Anttonen, Robert Graham, Amanda Elliott, Ali Abbasi, Bridget Riley-Gills, Dirk Paul, Katherine Klinger, Deepak Raipal, Antti Hakanen, Raisa Serpi, Johanna Mäkelä, Mengzhen Liu, Neha Raghavan, Adriana Huertas-Vazquez, Nicole Renaud, Roosa Kallionpää, John Eicher, Minna Raivio, Juulia Partanen, Riitta Lahesmaa, Glenda Lassi, Joanna Betts, Rajashree Mishra, Felix Vaura, Joel Rämö, Mary Pat Reeve, Johanna Mattson, Sauli Vuoti, Esa Pitkänen, Joni A Turunen, Stephanie Loomis, Pirkko Pussinen, Aino Salminen, Tuula Salo, Ulla Palotie, Maria Siponen, Liisa Suominen, Päivi Mäntylä, Ulvi Gursoy, Kirsi Sipilä, Venla Kurra, Laura Kotaniemi-Talonen, Outi Uimari, Taru Tukiainen, Niko Välimäki, Janet Kumar, Juha Mehtonen, Shabbeer Hassan, Pietro Della Briotta Parolo, Mutaamba Maasha, Javier Garcia-Tabuenca, Jiwoo Lee, Kristin Tsuo, Nina Pitkänen, Eero Punkka, Huei-Yi Shen, Mervi Aavikko, L. Elisa Lahtela, Timo P. Sipilä, Awaisa Ghazal, Sami Koskelainen, Teemu Paajanen, Shuang Luo, Tiina Luukkaala, Iida Vähätalo, Tero Jyrhämä, Marco Hautalahti, Tom Southerington, Jaana Suvisaari, Zhihao Ding, Qingqin S Li, Amy Hart, Rodosthenis S Rodosthenous, Mari E K Niemi, Merja Perala, Perttu Terho, Theresa Knopp, Enni M Makkonen, Paula Nurmi, Pauli Wihuri, Corianna Moffatt, Paolo Martini, Laura Germine, Viola A Makela, Oona A Karhunen, Tero S Hiekkalinna, Alessandro Porello, Anastasia Kytölä, Antti Aarnisalo, Aoxing Liu, Argyro Bizaki-Vallaskangas, Auli Toivola, Debby Ngo, Dermot Reilly, Ekaterina Khramtsova, Elisa Rahikkala, Eric Green, Eveliina Salminen, Fabiana Farias, George Okafo, Heidi Silven, Heli Salminen-Mankonen, Henna Palin, Iiris Hovatta, Jaakko Tyrmi, Jae-Hoon Sul, Jenni Aittokallio, Jyrki Pitkänen, Karen He, Katriina Aalto-Setälä, Maarit Niinimäki, Malla-Maria Linna, Marc Jung, Margaret G. Ehm, Marianna Niemi, Meijian Guan, Mike Mendelson, Minna Brunfeldt, Natalia Pujol, Nathan Lawless, Oluwaseun Alexander Dada, Rigbe Weldatsadik, Riikka Arffman, Rion Pendergrass, Sahar Mozaffari, Samuel Lessard, Sanna Siltanen, Shanmukha Sampath Padmanabhuni, Simonne Longerich, Susanna Savukoski, Thomas Damm Als, Timo Hiltunen, Tomi P. Mäkelä, Triin Laisk, Tytti Willberg, and Varpu Jokimaa
Subjects: Medicine
Abstract: Objectives To recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform.Design Biobank-based recontacting pilot study.Setting Three Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021.Participants All eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s).Outcome measures The primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies.Results The overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18–69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92.Conclusion In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.
Published: 2022
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19. Editorial: Can population health be personalized? Estonia and Finland as examples

Author: Helena Kääriäinen, Andres Metspalu, and Markus Perola
Subjects: biobanks, population health, genomics, early diagnostics, health promotion, Genetics, QH426-470
Published: 2022
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20. Economic evaluation of using polygenic risk score to guide risk screening and interventions for the prevention of type 2 diabetes in individuals with high overall baseline risk

Author: Janne Martikainen, Aku-Ville Lehtimäki, Kari Jalkanen, Piia Lavikainen, Teemu Paajanen, Heidi Marjonen, Kati Kristiansson, Jaana Lindström, and Markus Perola
Subjects: type 2 diabetes, prevention, polygenic risk score, cost-effectiveness, QALY, Genetics, QH426-470
Abstract: Type 2 diabetes (T2D) with increasing prevalence is a significant global public health challenge. Obesity, unhealthy diet, and low physical activity are one of the major determinants of the rise in T2D prevalence. In addition, family history and genetic risk of diabetes also play a role in the process of developing T2D. Therefore, solutions for the early identification of individuals at high risk for T2D for early targeted detection of T2D, prevention, and intervention are highly preferred. Recently, novel genomic-based polygenic risk scores (PRSs) have been suggested to improve the accuracy of risk prediction supporting the targeting of preventive interventions to those at highest risk for T2D. Therefore, the aim of the present study was to assess the cost-utility of an additional PRS testing information (as a part of overall risk assessment) followed by a lifestyle intervention and an additional medical therapy when estimated 10-year overall risk for T2D exceeded 20% among Finnish individuals screened as at the high-risk category (i.e., 10%–20% 10-year overall risk of T2D) based on traditional risk factors only. For a cost-utility analysis, an individual-level state-transition model with probabilistic sensitivity analysis was constructed. A 1-year cycle length and a lifetime time horizon were applied in the base-case. A 3% discount rate was used for costs and QALYs. Cost-effectiveness acceptability curve (CEAC) and estimates for the expected value of perfect information (EVPI) were calculated to assist decision makers. The use of the targeted PRS strategy reclassified 12.4 percentage points of individuals to be very high-risk individuals who would have been originally classified as high risk using the usual strategy only. Over a lifetime horizon, the targeted PRS was a dominant strategy (i.e., less costly, more effective). One-way and scenario sensitivity analyses showed that results remained dominant in almost all simulations. However, there is uncertainty, since the probability (EVPI) of cost-effectiveness at a WTP of 0€/QALY was 63.0% (243€) indicating the probability that the PRS strategy is a dominant option. In conclusion, the results demonstrated that the PRS provides moderate additional value in Finnish population in risk screening leading to potential cost savings and better quality of life when compared with the current screening methods for T2D risk.
Published: 2022
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21. A Dynamic Aspartate‐to‐Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease

Author: Fredrik Åberg, Christopher J. Danford, Maja Thiele, Mats Talbäck, Ditlev Nytoft Rasmussen, Z. Gordon Jiang, Niklas Hammar, Patrik Nasr, Mattias Ekstedt, Anna But, Pauli Puukka, Aleksander Krag, Jouko Sundvall, Iris Erlund, Veikko Salomaa, Per Stål, Stergios Kechagias, Rolf Hultcrantz, Michelle Lai, Nezam Afdhal, Antti Jula, Satu Männistö, Annamari Lundqvist, Markus Perola, Martti Färkkilä, and Hannes Hagström
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: The aspartate‐to‐alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver‐related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population‐based health‐examination surveys (FINRISK, 2002‐2012; n = 18,067) with linked registry data for incident liver‐related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver‐related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol‐related liver disease (ALD). The dynamic AAR model predicted liver‐related outcomes both overall (optimism‐corrected C‐statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver‐related outcomes within 10 years. In independent cohorts, the C‐statistic for predicting liver‐related outcomes up to a 10‐year follow‐up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area‐under‐the‐curve (AUC) for detecting prevalent cirrhosis was 0.80‐0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C‐statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.
Published: 2021
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22. Taxonomic signatures of cause-specific mortality risk in human gut microbiome

Author: Aaro Salosensaari, Ville Laitinen, Aki S. Havulinna, Guillaume Meric, Susan Cheng, Markus Perola, Liisa Valsta, Georg Alfthan, Michael Inouye, Jeramie D. Watrous, Tao Long, Rodolfo A. Salido, Karenina Sanders, Caitriona Brennan, Gregory C. Humphrey, Jon G. Sanders, Mohit Jain, Pekka Jousilahti, Veikko Salomaa, Rob Knight, Leo Lahti, and Teemu Niiranen
Subjects: Science
Abstract: Gut microbiome composition has a role in health and disease. Here the authors show that microbiome signatures related to the Enterobacteriaceae family are associated with cause-specific mortality risk in a well phenotyped Finish population over a 15-year follow-up.
Published: 2021
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23. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)
Subjects: Science
Abstract: Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
Published: 2021
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24. Psychosocial Effects of Receiving Genome-Wide Polygenic Risk Information Concerning Type 2 Diabetes and Coronary Heart Disease: A Randomized Controlled Trial

Author: Otto Halmesvaara, Marleena Vornanen, Helena Kääriäinen, Markus Perola, Kati Kristiansson, and Hanna Konttinen
Subjects: polygenic risk, type 2 diabetes, coronary heart disease, Emotions, randomized controlled Trial, Genetics, QH426-470
Abstract: Receiving polygenic risk estimates of future disease through health care or direct-to-consumer companies is expected to become more common in the coming decades. However, only a limited number of studies have examined if such estimates might evoke an adverse psychosocial reaction in receivers. The present study utilized data from a sub-section of a personalized medicine project (the P5 study) that combines genomic and traditional health data to evaluate participants’ risk for certain common diseases. We investigated how communication of future disease risk estimates related to type 2 diabetes and coronary heart disease influenced respondents’ risk perception, self-efficacy, disease-related worry, and other emotions. A randomized controlled trial was conducted, where the experimental group (n = 714) received risk estimates based on traditional and polygenic risk factors and the control group (n = 649) based solely on traditional risk factors. On average, higher disease risk was associated with higher perceived risk (ps, 0.06).
Published: 2022
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25. Reaching for Precision Healthcare in Finland via Use of Genomic Data

Author: Tiina Wahlfors, Birgit Simell, Kati Kristiansson, Sirpa Soini, Terhi Kilpi, Marina Erhola, and Markus Perola
Subjects: genomics, public health, evidence-based design, policy and guidelines, multidiciplinary approaches, Genetics, QH426-470
Abstract: Concerns over future healthcare capacity along with continuing demands for sustainability call for novel solutions to improve citizens’ health and wellbeing through effective prevention and improved diagnosis and treatment. Part of the solution to tackle the challenge could be making the most of the exploitation of genomic data in personalized risk assessment, creating new opportunities for data-driven precision prevention and public health. Presently, the utilization of genomic data in the Finnish healthcare system is limited to a few medical specialty areas. To successfully extend the use of genomic information in everyday healthcare, evidence-based and feasible strategies are needed. The national actions that Finland is taking towards this goal are 1) providing scientific evidence for the utility of genomic information for healthcare purposes; 2) evaluating the potential health-economic impact of implementing precision healthcare in Finland; 3) developing a relevant legal framework and infrastructures for the utilization of genomic information; 4) building a national multidisciplinary expert network bringing together relevant professionals and initiatives to achieve consensus among the different stakeholders on specific issues vital for translating genomic data into precision healthcare; 5) building competence and genomic literacy skills among various target groups; and 6) public engagement (informing and educating the public). Taken together, these actions will enable building a roadmap towards the expedient application of genomic data in Finnish healthcare and promoting the health of our citizens.
Published: 2022
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26. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author: Valgerdur Steinthorsdottir, Ralph McGinnis, Nicholas O. Williams, Lilja Stefansdottir, Gudmar Thorleifsson, Scott Shooter, João Fadista, Jon K. Sigurdsson, Kirsi M. Auro, Galina Berezina, Maria-Carolina Borges, Suzannah Bumpstead, Jonas Bybjerg-Grauholm, Irina Colgiu, Vivien A. Dolby, Frank Dudbridge, Stephanie M. Engel, Christopher S. Franklin, Michael L. Frigge, Yr Frisbaek, Reynir T. Geirsson, Frank Geller, Solveig Gretarsdottir, Daniel F. Gudbjartsson, Quaker Harmon, David Michael Hougaard, Tatyana Hegay, Anna Helgadottir, Sigrun Hjartardottir, Tiina Jääskeläinen, Hrefna Johannsdottir, Ingileif Jonsdottir, Thorhildur Juliusdottir, Noor Kalsheker, Abdumadjit Kasimov, John P. Kemp, Katja Kivinen, Kari Klungsøyr, Wai K. Lee, Mads Melbye, Zosia Miedzybrodska, Ashley Moffett, Dilbar Najmutdinova, Firuza Nishanova, Thorunn Olafsdottir, Markus Perola, Fiona Broughton Pipkin, Lucilla Poston, Gordon Prescott, Saedis Saevarsdottir, Damilya Salimbayeva, Paula Juliet Scaife, Line Skotte, Eleonora Staines-Urias, Olafur A. Stefansson, Karina Meden Sørensen, Liv Cecilie Vestrheim Thomsen, Vinicius Tragante, Lill Trogstad, Nigel A. B. Simpson, FINNPEC Consortium, GOPEC Consortium, Tamara Aripova, Juan P. Casas, Anna F. Dominiczak, James J. Walker, Unnur Thorsteinsdottir, Ann-Charlotte Iversen, Bjarke Feenstra, Deborah A. Lawlor, Heather Allison Boyd, Per Magnus, Hannele Laivuori, Nodira Zakhidova, Gulnara Svyatova, Kari Stefansson, and Linda Morgan
Subjects: Science
Abstract: Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.
Published: 2020
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27. An epigenome-wide association study of metabolic syndrome and its components

Author: Marja-Liisa Nuotio, Natalia Pervjakova, Anni Joensuu, Ville Karhunen, Tero Hiekkalinna, Lili Milani, Johannes Kettunen, Marjo-Riitta Järvelin, Pekka Jousilahti, Andres Metspalu, Veikko Salomaa, Kati Kristiansson, and Markus Perola
Subjects: Medicine, Science
Abstract: Abstract The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP —previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10−8). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10−9) and waist circumference (P = 5.21 × 10−9). The previously identified type 2 diabetes–associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10−7). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10−8). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.
Published: 2020
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28. Diabetes is associated with familial idiopathic normal pressure hydrocephalus: a case–control comparison with family members

Author: Joel Räsänen, Joel Huovinen, Ville E. Korhonen, Antti Junkkari, Sami Kastinen, Simo Komulainen, Minna Oinas, Cecilia Avellan, Janek Frantzen, Jaakko Rinne, Antti Ronkainen, Mikko Kauppinen, Kimmo Lönnrot, Markus Perola, Anne M. Koivisto, Anne M. Remes, Hilkka Soininen, Mikko Hiltunen, Seppo Helisalmi, Mitja I. Kurki, Juha E. Jääskeläinen, and Ville Leinonen
Subjects: Normal pressure hydrocephalus, Familial, Comorbidities, Diabetes, Depression, Genetics, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families. Methods Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher’s exact test (two-tailed), the Mann–Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses. Results Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1–12.9, p = 0.030). Conclusions Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.
Published: 2020
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29. A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Author: Ivana Prokić, Lies Lahousse, Maaike de Vries, Jun Liu, Marita Kalaoja, Judith M. Vonk, Diana A. van der Plaat, Cleo C. van Diemen, Ashley van der Spek, Alexandra Zhernakova, Jingyuan Fu, Mohsen Ghanbari, Mika Ala-Korpela, Johannes Kettunen, Aki S. Havulinna, Markus Perola, Veikko Salomaa, Lars Lind, Johan Ärnlöv, Bruno H. C. Stricker, Guy G. Brusselle, H. Marike Boezen, Cornelia M. van Duijn, and Najaf Amin
Subjects: COPD, Metabolomics, Mendelian randomization, Glycoprotein acetyls, Biomarkers, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. Methods We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. Results There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20). Conclusions Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.
Published: 2020
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30. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author: Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. Biggs, Heather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Stefan Gross, Daníel F. Guðbjartsson, Rebecca Gutmann, Christopher M. Haggerty, Pim van der Harst, Craig L. Hyde, Erik Ingelsson, J. Wouter Jukema, Maryam Kavousi, Kay-Tee Khaw, Marcus E. Kleber, Lars Køber, Andrea Koekemoer, Claudia Langenberg, Lars Lind, Cecilia M. Lindgren, Barry London, Luca A. Lotta, Ruth C. Lovering, Jian’an Luan, Patrik Magnusson, Anubha Mahajan, Kenneth B. Margulies, Winfried März, Olle Melander, Ify R. Mordi, Thomas Morgan, Andrew D. Morris, Andrew P. Morris, Alanna C. Morrison, Michael W. Nagle, Christopher P. Nelson, Alexander Niessner, Teemu Niiranen, Michelle L. O’Donoghue, Anjali T. Owens, Colin N. A. Palmer, Helen M. Parry, Markus Perola, Eliana Portilla-Fernandez, Bruce M. Psaty, Regeneron Genetics Center, Kenneth M. Rice, Paul M. Ridker, Simon P. R. Romaine, Jerome I. Rotter, Perttu Salo, Veikko Salomaa, Jessica van Setten, Alaa A. Shalaby, Diane T. Smelser, Nicholas L. Smith, Steen Stender, David J. Stott, Per Svensson, Mari-Liis Tammesoo, Kent D. Taylor, Maris Teder-Laving, Alexander Teumer, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Christian Torp-Pedersen, Stella Trompet, Benoit Tyl, Andre G. Uitterlinden, Abirami Veluchamy, Uwe Völker, Adriaan A. Voors, Xiaosong Wang, Nicholas J. Wareham, Dawn Waterworth, Peter E. Weeke, Raul Weiss, Kerri L. Wiggins, Heming Xing, Laura M. Yerges-Armstrong, Bing Yu, Faiez Zannad, Jing Hua Zhao, Harry Hemingway, Nilesh J. Samani, John J. V. McMurray, Jian Yang, Peter M. Visscher, Christopher Newton-Cheh, Anders Malarstig, Hilma Holm, Steven A. Lubitz, Naveed Sattar, Michael V. Holmes, Thomas P. Cappola, Folkert W. Asselbergs, Aroon D. Hingorani, Karoline Kuchenbaecker, Patrick T. Ellinor, Chim C. Lang, Kari Stefansson, J. Gustav Smith, Ramachandran S. Vasan, Daniel I. Swerdlow, and R. Thomas Lumbers
Subjects: Science
Abstract: Heart failure is a complex syndrome that is associated with many different underlying risk factors. Here, to increase power, the authors jointly analyse cases of heart failure of different aetiologies in a genome-wide association study and identify 11 loci of which ten had not been previously reported.
Published: 2020
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31. Feasibility study of using high-throughput drug sensitivity testing to target recurrent glioblastoma stem cells for individualized treatment

Author: Erlend Skaga, Evgeny Kulesskiy, Marit Brynjulvsen, Cecilie J. Sandberg, Swapnil Potdar, Iver A. Langmoen, Aki Laakso, Emília Gaál-Paavola, Markus Perola, Krister Wennerberg, and Einar O. Vik-Mo
Subjects: Glioblastoma, Recurrent glioblastoma, Glioblastoma stem cells, High-throughput drug screening, Drug sensitivity and resistance testing, Individualized medicine, Medicine (General), R5-920
Abstract: Abstract Background Despite the well described heterogeneity in glioblastoma (GBM), treatment is standardized, and clinical trials investigate treatment effects at population level. Genomics-driven oncology for stratified treatments allow clinical decision making in only a small minority of screened patients. Addressing tumor heterogeneity, we aimed to establish a clinical translational protocol in recurrent GBM (recGBM) utilizing autologous glioblastoma stem cell (GSC) cultures and automated high-throughput drug sensitivity and resistance testing (DSRT) for individualized treatment within the time available for clinical application. Results From ten patients undergoing surgery for recGBM, we established individual cell cultures and characterized the GSCs by functional assays. 7/10 GSC cultures could be serially expanded. The individual GSCs displayed intertumoral differences in their proliferative capacity, expression of stem cell markers and variation in their in vitro and in vivo morphology. We defined a time frame of 10 weeks from surgery to complete the entire pre-clinical work-up; establish individualized GSC cultures, evaluate drug sensitivity patterns of 525 anticancer drugs, and identify options for individualized treatment. Within the time frame for clinical translation 5/7 cultures reached sufficient cell yield for complete drug screening. The DSRT revealed significant intertumoral heterogeneity to anticancer drugs (p
Published: 2019
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32. Metabolic Biomarker Discovery for Risk of Peripheral Artery Disease Compared With Coronary Artery Disease: Lipoprotein and Metabolite Profiling of 31 657 Individuals From 5 Prospective Cohorts

Author: Emmi Tikkanen, Vilma Jägerroos, Michael V. Holmes, Naveed Sattar, Mika Ala‐Korpela, Pekka Jousilahti, Annamari Lundqvist, Markus Perola, Veikko Salomaa, and Peter Würtz
Subjects: biomarker, coronary artery disease, magnetic resonance spectroscopy, metabolomics, peripheral artery disease, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Peripheral artery disease (PAD) and coronary artery disease (CAD) represent atherosclerosis in different vascular beds. We used detailed metabolic biomarker profiling to identify common and discordant biomarkers and clarify pathophysiological differences for these vascular diseases. Methods and Results We used 5 prospective cohorts from Finnish population (FINRISK 1997, 2002, 2007, and 2012, and Health 2000; n=31 657; median follow‐up time of 14 years) to estimate associations between >200 metabolic biomarkers and incident PAD and CAD. Metabolic biomarkers were measured with nuclear magnetic resonance, and disease events were obtained from nationwide hospital records. During the follow‐up, 498 incident PAD and 2073 incident CAD events occurred. In age‐ and sex‐adjusted Cox models, apolipoproteins and cholesterol measures were robustly associated with incident CAD (eg, hazard ratio [HR] per SD for higher apolipoprotein B/A‐1 ratio, 1.30; 95% CI, 1.25–1.36), but not with incident PAD (HR per SD for higher apolipoprotein B/A‐1 ratio, 1.04; 95% CI, 0.95–1.14; Pheterogeneity0.05). Lower proportion of polyunsaturated fatty acids relative to total fatty acids, and higher concentrations of monounsaturated fatty acids, glycolysis‐related metabolites, and inflammatory protein markers were strongly associated with incident PAD, and many of these associations were stronger for PAD than for CAD (Pheterogeneity
Published: 2021
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33. Sleep apnoea is a risk factor for severe COVID-19

Author: Riitta Kaarteenaho, Nina Hautala, Athena Matakidou, Jaakko Kaprio, Ying Wu, Kai Kaarniranta, Peeter Karihtala, Kari Pulkki, Wei Zhou, Caroline Fox, Jussi Pihlajamäki, Apinya Lertratanakul, Juha Paloneva, Johannes Kettunen, Marita Kalaoja, Markus Perola, Veikko Salomaa, Hilkka Soininen, Mika Kähönen, Hao Chen, Andrey Loboda, Soumitra Ghosh, Anders Mälarstig, Markku Laakso, Marja Luodonpää, Markus Juonala, Xing Chen, Marika Crohns, Juhani Junttila, Sirkku Peltonen, Keith Usiskin, Juha Sinisalo, Aarno Palotie, Samuli Ripatti, Oili Kaipiainen-Seppänen, Aki Havulinna, Satu Strausz, Tuomo Kiiskinen, Martin Broberg, Sanni Ruotsalainen, Jukka Koskela, Adel Bachour, Tuula Palotie, Hanna M. Ollila, Mark Daly, Howard Jacob, Heiko Runz, Sally John, Robert Plenge, Mark McCarthy, Julie Hunkapiller, Meg Ehm, Dawn Waterworth, Kathy Klinger, Kathy Call, Tomi Mäkelä, Petri Virolainen, Terhi Kilpi, Jukka Partanen, Anne Pitkäranta, Seppo Vainio, Kimmo Savinainen, Veli-Matti Kosma, Urho Kujala, Outi Tuovila, Minna Hendolin, Raimo Pakkanen, Jeff Waring, States Bridget Riley-Gillis, Jimmy Liu, Shameek Biswas, Dorothee Diogo, Anders Pfizer, Catherine Marshall, Xinli Hu, Matthias Gossel, Johanna Schleutker, Mikko Arvas, Olli Carpen, Reetta Hinttala, Reijo Laaksonen, Arto Mannermaa, Valtteri Julkunen, Anne Remes, Reetta Kälviäinen, Mikko Hiltunen, Jukka Peltola, Pentti Tienari, Juha Rinne, Adam Ziemann, Jeffrey Waring, Sahar Esmaeeli, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Sanni Lahdenperä, John Michon, Geoff Kerchner, Natalie Bowers, Edmond Teng, John Merck, Vinay Mehta, Padhraig Gormley, Kari Linden, Christopher Whelan, Fanli Xu, David Pulford, Martti Färkkilä, Sampsa Pikkarainen, Airi Jussila, Timo Blomster, Mikko Kiviniemi, Markku Voutilainen, Bob Georgantas, Graham Heap, Fedik Rahimov, Joseph Maranville, Tim Lu, Danny Oh, Kirsi Kalpala, Melissa Miller, Linda McCarthy, Kari Eklund, Antti Palomäki, Pia Isomäki, Laura Pirilä, Johanna Huhtakangas, David Close, Marla Hochfeld, Nan Bing, Jorge Esparza Gordillo, Nina Mars, Tarja Laitinen, Margit Pelkonen, Paula Kauppi, Hannu Kankaanranta, Terttu Harju, Steven GreenbergCelgene, Hubert Chen, Jo Betts, Teemu Niiranen, Kaj Metsärinne, Marja-Riitta Taskinen, Tiinamaija Tuomi, Jari Laukkanen, Andrew Peterson Ben Challis, Audrey Chu, Jaakko Parkkinen, Anthony Muslin, Heikki Joensuu, Tuomo Meretoja, Lauri Aaltonen, Annika Auranen, Saila Kauppila, Päivi Auvinen, Klaus Elenius, Relja Popovic, Bridget Riley-Gillis, Jennifer Schutzman, Aparna Chhibber, Heli Lehtonen, Stefan McDonough, Diptee Kulkarni, Joni Turunen, Terhi Ollila, Sanna Seitsonen, Hannu Uusitalo, Vesa Aaltonen, Hannele Uusitalo-Järvinen, Erich Strauss, Anna Podgornaia, Joshua Hoffman, Kaisa Tasanen, Laura Huilaja, Katariina Hannula-Jouppi, Teea Salmi, Leena Koulu, Ilkka Harvima, David Choy, Anu Jalanko, Risto Kajanne, Ulrike Lyhs, Mari Kaunisto, Justin Davis, Danjuma Quarless, Slavé Petrovski, Chia-Yen Chen, Paola Bronson, Robert Yang, Diana Chang, Tushar Bhangale, Emily Holzinger, Xulong Wang, Åsa Hedman, Kirsi Auro, Clarence Wang, Ethan Xu, Franck Auge, Clement Chatelain, Mitja Kurki, Juha Karjalainen, Kimmo Palin, Priit Palta, Pietro Della, Susanna Lemmelä, Manuel Rivas, Jarmo Harju, Arto Lehisto, Andrea Ganna, Vincent Llorens, Antti Karlsson, Kati Kristiansson, Kati Hyvärinen, Jarmo Ritari, Tiina Wahlfors, Miika Koskinen, Katri Pylkäs, Minna Karjalainen, Tuomo Mantere, Eeva Kangasniemi, Sami Heikkinen, Eija Laakkonen, Juha Kononen, Anu Loukola, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Hannele Mattsson, Tero Hiekkalinna, Manuel Jiménez, Kati Donner, Kalle Pärn, Javier Nunez-Fontarnau, Elina Kilpeläinen, Timo Sipilä, Georg Brein, Alexander Dada, Ghazal Awaisa, Anastasia Shcherban, Tuomas Sipilä, Hannele Laivuori, Harri Siirtola, Javier Tabuenca, Lila Kallio, Sirpa Soini, Kimmo Pitkänen, and Teijo Kuopio
Subjects: Medicine, Diseases of the respiratory system, RC705-779
Abstract: Background Obstructive sleep apnoea (OSA) is associated with higher body mass index (BMI), diabetes, older age and male gender, which are all risk factors for severe COVID-19.We aimed to study if OSA is an independent risk factor for COVID-19 infection or for severe COVID-19.Methods OSA diagnosis and COVID-19 infection were extracted from the hospital discharge, causes of death and infectious diseases registries in individuals who participated in the FinnGen study (n=260 405). Severe COVID-19 was defined as COVID-19 requiring hospitalisation. Multivariate logistic regression model was used to examine association. Comorbidities for either COVID-19 or OSA were selected as covariates. We performed a meta-analysis with previous studies.Results We identified 445 individuals with COVID-19, and 38 (8.5%) of them with OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19 hospitalisation independent from age, sex, BMI and comorbidities (p-unadjusted=5.13×10−5, OR-adjusted=2.93 (95% CI 1.02 to 8.39), p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19 (p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across 15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021).Conclusion Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19.
Published: 2021
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34. Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke

Author: Jaakko Leskelä, Iiro Toppila, Mari‐Anne Härma, Teemu Palviainen, Aino Salminen, Niina Sandholm, Milla Pietiäinen, Elisa Kopra, Jean‐Paul Pais de Barros, Mariann I. Lassenius, Anmol Kumar, Valma Harjutsalo, Kajsa Roslund, Carol Forsblom, Anu Loukola, Aki S. Havulinna, Laurent Lagrost, Veikko Salomaa, Per‐Henrik Groop, Markus Perola, Jaakko Kaprio, Markku Lehto, and Pirkko J. Pussinen
Subjects: coagulation, contact activation, endotoxin, gene, genome‐wide association study, lipopolysaccharide, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Translocation of lipopolysaccharide from gram‐negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome‐wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high‐performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis‐related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome‐wide significant association with 741 single‐nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included KNG1, KLKB1, F12, SLC34A1, YPEL4, CLP1, ZDHHC5, SERPING1, CBX5, and LIPC. The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism. Conclusions The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.
Published: 2021
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35. A Web Portal for Communicating Polygenic Risk Score Results for Health Care Use—The P5 Study

Author: Heidi Marjonen, Minttu Marttila, Teemu Paajanen, Marleena Vornanen, Minna Brunfeldt, Anni Joensuu, Otto Halmesvaara, Kimmo Aro, Mervi Alanne-Kinnunen, Pekka Jousilahti, Katja Borodulin, Seppo Koskinen, Tiinamaija Tuomi, Pirjo Ilanne-Parikka, Jaana Lindström, Merja K. Laine, Kirsi Auro, Helena Kääriäinen, Markus Perola, and Kati Kristiansson
Subjects: web portal, type 2 diabetes, coronary heart disease, venous thromboembolism, polygenic risk sore, finhealth 2017 study, Genetics, QH426-470
Abstract: We present a method for communicating personalized genetic risk information to citizens and their physicians using a secure web portal. We apply the method for 3,177 Finnish individuals in the P5 Study where estimates of genetic and absolute risk, based on genetic and clinical risk factors, of future disease are reported to study participants, allowing individuals to participate in managing their own health. Our method facilitates using polygenic risk score as a personalized tool to estimate a person’s future disease risk while offering a way for health care professionals to utilize the polygenic risk scores as a preventive tool in patient care.
Published: 2021
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36. Plasma N-glycome shows continuous deterioration as the diagnosis of insulin resistance approaches

Author: Gordan Lauc, Markus Perola, Domagoj Kifer, Olga Gornik, Cristina Menni, Mario Falchi, Massimo Mangino, Ana Cvetko, Marko Tijardović, and Toma Keser
Subjects: Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2021
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37. Substantial Fat Loss in Physique Competitors Is Characterized by Increased Levels of Bile Acids, Very-Long Chain Fatty Acids, and Oxylipins

Author: Heikki V. Sarin, Juha J. Hulmi, Youwen Qin, Michael Inouye, Scott C. Ritchie, Susan Cheng, Jeramie D. Watrous, Thien-Tu C. Nguyen, Joseph H. Lee, Zhezhen Jin, Joseph D. Terwilliger, Teemu Niiranen, Aki Havulinna, Veikko Salomaa, Kirsi H. Pietiläinen, Ville Isola, Juha P. Ahtiainen, Keijo Häkkinen, Mohit Jain, and Markus Perola
Subjects: weight loss, exercise, visceral fat mass, LC-MS metabolome, bioactive metabolites, Microbiology, QR1-502
Abstract: Weight loss and increased physical activity may promote beneficial modulation of the metabolome, but limited evidence exists about how very low-level weight loss affects the metabolome in previously non-obese active individuals. Following a weight loss period (21.1 ± 3.1 weeks) leading to substantial fat mass loss of 52% (−7.9 ± 1.5 kg) and low body fat (12.7 ± 4.1%), the liquid chromatography-mass spectrometry-based metabolic signature of 24 previously young, healthy, and normal weight female physique athletes was investigated. We observed uniform increases (FDR < 0.05) in bile acids, very-long-chain free fatty acids (FFA), and oxylipins, together with reductions in unsaturated FFAs after weight loss. These widespread changes, especially in the bile acid profile, were most strongly explained (FDR < 0.05) by changes in android (visceral) fat mass. The reported changes did not persist, as all of them were reversed after the subsequent voluntary weight regain period (18.4 ± 2.9 weeks) and were unchanged in non-dieting controls (n = 16). Overall, we suggest that the reported changes in FFA, bile acid, and oxylipin profiles reflect metabolic adaptation to very low levels of fat mass after prolonged periods of intense exercise and low-energy availability. However, the effects of the aforementioned metabolome subclass alteration on metabolic homeostasis remain controversial, and more studies are warranted to unravel the complex physiology and potentially associated health implications. In the end, our study reinforced the view that transient weight loss seems to have little to no long-lasting molecular and physiological effects.
Published: 2022
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38. Serum lipopolysaccharides predict advanced liver disease in the general population

Author: Ville Männistö, Martti Färkkilä, Pirkko Pussinen, Antti Jula, Satu Männistö, Annamari Lundqvist, Liisa Valsta, Veikko Salomaa, Markus Perola, and Fredrik Åberg
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Gut-derived endotoxemia has been implicated in the development of chronic liver disease, but its relevance at the population level remains unclear. We analyzed whether endotoxemia is associated with incident advanced liver disease in the general population. Methods: Serum lipopolysaccharide (LPS) was measured in 6,727 (3,455 male and 3,272 female, mean age 53.4 ± 10.9 years, mean body mass index 27.2 ± 4.5) individuals participating in the Finnish population-based health examination survey FINRISK 1997. Data were linked with electronic health registers for incident advanced liver disease (hospitalization, cancer or death related to liver disease). During a mean follow-up of 16.3 ± 3.8 years (109,282 person-years), 86 liver events occurred. Univariate and multivariate Cox regression, and Kaplan-Meier analyses were performed. Results: Serum LPS predicted incident advanced liver disease with a hazard ratio per 1 SD of 1.41 (95% CI 1.24–1.59; p ≪0.001) when adjusted for age, sex, gamma-glutamyltransferase, metabolic syndrome, alcohol use, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M, waist-hip ratio and type 2 diabetes. This association remained robustly significant in additional multivariate analyses with various levels of adjustment. The association was accentuated among carriers of the PNPLA3 risk variant. The population attributable fraction of the highest LPS tertile for liver events was 29.7%. However, LPS was not associated with all-cause mortality. Conclusion: Serum LPS is associated with hospitalization, cancer or death related to liver disease in the general population, with the highest tertile potentially accounting for 30% of the risk of liver disease. Lay summary: Lipopolysaccharide, a gut-derived bacterial endotoxin, has been implicated in the development of chronic liver disease, but its relevance at the population level remains unclear. We found that serum lipopolysaccharide levels were associated with incident advanced liver disease in the general population, with the highest tertile accounting for up to 30% of the risk of hospitalization, cancer or death related to liver disease. Key words: Cirrhosis, Endotoxemia, Genetics, Gut, Hospitalization
Published: 2019
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39. Associations of autozygosity with a broad range of human phenotypes

Author: David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson
Subjects: Science
Abstract: Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
Published: 2019
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40. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals

Author: Joris Deelen, Johannes Kettunen, Krista Fischer, Ashley van der Spek, Stella Trompet, Gabi Kastenmüller, Andy Boyd, Jonas Zierer, Erik B. van den Akker, Mika Ala-Korpela, Najaf Amin, Ayse Demirkan, Mohsen Ghanbari, Diana van Heemst, M. Arfan Ikram, Jan Bert van Klinken, Simon P. Mooijaart, Annette Peters, Veikko Salomaa, Naveed Sattar, Tim D. Spector, Henning Tiemeier, Aswin Verhoeven, Melanie Waldenberger, Peter Würtz, George Davey Smith, Andres Metspalu, Markus Perola, Cristina Menni, Johanna M. Geleijnse, Fotios Drenos, Marian Beekman, J. Wouter Jukema, Cornelia M. van Duijn, and P. Eline Slagboom
Subjects: Science
Abstract: Biomarkers that predict mortality are of interest for clinical as well as research applications. Here, the authors analyze metabolomics data from 44,168 individuals and identify key metabolites independently associated with all-cause mortality risk.
Published: 2019
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41. Intertumoral heterogeneity in patient-specific drug sensitivities in treatment-naïve glioblastoma

Author: Erlend Skaga, Evgeny Kulesskiy, Artem Fayzullin, Cecilie J. Sandberg, Swapnil Potdar, Aija Kyttälä, Iver A. Langmoen, Aki Laakso, Emília Gaál-Paavola, Markus Perola, Krister Wennerberg, and Einar O. Vik-Mo
Subjects: Glioblastoma, Glioblastoma stem cells, High-throughput drug screening, Individualized medicine, Drug sensitivity, Functional precision medicine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear. Methods We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation. Results Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p
Published: 2019
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42. Changes in the fine-scale genetic structure of Finland through the 20th century.

Author: Sini Kerminen, Nicola Cerioli, Darius Pacauskas, Aki S Havulinna, Markus Perola, Pekka Jousilahti, Veikko Salomaa, Mark J Daly, Rupesh Vyas, Samuli Ripatti, and Matti Pirinen
Subjects: Genetics, QH426-470
Abstract: Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results.
Published: 2021
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43. Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma.

Author: Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Guhan Venkataraman, Susanna Lemmelä, Joni A Turunen, Robert R Graham, Aki S Havulinna, Markus Perola, Aarno Palotie, FinnGen, Mark J Daly, and Manuel A Rivas
Subjects: Genetics, QH426-470
Abstract: Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10-9 and 1.07 x 10-13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10-12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.
Published: 2020
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44. Correction: Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

Author: Johannes Kettunen, Michael V Holmes, Elias Allara, Olga Anufrieva, Pauli Ohukainen, Clare Oliver-Williams, Qin Wang, Therese Tillin, Alun D Hughes, Mika Kähönen, Terho Lehtimäki, Jorma Viikari, Olli T Raitakari, Veikko Salomaa, Marjo-Riitta Järvelin, Markus Perola, George Davey Smith, Nish Chaturvedi, John Danesh, Emanuele Di Angelantonio, Adam S Butterworth, and Mika Ala-Korpela
Subjects: Biology (General), QH301-705.5
Abstract: [This corrects the article DOI: 10.1371/journal.pbio.3000572.].
Published: 2020
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45. Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

Author: Johannes Kettunen, Michael V Holmes, Elias Allara, Olga Anufrieva, Pauli Ohukainen, Clare Oliver-Williams, Qin Wang, Therese Tillin, Alun D Hughes, Mika Kähönen, Terho Lehtimäki, Jorma Viikari, Olli T Raitakari, Veikko Salomaa, Marjo-Riitta Järvelin, Markus Perola, George Davey Smith, Nish Chaturvedi, John Danesh, Emanuele Di Angelantonio, Adam S Butterworth, and Mika Ala-Korpela
Subjects: Biology (General), QH301-705.5
Abstract: Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.
Published: 2019
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46. Mendelian randomisation analysis of clustered causal effects of body mass on cardiometabolic biomarkers

Author: Susana Conde, Xiaoguang Xu, Hui Guo, Markus Perola, Teresa Fazia, Luisa Bernardinelli, and Carlo Berzuini
Subjects: Cardiovascular disease, Causal inference, Egger regression, Metabolomics, Multiple instrumental variables, Weighted median estimator, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract: Abstract Background Recent advances in data analysis methods based on principles of Mendelian Randomisation, such as Egger regression and the weighted median estimator, add to the researcher’s ability to infer cause-effect links from observational data. Now is the time to gauge the potential of these methods within specific areas of biomedical research. In this paper, we choose a study in metabolomics as an illustrative testbed. We apply Mendelian Randomisation methods in the analysis of data from the DILGOM (Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome) study, in the context of an effort to identify molecular pathways of cardiovascular disease. In particular, our illustrative analysis addresses the question whether body mass, as measured by body mass index (BMI), exerts a causal effect on the concentrations of a collection of 137 cardiometabolic markers with different degrees of atherogenic power, such as the (highly atherogenic) lipoprotein metabolites with very low density (VLDLs) and the (protective) high density lipoprotein metabolites. Results We found strongest evidence of a positive BMI effect (that is, evidence that an increase in BMI causes an increase in the metabolite concentration) on those metabolites known to represent strong risk factors for coronary artery disease, such as the VLDLs, and evidence of a negative effect on protective biomarkers. Conclusions The methods discussed represent a useful scientific tool, although they assume the validity of conditions that are (at best) only partially verifiable. This paper provides a rigorous account of such conditions. The results of our analysis provide a proof-of-concept illustration of the potential usefulness of Mendelian Randomisation in genomic biobank studies aiming to dissect the molecular causes of disease, and to identify candidate pharmacological targets.
Published: 2018
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47. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)
Subjects: Science
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3
Published: 2021
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48. Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Author: M. Carola Zillikens, Serkalem Demissie, Yi-Hsiang Hsu, Laura M. Yerges-Armstrong, Wen-Chi Chou, Lisette Stolk, Gregory Livshits, Linda Broer, Toby Johnson, Daniel L. Koller, Zoltán Kutalik, Jian’an Luan, Ida Malkin, Janina S. Ried, Albert V. Smith, Gudmar Thorleifsson, Liesbeth Vandenput, Jing Hua Zhao, Weihua Zhang, Ali Aghdassi, Kristina Åkesson, Najaf Amin, Leslie J. Baier, Inês Barroso, David A. Bennett, Lars Bertram, Rainer Biffar, Murielle Bochud, Michael Boehnke, Ingrid B. Borecki, Aron S. Buchman, Liisa Byberg, Harry Campbell, Natalia Campos Obanda, Jane A. Cauley, Peggy M. Cawthon, Henna Cederberg, Zhao Chen, Nam H. Cho, Hyung Jin Choi, Melina Claussnitzer, Francis Collins, Steven R. Cummings, Philip L. De Jager, Ilja Demuth, Rosalie A. M. Dhonukshe-Rutten, Luda Diatchenko, Gudny Eiriksdottir, Anke W. Enneman, Mike Erdos, Johan G. Eriksson, Joel Eriksson, Karol Estrada, Daniel S. Evans, Mary F. Feitosa, Mao Fu, Melissa Garcia, Christian Gieger, Thomas Girke, Nicole L. Glazer, Harald Grallert, Jagvir Grewal, Bok-Ghee Han, Robert L. Hanson, Caroline Hayward, Albert Hofman, Eric P. Hoffman, Georg Homuth, Wen-Chi Hsueh, Monica J. Hubal, Alan Hubbard, Kim M. Huffman, Lise B. Husted, Thomas Illig, Erik Ingelsson, Till Ittermann, John-Olov Jansson, Joanne M. Jordan, Antti Jula, Magnus Karlsson, Kay-Tee Khaw, Tuomas O. Kilpeläinen, Norman Klopp, Jacqueline S. L. Kloth, Heikki A. Koistinen, William E. Kraus, Stephen Kritchevsky, Teemu Kuulasmaa, Johanna Kuusisto, Markku Laakso, Jari Lahti, Thomas Lang, Bente L. Langdahl, Lenore J. Launer, Jong-Young Lee, Markus M. Lerch, Joshua R. Lewis, Lars Lind, Cecilia Lindgren, Yongmei Liu, Tian Liu, Youfang Liu, Östen Ljunggren, Mattias Lorentzon, Robert N. Luben, William Maixner, Fiona E. McGuigan, Carolina Medina-Gomez, Thomas Meitinger, Håkan Melhus, Dan Mellström, Simon Melov, Karl Michaëlsson, Braxton D. Mitchell, Andrew P. Morris, Leif Mosekilde, Anne Newman, Carrie M. Nielson, Jeffrey R. O’Connell, Ben A. Oostra, Eric S. Orwoll, Aarno Palotie, Stephen C. J. Parker, Munro Peacock, Markus Perola, Annette Peters, Ozren Polasek, Richard L. Prince, Katri Räikkönen, Stuart H. Ralston, Samuli Ripatti, John A. Robbins, Jerome I. Rotter, Igor Rudan, Veikko Salomaa, Suzanne Satterfield, Eric E. Schadt, Sabine Schipf, Laura Scott, Joban Sehmi, Jian Shen, Chan Soo Shin, Gunnar Sigurdsson, Shad Smith, Nicole Soranzo, Alena Stančáková, Elisabeth Steinhagen-Thiessen, Elizabeth A. Streeten, Unnur Styrkarsdottir, Karin M. A. Swart, Sian-Tsung Tan, Mark A. Tarnopolsky, Patricia Thompson, Cynthia A. Thomson, Unnur Thorsteinsdottir, Emmi Tikkanen, Gregory J. Tranah, Jaakko Tuomilehto, Natasja M. van Schoor, Arjun Verma, Peter Vollenweider, Henry Völzke, Jean Wactawski-Wende, Mark Walker, Michael N. Weedon, Ryan Welch, H.-Erich Wichmann, Elisabeth Widen, Frances M. K. Williams, James F. Wilson, Nicole C. Wright, Weijia Xie, Lei Yu, Yanhua Zhou, John C. Chambers, Angela Döring, Cornelia M. van Duijn, Michael J. Econs, Vilmundur Gudnason, Jaspal S. Kooner, Bruce M. Psaty, Timothy D. Spector, Kari Stefansson, Fernando Rivadeneira, André G. Uitterlinden, Nicholas J. Wareham, Vicky Ossowski, Dawn Waterworth, Ruth J. F. Loos, David Karasik, Tamara B. Harris, Claes Ohlsson, and Douglas P. Kiel
Subjects: Science
Abstract: A correction to this article has been published and is linked from the HTML version of this article.
Published: 2017
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49. Fine-Scale Genetic Structure in Finland

Author: Sini Kerminen, Aki S. Havulinna, Garrett Hellenthal, Alicia R. Martin, Antti-Pekka Sarin, Markus Perola, Aarno Palotie, Veikko Salomaa, Mark J. Daly, Samuli Ripatti, and Matti Pirinen
Subjects: population genetics, population structure, haplotype sharing, Genetics, QH426-470
Abstract: Coupling dense genotype data with new computational methods offers unprecedented opportunities for individual-level ancestry estimation once geographically precisely defined reference data sets become available. We study such a reference data set for Finland containing 2376 such individuals from the FINRISK Study survey of 1997 both of whose parents were born close to each other. This sampling strategy focuses on the population structure present in Finland before the 1950s. By using the recent haplotype-based methods ChromoPainter (CP) and FineSTRUCTURE (FS) we reveal a highly geographically clustered genetic structure in Finland and report its connections to the settlement history as well as to the current dialectal regions of the Finnish language. The main genetic division within Finland shows striking concordance with the 1323 borderline of the treaty of Nöteborg. In general, we detect genetic substructure throughout the country, which reflects stronger regional genetic differences in Finland compared to, for example, the UK, which in a similar analysis was dominated by a single unstructured population. We expect that similar population genetic reference data sets will become available for many more populations in the near future with important applications, for example, in forensic genetics and in genetic association studies. With this in mind, we report those extensions of the CP + FS approach that we found most useful in our analyses of the Finnish data.
Published: 2017
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50. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Author: Aurélien Macé, Marcus A. Tuke, Patrick Deelen, Kati Kristiansson, Hannele Mattsson, Margit Nõukas, Yadav Sapkota, Ursula Schick, Eleonora Porcu, Sina Rüeger, Aaron F. McDaid, David Porteous, Thomas W. Winkler, Erika Salvi, Nick Shrine, Xueping Liu, Wei Q. Ang, Weihua Zhang, Mary F. Feitosa, Cristina Venturini, Peter J. van der Most, Anders Rosengren, Andrew R. Wood, Robin N. Beaumont, Samuel E. Jones, Katherine S. Ruth, Hanieh Yaghootkar, Jessica Tyrrell, Aki S. Havulinna, Harmen Boers, Reedik Mägi, Jennifer Kriebel, Martina Müller-Nurasyid, Markus Perola, Markku Nieminen, Marja-Liisa Lokki, Mika Kähönen, Jorma S. Viikari, Frank Geller, Jari Lahti, Aarno Palotie, Päivikki Koponen, Annamari Lundqvist, Harri Rissanen, Erwin P. Bottinger, Saima Afaq, Mary K. Wojczynski, Petra Lenzini, Ilja M. Nolte, Thomas Sparsø, Nicole Schupf, Kaare Christensen, Thomas T. Perls, Anne B. Newman, Thomas Werge, Harold Snieder, Timothy D. Spector, John C. Chambers, Seppo Koskinen, Mads Melbye, Olli T. Raitakari, Terho Lehtimäki, Martin D. Tobin, Louise V. Wain, Juha Sinisalo, Annette Peters, Thomas Meitinger, Nicholas G. Martin, Naomi R. Wray, Grant W. Montgomery, Sarah E. Medland, Morris A. Swertz, Erkki Vartiainen, Katja Borodulin, Satu Männistö, Anna Murray, Murielle Bochud, Sébastien Jacquemont, Fernando Rivadeneira, Thomas F. Hansen, Albertine J. Oldehinkel, Massimo Mangino, Michael A. Province, Panos Deloukas, Jaspal S. Kooner, Rachel M. Freathy, Craig Pennell, Bjarke Feenstra, David P. Strachan, Guillaume Lettre, Joel Hirschhorn, Daniele Cusi, Iris M. Heid, Caroline Hayward, Katrin Männik, Jacques S. Beckmann, Ruth J. F. Loos, Dale R. Nyholt, Andres Metspalu, Johan G. Eriksson, Michael N. Weedon, Veikko Salomaa, Lude Franke, Alexandre Reymond, Timothy M. Frayling, and Zoltán Kutalik
Subjects: Science
Abstract: Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.
Published: 2017
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