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1. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author: Hao Mei, Jeannette Simino, Lianna Li, Fan Jiang, Joshua C. Bis, Gail Davies, W David Hill, Charley Xia, Vilmundur Gudnason, Qiong Yang, Jari Lahti, Jennifer A. Smith, Mirna Kirin, Philip De Jager, Nicola J. Armstrong, Mohsen Ghanbari, Ivana Kolcic, Christopher Moran, Alexander Teumer, Murali Sargurupremraj, Shamsed Mahmud, Myriam Fornage, Wei Zhao, Claudia L. Satizabal, Ozren Polasek, Katri Räikkönen, David C. Liewald, Georg Homuth, Michele Callisaya, Karen A. Mather, B. Gwen Windham, Tatijana Zemunik, Aarno Palotie, Alison Pattie, Sandra van der Auwera, Anbupalam Thalamuthu, David S. Knopman, Igor Rudan, John M. Starr, Katharina Wittfeld, Nicole A. Kochan, Michael E. Griswold, Veronique Vitart, Henry Brodaty, Rebecca Gottesman, Simon R. Cox, Bruce M. Psaty, Eric Boerwinkle, Daniel I. Chasman, Francine Grodstein, Perminder S. Sachdev, Velandai Srikanth, Caroline Hayward, James F. Wilson, Johan G. Eriksson, Sharon L. R. Kardia, Hans J. Grabe, David A. Bennett, M. Arfan Ikram, Ian J. Deary, Cornelia M. van Duijn, Lenore Launer, Annette L. Fitzpatrick, Sudha Seshadri, Jan Bressler, Stephanie Debette, and Thomas H. Mosley
Subjects: Genome-wide association study, Memory, Expression, Immunity, Multi-omics, Delayed recall, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.
Published: 2024
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2. Proteomic associations with forced expiratory volume: a Mendelian randomisation study

Author: Gisli Thor Axelsson, Thorarinn Jonmundsson, Youngjae Woo, Elisabet Alexandra Frick, Thor Aspelund, Joseph J. Loureiro, Anthony P. Orth, Lori L. Jennings, Gunnar Gudmundsson, Valur Emilsson, Valborg Gudmundsdottir, and Vilmundur Gudnason
Subjects: Lung function tests, Forced expiratory volume, Proteomics, Mendelian randomisation, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background A decline in forced expiratory volume (FEV1) is a hallmark of respiratory diseases that are an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1. Methods Data from the population-based AGES-Reykjavik study were used. Serum proteomic measurements were done using 4782 DNA aptamers (SOMAmers). Data from 1479 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional two-sample Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102). Results In observational analyses, 530 SOMAmers were associated with FEV1 after multiple testing adjustment (FDR
Published: 2024
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3. 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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4. User Engagement, Acceptability, and Clinical Markers in a Digital Health Program for Nonalcoholic Fatty Liver Disease: Prospective, Single-Arm Feasibility Study

Author: Sigridur Björnsdottir, Hildigunnur Ulfsdottir, Elias Freyr Gudmundsson, Kolbrun Sveinsdottir, Ari Pall Isberg, Bartosz Dobies, Gudlaug Erla Akerlie Magnusdottir, Thrudur Gunnarsdottir, Tekla Karlsdottir, Gudlaug Bjornsdottir, Sigurdur Sigurdsson, Saemundur Oddsson, and Vilmundur Gudnason
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: BackgroundNonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. Common comorbidities are central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. Cardiovascular disease is the most common cause of death among people with NAFLD, and lifestyle changes can improve health outcomes. ObjectiveThis study aims to explore the acceptability of a digital health program in terms of engagement, retention, and user satisfaction in addition to exploring changes in clinical outcomes, such as weight, cardiometabolic risk factors, and health-related quality of life. MethodsWe conducted a prospective, open-label, single-arm, 12-week study including 38 individuals with either a BMI >30, metabolic syndrome, or type 2 diabetes mellitus and NAFLD screened by FibroScan. An NAFLD-specific digital health program focused on disease education, lowering carbohydrates in the diet, food logging, increasing activity level, reducing stress, and healthy lifestyle coaching was offered to participants. The coach provided weekly feedback on food logs and other in-app activities and opportunities for participants to ask questions. The coaching was active throughout the 12-week intervention period. The primary outcome was feasibility and acceptability of the 12-week program, assessed through patient engagement, retention, and satisfaction with the program. Secondary outcomes included changes in weight, liver fat, body composition, and other cardiometabolic clinical parameters at baseline and 12 weeks. ResultsIn total, 38 individuals were included in the study (median age 59.5, IQR 46.3-68.8 years; n=23, 61% female). Overall, 34 (89%) participants completed the program and 29 (76%) were active during the 12-week program period. The median satisfaction score was 6.3 (IQR 5.8-6.7) of 7. Mean weight loss was 3.5 (SD 3.7) kg (P
Published: 2024
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5. Association of impaired lung function with dementia and cognitive function: The AGES-Reykjavik Study

Author: Yume Imahori, Djass Mbangdadji, Vilmundur Gudnason, Chengxuan Qiu, and Lenore Launer
Subjects: Specialties of internal medicine, RC581-951, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Introduction: Emerging evidence has linked impaired lung function with dementia and cognitive decline. However, unlike obstructive lung impairment (e.g., chronic obstructive pulmonary disease (COPD), asthma), the association of preserved ratio impaired spirometry (PRISm) with cognitive function remains under-investigated. We aimed to investigate the association of COPD and PRISm with dementia and cognitive function in older adults. Methods: This population-based study involved 2421 dementia-free participants (age >65 years, mean age 76.3, 57% female) derived from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study who had spirometry data assessed at baseline (2002-2006) and were re-examined in the follow-up (2007-2011). Lung function was categorized as normal, PRISm, and COPD based on spirometry data. Incident dementia cases occurred during the follow-up period through 2015 were ascertained using study examination, nursing home records, hospital records or vital statistic data (median follow-up time=10.3 years; no. of incident dementia cases=650). The association between baseline lung function and incident dementia was investigated using the Cox regression and Fine-Grey competing death risk models. In a subsample (n=1363). We used the linear regression models to investigate baseline lung function in association with function of cognitive domains assessed at follow-up (2007-2011). Results: PRISm (vs. normal lung function) was associated with a multivariable-adjusted hazard ratio of 1.59 (95%CI 1.28-1.97) for incident dementia. The association remained significant even after considering the competing risk due to death. In subsample analysis, baseline PRISm was significantly associated with lower scores of executive function and processing speed at follow-up, while COPD was associated with a lower score of processing speed (p
Published: 2024
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6. Identification of biomarkers for glycaemic deterioration in type 2 diabetes

Author: Roderick C. Slieker, Louise A. Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N. Giordano, Mikael Åkerlund, Emma Ahlqvist, Ashfaq Ali, Karina Banasik, Søren Brunak, Marko Barovic, Gerard A. Bouland, Frédéric Burdet, Mickaël Canouil, Iulian Dragan, Petra J. M. Elders, Celine Fernandez, Andreas Festa, Hugo Fitipaldi, Phillippe Froguel, Valborg Gudmundsdottir, Vilmundur Gudnason, Mathias J. Gerl, Amber A. van der Heijden, Lori L. Jennings, Michael K. Hansen, Min Kim, Isabelle Leclerc, Christian Klose, Dmitry Kuznetsov, Dina Mansour Aly, Florence Mehl, Diana Marek, Olle Melander, Anne Niknejad, Filip Ottosson, Imre Pavo, Kevin Duffin, Samreen K. Syed, Janice L. Shaw, Over Cabrera, Timothy J. Pullen, Kai Simons, Michele Solimena, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido Quigley, Leif Groop, Bernard Thorens, Paul W. Franks, Gareth E. Lim, Jennifer Estall, Mark Ibberson, Joline W. J. Beulens, Leen M ’t Hart, Ewan R. Pearson, and Guy A. Rutter
Subjects: Science
Abstract: Abstract We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
Published: 2023
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7. Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Author: Lisa de las Fuentes, Karen L. Schwander, Michael R. Brown, Amy R. Bentley, Thomas W. Winkler, Yun Ju Sung, Patricia B. Munroe, Clint L. Miller, Hugo Aschard, Stella Aslibekyan, Traci M. Bartz, Lawrence F. Bielak, Jin Fang Chai, Ching-Yu Cheng, Rajkumar Dorajoo, Mary F. Feitosa, Xiuqing Guo, Fernando P. Hartwig, Andrea Horimoto, Ivana Kolčić, Elise Lim, Yongmei Liu, Alisa K. Manning, Jonathan Marten, Solomon K. Musani, Raymond Noordam, Sandosh Padmanabhan, Tuomo Rankinen, Melissa A. Richard, Paul M. Ridker, Albert V. Smith, Dina Vojinovic, Alan B. Zonderman, Maris Alver, Mathilde Boissel, Kaare Christensen, Barry I. Freedman, Chuan Gao, Franco Giulianini, Sarah E. Harris, Meian He, Fang-Chi Hsu, Brigitte Kühnel, Federica Laguzzi, Xiaoyin Li, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Alaitz Poveda, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Tamar Sofer, Fumihiko Takeuchi, Bamidele O. Tayo, Peter J. van der Most, Niek Verweij, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Yiqiang Zhan, Najaf Amin, Dan E. Arking, Christie Ballantyne, Eric Boerwinkle, Jennifer A. Brody, Ulrich Broeckel, Archie Campbell, Mickaël Canouil, Xiaoran Chai, Yii-Der Ida Chen, Xu Chen, Kumaraswamy Naidu Chitrala, Maria Pina Concas, Ulf de Faire, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ahn Do, Jessica D. Faul, Virginia Fisher, James S. Floyd, Terrence Forrester, Yechiel Friedlander, Giorgia Girotto, C. Charles Gu, Göran Hallmans, Sami Heikkinen, Chew-Kiat Heng, Georg Homuth, Steven Hunt, M. Arfan Ikram, David R. Jacobs, Maryam Kavousi, Chiea Chuen Khor, Tuomas O. Kilpeläinen, Woon-Puay Koh, Pirjo Komulainen, Carl D. Langefeld, Jingjing Liang, Kiang Liu, Jianjun Liu, Kurt Lohman, Reedik Mägi, Ani W. Manichaikul, Colin A. McKenzie, Thomas Meitinger, Yuri Milaneschi, Matthias Nauck, Christopher P. Nelson, Jeffrey R. O’Connell, Nicholette D. Palmer, Alexandre C. Pereira, Thomas Perls, Annette Peters, Ozren Polašek, Olli T. Raitakari, Kenneth Rice, Treva K. Rice, Stephen S. Rich, Charumathi Sabanayagam, Pamela J. Schreiner, Xiao-Ou Shu, Stephen Sidney, Mario Sims, Jennifer A. Smith, John M. Starr, Konstantin Strauch, E. Shyong Tai, Kent D. Taylor, Michael Y. Tsai, André G. Uitterlinden, Diana van Heemst, Melanie Waldenberger, Ya-Xing Wang, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Diane M. Becker, Amélie Bonnefond, Donald W. Bowden, Richard S. Cooper, Ian J. Deary, Jasmin Divers, Tõnu Esko, Paul W. Franks, Philippe Froguel, Christian Gieger, Jost B. Jonas, Norihiro Kato, Timo A. Lakka, Karin Leander, Terho Lehtimäki, Patrik K. E. Magnusson, Kari E. North, Ioanna Ntalla, Brenda Penninx, Nilesh J. Samani, Harold Snieder, Beatrice Spedicati, Pim van der Harst, Henry Völzke, Lynne E. Wagenknecht, David R. Weir, Mary K. Wojczynski, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Claude Bouchard, Daniel I. Chasman, Michele K. Evans, Ervin R. Fox, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Sharon L. R. Kardia, Jose Eduardo Krieger, Dennis O. Mook-Kanamori, Patricia A. Peyser, Michael M. Province, Bruce M. Psaty, Igor Rudan, Xueling Sim, Blair H. Smith, Rob M. van Dam, Cornelia M. van Duijn, Tien Yin Wong, Donna K. Arnett, Dabeeru C. Rao, James Gauderman, Ching-Ti Liu, Alanna C. Morrison, Jerome I. Rotter, and Myriam Fornage
Subjects: educational attainment, lipids, cholesterol, triglycerides, genome-wide association study, meta-analysis, Genetics, QH426-470
Abstract: Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes.Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10−8) and suggestive (p < 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals).Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue.Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.
Published: 2023
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8. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization [version 1; peer review: 2 approved]

Author: Natasha H. J. Ng, Sara M. Willems, Jian'an Luan, Rebecca S. Fine, Juan Fernandez, Jennifer Wessel, Eleanor Wheeler, Gaelle Marenne, Hidetoshi Kitajima, Hanieh Yaghootkar, Xueling Sim, Ian J. Deary, Sai Chen, Shuai Wang, Yii-Der Ida Chen, Caroline Hayward, Yuning Chen, Jennifer L. Asimit, Claudia Langenberg, Tibor V. Varga, Archie Campbell, Rona J. Strawbridge, Shuang Feng, Tarunveer S. Ahluwalia, Erica L. Kleinbrink, Emil V. Appel, Ping An, Lawrence F. Bielak, Dan E. Arking, Jennifer A. Brody, Nathan A. Bihlmeyer, David Porteous, Ayse Demirkan, Audrey Y. Chu, Franco Giulianini, James S. Floyd, Stefan Gustafsson, Xiuqing Guo, Johanna Jakobsdottir, Anne U. Jackson, Stavroula Kanoni, Richard A. Jensen, Igor Rudan, Man Li, Sirkka Keinanen-Kiukaanniemi, Alisa K. Manning, Yingchang Lu, Karina Meidtner, Jonathan Marten, Giorgio Pistis, Taulant Muka, Kenneth M. Rice, Bram Prins, Albert Vernon Smith, Serena Sanna, Lorraine Southam, Jennifer A. Smith, Vinicius Tragante, Heather M. Stringham, Helen R. Warren, Sander W. van der Laan, Andrianos M. Yiorkas, Jie Yao, Wei Zhao, Weihua Zhang, Heather M. Highland, Mariaelisa Graff, Eirini Marouli, Anne E. Justice, Wesam A. Alhejily, Saima Afaq, Folkert W. Asselbergs, Najaf Amin, Michiel L. Bots, Lori L. Bonnycastle, Ji Chen, Ivan Brandslund, Abbas Dehghan, John Danesh, Tapani Ebeling, Jessica D. Faul, Aliki-Eleni Farmaki, Steve Franks, Paul W. Franks, Anette P. Gjesing, Andreas Fritsche, Göran Hallmans, Mark O. Goodarzi, Karl-Heinz Herzig, Tamara B. Harris, Min A Jhun, Marie-France Hivert, Marit E. Jørgensen, Torben Jørgensen, Eero Kajantie, Pekka Jousilahti, Sharon L.R. Kardia, Maria Karaleftheri, Heikki A. Koistinen, Leena Kinnunen, Peter Kovacs, Pirjo Komulainen, Markku Laakso, Johanna Kuusisto, Aaron Leong, Lenore J. Launer, Jocelyn E. Manning Fox, Jaana Lindström, Nisa M. Maruthur, Satu Männistö, Antonella Mulas, Leena Moilanen, Matthew Neville, Mike A. Nalls, Alison Pattie, James S. Pankow, Hannu Puolijoki, Eva R.B. Petersen, Paul Redmond, Asif Rasheed, Michael Roden, Frida Renström, Juha Saltevo, Danish Saleheen, Sylvain Sebert, Kai Savonen, Alena Stančáková, Kerrin S. Small, Konstantin Strauch, Jakob Stokholm, Betina H. Thuesen, Juha Auvinen, E-Shyong Tai, Emmanouil Tsafantakis, Anke Tönjes, Jaakko Tuomilehto, Tiinamaija Tuomi, Marja Vääräsmäki, Matti Uusitupa, Magdalena Zoledziewska, Ilonca Vaartjes, Beverley Balkau, Goncalo Abecasis, Alexandra I. Blakemore, Hans Bisgaard, Heiner Boeing, Ruth J.F. Loos, Matthias Blüher, Klaus Bønnelykke, Eric Boerwinkle, Mark J. Caulfield, Erwin P. Bottinger, Daniel I. Chasman, John C. Chambers, Francis S. Collins, Ching-Yu Cheng, Francesco Cucca, Josef Coresh, George Dedoussis, Gert J. de Borst, Hester M. den Ruijter, Panos Deloukas, Ele Ferrannini, Michele K. Evans, Harald Grallert, Oscar H. Franco, Arfan Ikram, Joel N. Hirschhorn, Fredrik Karpe, Erik Ingelsson, Wieland Kiess, Carolina Medina-Gomez, Kay-Tee Kaw, Antje Körner, Jaspal S. Kooner, Cecilia M. Lindgren, Timo Lakka, Ching-Ti Liu, Leonard Lipovich, Patrick E. MacDonald, Jun Liu, Andrew D. Morris, Karen L. Mohlke, Alison Murray, Patricia B. Munroe, Gerard Pasterkamp, Colin N. A . Palmer, Patricia A. Peyser, Oluf Pedersen, Paul M. Ridker, Rainer Rauramaa, Patrik Rorsman, Olov Rolandsson, Veikko Salomaa, Frits R. Rosendaal, Robert Sladek, Matthias B. Schulze, Michael Stumvoll, Timothy D. Spector, Mark Walker, Cornelia M. van Duijn, David R. Weir, Nick J. Wareham, Tien Yin Wong, James G. Wilson, Alan B. Zonderman, Eleftheria Zeggini, Andrew P. Morris, Jerome I. Rotter, Jose C. Florez, Michael Boehnke, James B. Meigs, Mark I. McCarthy, Robert A. Scott, Anubha Mahajan, Inês Barroso, Anna L. Gloyn, Michael A. Province, Niels Grarup, Ruifang Li-Gao, Jette Bork-Jensen, Yongmei Liu, Allan Linneberg, Leslie A. Lange, Sandosh Padmanabhan, Gail Davies, Lars Lind, Bruce M. Psaty, Tea Skaaby, Torben Hansen, Ozren Polasek, John M. Starr, Dennis O. Mook-Kanamori, Vilmundur Gudnason, Kent D. Taylor, Marjo-Riitta Järvelin, Renée de Mutsert, Paul Elliott, Josée Dupuis, Blair H. Smith, and Andrew T. Hattersley
Subjects: exome chip, glycaemic traits, genetic discovery, effector genes, summary statistics resources, eng, Medicine, Science
Abstract: Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
Published: 2023
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9. Discordance Between Creatinine-Based and Cystatin C–Based Estimated GFR: Interpretation According to Performance Compared to Measured GFRPlain-Language Summary

Author: Yeli Wang, Ogechi M. Adingwupu, Michael G. Shlipak, Alessandro Doria, Michelle M. Estrella, Marc Froissart, Vilmundur Gudnason, Anders Grubb, Roberto Kalil, Michael Mauer, Peter Rossing, Jesse Seegmiller, Josef Coresh, Andrew S. Levey, and Lesley A. Inker
Subjects: Glomerular filtration rate, creatinine, cystatin, estimated GFR, Diseases of the genitourinary system. Urology, RC870-923
Abstract: Rationale & Objective: Use of cystatin C in addition to creatinine to estimate glomerular filtration rate (estimated glomerular filtration rate based on cystatin C [eGFRcys] and estimated glomerular filtration rate based on creatinine [eGFRcr], respectively) is increasing. When eGFRcr and eGFRcys are discordant, it is not known which is more accurate, leading to uncertainty in clinical decision making. Study Design: Cross-sectional analysis. Setting & Participants: Four thousand fifty participants with measured glomerular filtration rate (mGFR) from 12 studies in North America and Europe. Exposures: Serum creatinine and serum cystatin C. Outcome(s): Performance of creatinine-based and cystatin C–based glomerular filtration rate estimating equations compared to mGFR. Analytical Approach: We evaluated the accuracy of eGFRcr, eGFRcys, and the combination (eGFRcr-cys) compared to mGFR according to the magnitude of the difference between eGFRcr and eGFRcys (eGFRdiff). We used CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations to estimate glomerular filtration rate. eGFRdiff was defined as eGFRcys minus eGFRcr and categorized as less than −15, −15 to
Published: 2023
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10. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author: Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso
Subjects: Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract: Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Published: 2022
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11. Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

Author: Shaza B. Zaghlool, Anna Halama, Nisha Stephan, Valborg Gudmundsdottir, Vilmundur Gudnason, Lori L. Jennings, Manonanthini Thangam, Emma Ahlqvist, Rayaz A. Malik, Omar M. E. Albagha, Abdul Badi Abou‑Samra, and Karsten Suhre
Subjects: Science
Abstract: Four T2D subtypes were previously identified: severe insulin deficient, severe insulin resistant, mild obesity-related, and mild age-related diabetes. Here, the authors show that these subtypes can be translated to an Arabic population and identify distinct subtype-specific metabolic and proteomic signatures.
Published: 2022
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12. A population‐based meta‐analysis of circulating GFAP for cognition and dementia risk

Author: Mitzi M. Gonzales, Crystal Wiedner, Chen‐Pin Wang, Qianqian Liu, Joshua C. Bis, Zhiguang Li, Jayandra J. Himali, Saptaparni Ghosh, Emy A. Thomas, Danielle M. Parent, Tiffany F. Kautz, Matthew P. Pase, Hugo J. Aparicio, Luc Djoussé, Kenneth J. Mukamal, Bruce M. Psaty, William T. Longstreth Jr, Thomas H. Mosley Jr, Vilmundur Gudnason, Djass Mbangdadji, Oscar L. Lopez, Kristine Yaffe, Stephen Sidney, R. Nick Bryan, Ilya M. Nasrallah, Charles S. DeCarli, Alexa S. Beiser, Lenore J. Launer, Myriam Fornage, Russell P. Tracy, Sudha Seshadri, and Claudia L. Satizabal
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Objective Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability to community settings. Methods Circulating GFAP levels were assayed using a Simoa HD‐1 analyzer in 4338 adults without prevalent dementia from four longitudinal community‐based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random‐effects models. Results Meta‐analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log‐transformed GFAP levels was significantly associated with a 2.5‐fold higher risk of incident all‐cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15‐years of follow‐up. Interpretation Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.
Published: 2022
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13. 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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14. A proteogenomic signature of age-related macular degeneration in blood

Author: Valur Emilsson, Elias F. Gudmundsson, Thorarinn Jonmundsson, Brynjolfur G. Jonsson, Michael Twarog, Valborg Gudmundsdottir, Zhiguang Li, Nancy Finkel, Stephen Poor, Xin Liu, Robert Esterberg, Yiyun Zhang, Sandra Jose, Chia-Ling Huang, Sha-Mei Liao, Joseph Loureiro, Qin Zhang, Cynthia L. Grosskreutz, Andrew A. Nguyen, Qian Huang, Barrett Leehy, Rebecca Pitts, Thor Aspelund, John R. Lamb, Fridbert Jonasson, Lenore J. Launer, Mary Frances Cotch, Lori L. Jennings, Vilmundur Gudnason, and Tony E. Walshe
Subjects: Science
Abstract: Age related macular degeneration is a common cause of visual impairment in the elderly, but the etiology is not fully understood. Here, the authors use genetic data, serum proteomics, and AMD phenotypic data from a large Icelandic cohort to discover proteins altered in, causally related to AMD or signifying progression of advanced AMD.
Published: 2022
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15. A genome-wide association study of serum proteins reveals shared loci with common diseases

Author: Alexander Gudjonsson, Valborg Gudmundsdottir, Gisli T. Axelsson, Elias F. Gudmundsson, Brynjolfur G. Jonsson, Lenore J. Launer, John R. Lamb, Lori L. Jennings, Thor Aspelund, Valur Emilsson, and Vilmundur Gudnason
Subjects: Science
Abstract: Circulating proteins have been linked to many conditions, and understanding their genetic control can lead to understanding of disease. Here, the authors associate common genetic variants with protein levels, finding overlap of genetic associations with circulating proteins and complex disease.
Published: 2022
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16. Coding and regulatory variants are associated with serum protein levels and disease

Author: Valur Emilsson, Valborg Gudmundsdottir, Alexander Gudjonsson, Thorarinn Jonmundsson, Brynjolfur G. Jonsson, Mohd A. Karim, Marjan Ilkov, James R. Staley, Elias F. Gudmundsson, Lenore J. Launer, Jan H. Lindeman, Nicholas M. Morton, Thor Aspelund, John R. Lamb, Lori L. Jennings, and Vilmundur Gudnason
Subjects: Science
Abstract: Finding the genetic basis of protein expression can elucidate the genetic mechanisms of disease. Here, the authors link low-frequency and common DNA sequence variants to thousands of serum proteins, finding genetic overlap between circulating proteins and a wide range of common diseases.
Published: 2022
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17. Association of low-frequency and rare coding variants with information processing speed

Author: Jan Bressler, Gail Davies, Albert V. Smith, Yasaman Saba, Joshua C. Bis, Xueqiu Jian, Caroline Hayward, Lisa Yanek, Jennifer A. Smith, Saira S. Mirza, Ruiqi Wang, Hieab H. H. Adams, Diane Becker, Eric Boerwinkle, Archie Campbell, Simon R. Cox, Gudny Eiriksdottir, Chloe Fawns-Ritchie, Rebecca F. Gottesman, Megan L. Grove, Xiuqing Guo, Edith Hofer, Sharon L. R. Kardia, Maria J. Knol, Marisa Koini, Oscar L. Lopez, Riccardo E. Marioni, Paul Nyquist, Alison Pattie, Ozren Polasek, David J. Porteous, Igor Rudan, Claudia L. Satizabal, Helena Schmidt, Reinhold Schmidt, Stephen Sidney, Jeannette Simino, Blair H. Smith, Stephen T. Turner, Sven J. van der Lee, Erin B. Ware, Rachel A. Whitmer, Kristine Yaffe, Qiong Yang, Wei Zhao, Vilmundur Gudnason, Lenore J. Launer, Annette L. Fitzpatrick, Bruce M. Psaty, Myriam Fornage, M. Arfan Ikram, Cornelia M. van Duijn, Sudha Seshadri, Thomas H. Mosley, and Ian J. Deary
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Abstract Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.
Published: 2021
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18. Soft tissue radiodensity parameters mediate the relationship between self-reported physical activity and lower extremity function in AGES-Reykjavík participants

Author: Kyle J. Edmunds, Ozioma C. Okonkwo, Sigurdur Sigurdsson, Sarah R. Lose, Vilmundur Gudnason, Ugo Carraro, and Paolo Gargiulo
Subjects: Medicine, Science
Abstract: Abstract Although previous studies have highlighted the association between physical activity and lower extremity function (LEF) in elderly individuals, the mechanisms underlying this relationship remain debated. Our recent work has recognized the utility of nonlinear trimodal regression analysis (NTRA) parameters in characterizing changes in soft tissue radiodensity as a quantitative construct for sarcopenia in the longitudinal, population-based cohort of the AGES-Reykjavík study. For the present work, we assembled a series of prospective multivariate regression models to interrogate whether NTRA parameters mediate the 5-year longitudinal relationship between physical activity and LEF in AGES-Reykjavík participants. Healthy elderly volunteers from the AGES-Reykjavík cohort underwent mid-thigh X-ray CT scans along with a four-part battery of LEF tasks: normal gait speed, fastest-comfortable gait speed, isometric leg strength, and timed up-and-go. These data were recorded at two study timepoints which were separated by approximately 5 years: AGES-I (n = 3157) and AGES-II (n = 3098). Participants in AGES-I were likewise administered a survey to approximate their weekly frequency of engaging in moderate-to-vigorous physical activity (PAAGES-I). Using a multivariate mediation analysis framework, linear regression models were assembled to test whether NTRA parameters mediated the longitudinal relationship between PAAGES-I and LEFAGES-II; all models were covariate-adjusted for age, sex, BMI, and baseline LEF, and results were corrected for multiple statistical comparisons. Our first series of models confirmed that all four LEF tasks were significantly related to PAAGES-I; next, modelling the relationship between PAAGES-I and NTRAAGES-II identified muscle amplitude (N m ) and location (μ m ) as potential mediators of LEF to test. Finally, adding these two parameters into our PAAGES-I → LEFAGES-II models attenuated the prior effect of PAAGES-I; bootstrapping confirmed N m and μ m as significant partial mediators of the PAAGES-I → LEFAGES-II relationship, with the strongest effect found in isometric leg strength. This work describes a novel approach toward clarifying the mechanisms that underly the relationship between physical activity and LEF in aging individuals. Identifying N m and μ m as significant partial mediators of this relationship provides strong evidence that physical activity protects aging mobility through the preservation of both lean tissue quantity and quality.
Published: 2021
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19. Serum levels of ACE2 are higher in patients with obesity and diabetes

Author: Valur Emilsson, Elias F. Gudmundsson, Thor Aspelund, Brynjolfur G. Jonsson, Alexander Gudjonsson, Lenore J. Launer, John R. Lamb, Valborg Gudmundsdottir, Lori L. Jennings, and Vilmundur Gudnason
Subjects: Internal medicine, RC31-1245
Abstract: Abstract Objective As severity of outcome in COVID‐19 is disproportionately higher among individuals with obesity, smokers, patients with hypertension, kidney disease, chronic pulmonary disease, coronary heart disease (CHD), and/or type 2 diabetes (T2D), serum levels of ACE2, the cellular entry point for the coronavirus SARS‐CoV‐2, were examined in these high‐risk groups. Methods Associations of ACE2 levels to smokers and patients with hypertension, T2D, obesity, CHD, or COPD were investigated in a single center population‐based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavík Study (AGES‐RS) of the elderly (mean age 75 ± 6 years), using multiple linear regression analysis. Results Serum levels of ACE2 were higher in smokers and individuals with T2D and/or obesity while they were unaffected in the other patient groups. Conclusion ACE2 levels are higher in some patient groups with comorbidities linked to COVID‐19 including obesity and T2D and as such may have an emerging role as a circulating biomarker for severity of outcome in the disease.
Published: 2021
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20. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies

Author: William S. Harris, Nathan L. Tintle, Fumiaki Imamura, Frank Qian, Andres V. Ardisson Korat, Matti Marklund, Luc Djoussé, Julie K. Bassett, Pierre-Hugues Carmichael, Yun-Yu Chen, Yoichiro Hirakawa, Leanne K. Küpers, Federica Laguzzi, Maria Lankinen, Rachel A. Murphy, Cécilia Samieri, Mackenzie K. Senn, Peilin Shi, Jyrki K. Virtanen, Ingeborg A. Brouwer, Kuo-Liong Chien, Gudny Eiriksdottir, Nita G. Forouhi, Johanna M. Geleijnse, Graham G. Giles, Vilmundur Gudnason, Catherine Helmer, Allison Hodge, Rebecca Jackson, Kay-Tee Khaw, Markku Laakso, Heidi Lai, Danielle Laurin, Karin Leander, Joan Lindsay, Renata Micha, Jaako Mursu, Toshiharu Ninomiya, Wendy Post, Bruce M. Psaty, Ulf Risérus, Jennifer G. Robinson, Aladdin H. Shadyab, Linda Snetselaar, Aleix Sala-Vila, Yangbo Sun, Lyn M. Steffen, Michael Y. Tsai, Nicholas J. Wareham, Alexis C. Wood, Jason H. Y. Wu, Frank Hu, Qi Sun, David S. Siscovick, Rozenn N. Lemaitre, Dariush Mozaffarian, and The Fatty Acids and Outcomes Research Consortium (FORCE)
Subjects: Science
Abstract: Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.
Published: 2021
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21. 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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22. Cerebral small vessel disease genomics and its implications across the lifespan

Author: Muralidharan Sargurupremraj, Hideaki Suzuki, Xueqiu Jian, Chloé Sarnowski, Tavia E. Evans, Joshua C. Bis, Gudny Eiriksdottir, Saori Sakaue, Natalie Terzikhan, Mohamad Habes, Wei Zhao, Nicola J. Armstrong, Edith Hofer, Lisa R. Yanek, Saskia P. Hagenaars, Rajan B. Kumar, Erik B. van den Akker, Rebekah E. McWhirter, Stella Trompet, Aniket Mishra, Yasaman Saba, Claudia L. Satizabal, Gregory Beaudet, Laurent Petit, Ami Tsuchida, Laure Zago, Sabrina Schilling, Sigurdur Sigurdsson, Rebecca F. Gottesman, Cora E. Lewis, Neelum T. Aggarwal, Oscar L. Lopez, Jennifer A. Smith, Maria C. Valdés Hernández, Jeroen van der Grond, Margaret J. Wright, Maria J. Knol, Marcus Dörr, Russell J. Thomson, Constance Bordes, Quentin Le Grand, Marie-Gabrielle Duperron, Albert V. Smith, David S. Knopman, Pamela J. Schreiner, Denis A. Evans, Jerome I. Rotter, Alexa S. Beiser, Susana Muñoz Maniega, Marian Beekman, Julian Trollor, David J. Stott, Meike W. Vernooij, Katharina Wittfeld, Wiro J. Niessen, Aicha Soumaré, Eric Boerwinkle, Stephen Sidney, Stephen T. Turner, Gail Davies, Anbupalam Thalamuthu, Uwe Völker, Mark A. van Buchem, R. Nick Bryan, Josée Dupuis, Mark E. Bastin, David Ames, Alexander Teumer, Philippe Amouyel, John B. Kwok, Robin Bülow, Ian J. Deary, Peter R. Schofield, Henry Brodaty, Jiyang Jiang, Yasuharu Tabara, Kazuya Setoh, Susumu Miyamoto, Kazumichi Yoshida, Manabu Nagata, Yoichiro Kamatani, Fumihiko Matsuda, Bruce M. Psaty, David A. Bennett, Philip L. De Jager, Thomas H. Mosley, Perminder S. Sachdev, Reinhold Schmidt, Helen R. Warren, Evangelos Evangelou, David-Alexandre Trégouët, International Network against Thrombosis (INVENT) Consortium, International Headache Genomics Consortium (IHGC), Mohammad A. Ikram, Wei Wen, Charles DeCarli, Velandai K. Srikanth, J. Wouter Jukema, Eline P. Slagboom, Sharon L. R. Kardia, Yukinori Okada, Bernard Mazoyer, Joanna M. Wardlaw, Paul A. Nyquist, Karen A. Mather, Hans J. Grabe, Helena Schmidt, Cornelia M. Van Duijn, Vilmundur Gudnason, William T. Longstreth, Lenore J. Launer, Mark Lathrop, Sudha Seshadri, Christophe Tzourio, Hieab H. Adams, Paul M. Matthews, Myriam Fornage, and Stéphanie Debette
Subjects: Science
Abstract: White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.
Published: 2020
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23. Automated femur segmentation from computed tomography images using a deep neural network.

Author: Pall Asgeir Bjornsson, Benedikt Helgason, Halldor Pálsson, Sigurður Sigurðsson, Vilmundur Gudnason, and Lotta Maria Ellingsen
Published: 2021
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24. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author: Ioanna Ntalla, Lu-Chen Weng, James H. Cartwright, Amelia Weber Hall, Gardar Sveinbjornsson, Nathan R. Tucker, Seung Hoan Choi, Mark D. Chaffin, Carolina Roselli, Michael R. Barnes, Borbala Mifsud, Helen R. Warren, Caroline Hayward, Jonathan Marten, James J. Cranley, Maria Pina Concas, Paolo Gasparini, Thibaud Boutin, Ivana Kolcic, Ozren Polasek, Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Fabiola Del Greco M, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo-Pekka Lyytikäinen, Olli T. Raitakari, Catriona L. K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Kenneth Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, and Patricia B. Munroe
Subjects: Science
Abstract: On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
Published: 2020
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25. Childhood overweight and obesity and the risk of depression across the lifespan

Author: Deborah Gibson-Smith, Thorhallur I. Halldorsson, Mariska Bot, Ingeborg A. Brouwer, Marjolein Visser, Inga Thorsdottir, Bryndis E. Birgisdottir, Vilmundur Gudnason, Gudny Eiriksdottir, Lenore J. Launer, Tamara B. Harris, and Ingibjorg Gunnarsdottir
Subjects: Childhood obesity, Depressive symptoms, Lifetime major depressive disorder, Body mass index, Pediatrics, RJ1-570
Abstract: Abstract Background Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). Method This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. Results One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16–13.96]P = 0.03 and age 13 = 2.65[0.69–10.26] P = 0.16, respectively). Conclusion Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.
Published: 2020
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26. A joint ventricle and WMH segmentation from MRI for evaluation of healthy and pathological changes in the aging brain.

Author: Hans E Atlason, Askell Love, Vidar Robertsson, Ari M Blitz, Sigurdur Sigurdsson, Vilmundur Gudnason, and Lotta M Ellingsen
Subjects: Medicine, Science
Abstract: Age-related changes in brain structure include atrophy of the brain parenchyma and white matter changes of presumed vascular origin. Enlargement of the ventricles may occur due to atrophy or impaired cerebrospinal fluid (CSF) circulation. The co-occurrence of these changes in neurodegenerative diseases and in aging brains often requires investigators to take both into account when studying the brain, however, automated segmentation of enlarged ventricles and white matter hyperintensities (WMHs) can be a challenging task. Here, we present a hybrid multi-atlas segmentation and convolutional autoencoder approach for joint ventricle parcellation and WMH segmentation from magnetic resonance images (MRIs). Our fully automated approach uses a convolutional autoencoder to generate a standardized image of grey matter, white matter, CSF, and WMHs, which, in conjunction with labels generated by a multi-atlas segmentation approach, is then fed into a convolutional neural network to parcellate the ventricular system. Hence, our approach does not depend on manually delineated training data for new data sets. The segmentation pipeline was validated on both healthy elderly subjects and subjects with normal pressure hydrocephalus using ground truth manual labels and compared with state-of-the-art segmentation methods. We then applied the method to a cohort of 2401 elderly brains to investigate associations of ventricle volume and WMH load with various demographics and clinical biomarkers, using a multiple regression model. Our results indicate that the ventricle volume and WMH load are both highly variable in a cohort of elderly subjects and there is an independent association between the two, which highlights the importance of taking both the possibility of enlarged ventricles and WMHs into account when studying the aging brain.
Published: 2022
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27. Predicting changes in quality of life for patients in vocational rehabilitation.

Author: Saemundur O. Haraldsson, Ragnheidur D. Brynjolfsdottir, Vilmundur Gudnason, Kristinn Tomasson, and Kristin Siggeirsdottir
Published: 2018
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28. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Author: Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
Subjects: Advanced and Specialized Nursing, Incidence, risk assessment, Smoking/epidemiology, intracranial aneurysm, genetic heterogeneity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Risk Factors, Intracranial Aneurysm/epidemiology, Humans, Subarachnoid Hemorrhage/epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, genetics, Neurology (clinical), aneurysmal subarachnoid hemorrhage, genetic, Cardiology and Cardiovascular Medicine
Abstract: Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Published: 2023

29. A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

Author: Mohd Anisul, Jarrod Shilts, Jeremy Schwartzentruber, James Hayhurst, Annalisa Buniello, Elmutaz Shaikho Elhaj Mohammed, Jie Zheng, Michael Holmes, David Ochoa, Miguel Carmona, Joseph Maranville, Tom R Gaunt, Valur Emilsson, Vilmundur Gudnason, Ellen M McDonagh, Gavin J Wright, Maya Ghoussaini, and Ian Dunham
Subjects: COVID-19, proteins, mendelian randomization, genetic colocalization, apoptosis, Medicine, Science, Biology (General), QH301-705.5
Abstract: Background: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. Results: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Published: 2021
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30. Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration

Author: Raymond Noordam, Maxime M. Bos, Heming Wang, Thomas W. Winkler, Amy R. Bentley, Tuomas O. Kilpeläinen, Paul S. de Vries, Yun Ju Sung, Karen Schwander, Brian E. Cade, Alisa Manning, Hugues Aschard, Michael R. Brown, Han Chen, Nora Franceschini, Solomon K. Musani, Melissa Richard, Dina Vojinovic, Stella Aslibekyan, Traci M. Bartz, Lisa de las Fuentes, Mary Feitosa, Andrea R. Horimoto, Marjan Ilkov, Minjung Kho, Aldi Kraja, Changwei Li, Elise Lim, Yongmei Liu, Dennis O. Mook-Kanamori, Tuomo Rankinen, Salman M. Tajuddin, Ashley van der Spek, Zhe Wang, Jonathan Marten, Vincent Laville, Maris Alver, Evangelos Evangelou, Maria E. Graff, Meian He, Brigitte Kühnel, Leo-Pekka Lyytikäinen, Pedro Marques-Vidal, Ilja M. Nolte, Nicholette D. Palmer, Rainer Rauramaa, Xiao-Ou Shu, Harold Snieder, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Correa Adolfo, Christie Ballantyne, Larry Bielak, Nienke R. Biermasz, Eric Boerwinkle, Niki Dimou, Gudny Eiriksdottir, Chuan Gao, Sina A. Gharib, Daniel J. Gottlieb, José Haba-Rubio, Tamara B. Harris, Sami Heikkinen, Raphaël Heinzer, James E. Hixson, Georg Homuth, M. Arfan Ikram, Pirjo Komulainen, Jose E. Krieger, Jiwon Lee, Jingmin Liu, Kurt K. Lohman, Annemarie I. Luik, Reedik Mägi, Lisa W. Martin, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Mike A. Nalls, Jeff O’Connell, Annette Peters, Patricia Peyser, Olli T. Raitakari, Alex P. Reiner, Patrick C. N. Rensen, Treva K. Rice, Stephen S. Rich, Till Roenneberg, Jerome I. Rotter, Pamela J. Schreiner, James Shikany, Stephen S. Sidney, Mario Sims, Colleen M. Sitlani, Tamar Sofer, Konstantin Strauch, Morris A. Swertz, Kent D. Taylor, André G. Uitterlinden, Cornelia M. van Duijn, Henry Völzke, Melanie Waldenberger, Robert B. Wallance, Ko Willems van Dijk, Caizheng Yu, Alan B. Zonderman, Diane M. Becker, Paul Elliott, Tõnu Esko, Christian Gieger, Hans J. Grabe, Timo A. Lakka, Terho Lehtimäki, Kari E. North, Brenda W. J. H. Penninx, Peter Vollenweider, Lynne E. Wagenknecht, Tangchun Wu, Yong-Bing Xiang, Wei Zheng, Donna K. Arnett, Claude Bouchard, Michele K. Evans, Vilmundur Gudnason, Sharon Kardia, Tanika N. Kelly, Stephen B. Kritchevsky, Ruth J. F. Loos, Alexandre C. Pereira, Mike Province, Bruce M. Psaty, Charles Rotimi, Xiaofeng Zhu, Najaf Amin, L. Adrienne Cupples, Myriam Fornage, Ervin F. Fox, Xiuqing Guo, W. James Gauderman, Kenneth Rice, Charles Kooperberg, Patricia B. Munroe, Ching-Ti Liu, Alanna C. Morrison, Dabeeru C. Rao, Diana van Heemst, and Susan Redline
Subjects: Science
Abstract: Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.
Published: 2019
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31. Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Author: Andries Paul Nagtegaal, Linda Broer, Nuno R. Zilhao, Johanna Jakobsdottir, Charles E. Bishop, Marco Brumat, Mark W. Christiansen, Massimiliano Cocca, Yan Gao, Nancy L. Heard-Costa, Daniel S. Evans, Nathan Pankratz, Sheila R. Pratt, T. Ryan Price, Christopher Spankovich, Mary R. Stimson, Karen Valle, Dragana Vuckovic, Helena Wells, Gudny Eiriksdottir, Erik Fransen, Mohammad Arfan Ikram, Chuang-Ming Li, W. T. Longstreth, Claire Steves, Guy Van Camp, Adolfo Correa, Karen J. Cruickshanks, Paolo Gasparini, Giorgia Girotto, Robert C. Kaplan, Michael Nalls, John M. Schweinfurth, Sudha Seshadri, Nona Sotoodehnia, Gregory J. Tranah, André G. Uitterlinden, James G. Wilson, Vilmundur Gudnason, Howard J. Hoffman, Frances M. K. Williams, and André Goedegebure
Subjects: Medicine, Science
Abstract: Abstract Previous research has shown that genes play a substantial role in determining a person’s susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
Published: 2019
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32. 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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33. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Author: Alexander Teumer, Yong Li, Sahar Ghasemi, Bram P. Prins, Matthias Wuttke, Tobias Hermle, Ayush Giri, Karsten B. Sieber, Chengxiang Qiu, Holger Kirsten, Adrienne Tin, Audrey Y. Chu, Nisha Bansal, Mary F. Feitosa, Lihua Wang, Jin-Fang Chai, Massimiliano Cocca, Christian Fuchsberger, Mathias Gorski, Anselm Hoppmann, Katrin Horn, Man Li, Jonathan Marten, Damia Noce, Teresa Nutile, Sanaz Sedaghat, Gardar Sveinbjornsson, Bamidele O. Tayo, Peter J. van der Most, Yizhe Xu, Zhi Yu, Lea Gerstner, Johan Ärnlöv, Stephan J. L. Bakker, Daniela Baptista, Mary L. Biggs, Eric Boerwinkle, Hermann Brenner, Ralph Burkhardt, Robert J. Carroll, Miao-Li Chee, Miao-Ling Chee, Mengmeng Chen, Ching-Yu Cheng, James P. Cook, Josef Coresh, Tanguy Corre, John Danesh, Martin H. de Borst, Alessandro De Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Katalin Dittrich, Jasmin Divers, Kai-Uwe Eckardt, Georg Ehret, Karlhans Endlich, Janine F. Felix, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Ron T. Gansevoort, Vilmantas Giedraitis, Martin Gögele, Franziska Grundner-Culemann, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pavel Hamet, Tamara B. Harris, Andrew A. Hicks, Hilma Holm, Valencia Hui Xian Foo, Shih-Jen Hwang, M. Arfan Ikram, Erik Ingelsson, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Chiea-Chuen Khor, Wieland Kiess, Wolfgang Koenig, Antje Körner, Peter Kovacs, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jianjun Liu, Markus Loeffler, Leo-Pekka Lyytikäinen, Anubha Mahajan, Joseph C. Maranville, Deborah Mascalzoni, Barbara McMullen, Christa Meisinger, Thomas Meitinger, Kozeta Miliku, Dennis O. Mook-Kanamori, Martina Müller-Nurasyid, Josyf C. Mychaleckyj, Matthias Nauck, Kjell Nikus, Boting Ning, Raymond Noordam, Jeffrey O’ Connell, Isleifur Olafsson, Nicholette D. Palmer, Annette Peters, Anna I. Podgornaia, Belen Ponte, Tanja Poulain, Peter P. Pramstaller, Ton J. Rabelink, Laura M. Raffield, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Fernando Rivadeneira, Heiko Runz, Kathleen A. Ryan, Charumathi Sabanayagam, Kai-Uwe Saum, Ben Schöttker, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Konstantin Strauch, Michael Stumvoll, Benjamin B. Sun, Silke Szymczak, E-Shyong Tai, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Unnur Thorsteinsdottir, Anke Tönjes, Johanne Tremblay, André G. Uitterlinden, Pim van der Harst, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Melanie Waldenberger, Chaolong Wang, Otis D. Wilson, Charlene Wong, Tien-Yin Wong, Qiong Yang, Masayuki Yasuda, Shreeram Akilesh, Murielle Bochud, Carsten A. Böger, Olivier Devuyst, Todd L. Edwards, Kevin Ho, Andrew P. Morris, Afshin Parsa, Sarah A. Pendergrass, Bruce M. Psaty, Jerome I. Rotter, Kari Stefansson, James G. Wilson, Katalin Susztak, Harold Snieder, Iris M. Heid, Markus Scholz, Adam S. Butterworth, Adriana M. Hung, Cristian Pattaro, and Anna Köttgen
Subjects: Science
Abstract: Urinary albumin-to-creatinine ratio (UCAR) is associated with various clinical outcomes such as kidney disease and cardiovascular disease. Here, the authors report genome-wide meta-analysis in over 500,000 individuals and find 68 UACR loci, followed by statistical fine-mapping, gene prioritization and experimental validation in flies.
Published: 2019
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34. A meta-analysis of genome-wide association studies identifies multiple longevity genes

Author: Joris Deelen, Daniel S. Evans, Dan E. Arking, Niccolò Tesi, Marianne Nygaard, Xiaomin Liu, Mary K. Wojczynski, Mary L. Biggs, Ashley van der Spek, Gil Atzmon, Erin B. Ware, Chloé Sarnowski, Albert V. Smith, Ilkka Seppälä, Heather J. Cordell, Janina Dose, Najaf Amin, Alice M. Arnold, Kristin L. Ayers, Nir Barzilai, Elizabeth J. Becker, Marian Beekman, Hélène Blanché, Kaare Christensen, Lene Christiansen, Joanna C. Collerton, Sarah Cubaynes, Steven R. Cummings, Karen Davies, Birgit Debrabant, Jean-François Deleuze, Rachel Duncan, Jessica D. Faul, Claudio Franceschi, Pilar Galan, Vilmundur Gudnason, Tamara B. Harris, Martijn Huisman, Mikko A. Hurme, Carol Jagger, Iris Jansen, Marja Jylhä, Mika Kähönen, David Karasik, Sharon L. R. Kardia, Andrew Kingston, Thomas B. L. Kirkwood, Lenore J. Launer, Terho Lehtimäki, Wolfgang Lieb, Leo-Pekka Lyytikäinen, Carmen Martin-Ruiz, Junxia Min, Almut Nebel, Anne B. Newman, Chao Nie, Ellen A. Nohr, Eric S. Orwoll, Thomas T. Perls, Michael A. Province, Bruce M. Psaty, Olli T. Raitakari, Marcel J. T. Reinders, Jean-Marie Robine, Jerome I. Rotter, Paola Sebastiani, Jennifer Smith, Thorkild I. A. Sørensen, Kent D. Taylor, André G. Uitterlinden, Wiesje van der Flier, Sven J. van der Lee, Cornelia M. van Duijn, Diana van Heemst, James W. Vaupel, David Weir, Kenny Ye, Yi Zeng, Wanlin Zheng, Henne Holstege, Douglas P. Kiel, Kathryn L. Lunetta, P. Eline Slagboom, and Joanne M. Murabito
Subjects: Science
Abstract: Genome-wide association studies have only revealed a handful of genetic loci for longevity. Here, in a case–control design based on phenotype definitions of individuals surviving at or beyond the age corresponding to the 90th and 99th survival percentile, the authors report two additional loci located in the APOE locus and near GPR78.
Published: 2019
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35. Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes

Author: Llilda Barata, Mary F. Feitosa, Lawrence F. Bielak, Brian Halligan, Abigail S. Baldridge, Xiuqing Guo, Laura M. Yerges‐Armstrong, Albert V. Smith, Jie Yao, Nicholette D. Palmer, Lisa B. VanWagner, J. Jeffrey Carr, Yii‐Der I. Chen, Matthew Allison, Matthew J. Budoff, Samuel K. Handelman, Sharon L.R. Kardia, Thomas H. Mosley Jr., Kathleen Ryan, Tamara B. Harris, Lenore J. Launer, Vilmundur Gudnason, Jerome I. Rotter, Myriam Fornage, Laura J. Rasmussen‐Torvik, Ingrid B. Borecki, Jeffrey R. O’Connell, Patricia A. Peyser, Elizabeth K. Speliotes, and Michael A. Province
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, body mass index (BMI), and waist‐to‐hip ratio adjusted for BMI interact with genetic variants in or near the patatin‐like phospholipase domain containing 3 (PNPLA3) gene, the glucokinase regulatory protein (GCKR) gene, the neurocan/transmembrane 6 superfamily member 2 (NCAN/TM6SF2) gene, and the lysophospholipase‐like 1 (LYPLAL1) gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population‐based cohorts separately and then meta‐analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that PNPLA3‐rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, GCKR‐rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of PNPLA3‐rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, PNPLA3‐rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Conclusion: Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the PNPLA3‐rs738409‐G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying PNPLA3‐rs738409‐G may preferentially decrease hepatic steatosis.
Published: 2019
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36. Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author: Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, and Ian J. Deary
Subjects: Science
Abstract: Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
Published: 2019
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37. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Tuomas O. Kilpeläinen, Amy R. Bentley, Raymond Noordam, Yun Ju Sung, Karen Schwander, Thomas W. Winkler, Hermina Jakupović, Daniel I. Chasman, Alisa Manning, Ioanna Ntalla, Hugues Aschard, Michael R. Brown, Lisa de las Fuentes, Nora Franceschini, Xiuqing Guo, Dina Vojinovic, Stella Aslibekyan, Mary F. Feitosa, Minjung Kho, Solomon K. Musani, Melissa Richard, Heming Wang, Zhe Wang, Traci M. Bartz, Lawrence F. Bielak, Archie Campbell, Rajkumar Dorajoo, Virginia Fisher, Fernando P. Hartwig, Andrea R. V. R. Horimoto, Changwei Li, Kurt K. Lohman, Jonathan Marten, Xueling Sim, Albert V. Smith, Salman M. Tajuddin, Maris Alver, Marzyeh Amini, Mathilde Boissel, Jin Fang Chai, Xu Chen, Jasmin Divers, Evangelos Evangelou, Chuan Gao, Mariaelisa Graff, Sarah E. Harris, Meian He, Fang-Chi Hsu, Anne U. Jackson, Jing Hua Zhao, Aldi T. Kraja, Brigitte Kühnel, Federica Laguzzi, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Muhammad Riaz, Antonietta Robino, Rico Rueedi, Heather M. Stringham, Fumihiko Takeuchi, Peter J. van der Most, Tibor V. Varga, Niek Verweij, Erin B. Ware, Wanqing Wen, Xiaoyin Li, Lisa R. Yanek, Najaf Amin, Donna K. Arnett, Eric Boerwinkle, Marco Brumat, Brian Cade, Mickaël Canouil, Yii-Der Ida Chen, Maria Pina Concas, John Connell, Renée de Mutsert, H. Janaka de Silva, Paul S. de Vries, Ayşe Demirkan, Jingzhong Ding, Charles B. Eaton, Jessica D. Faul, Yechiel Friedlander, Kelley P. Gabriel, Mohsen Ghanbari, Franco Giulianini, Chi Charles Gu, Dongfeng Gu, Tamara B. Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Steven C. Hunt, M. Arfan Ikram, Jost B. Jonas, Woon-Puay Koh, Pirjo Komulainen, Jose E. Krieger, Stephen B. Kritchevsky, Zoltán Kutalik, Johanna Kuusisto, Carl D. Langefeld, Claudia Langenberg, Lenore J. Launer, Karin Leander, Rozenn N. Lemaitre, Cora E. Lewis, Jingjing Liang, Lifelines Cohort Study, Jianjun Liu, Reedik Mägi, Ani Manichaikul, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Karen L. Mohlke, Thomas H. Mosley, Alison D. Murray, Mike A. Nalls, Ei-Ei Khaing Nang, Christopher P. Nelson, Sotoodehnia Nona, Jill M. Norris, Chiamaka Vivian Nwuba, Jeff O’Connell, Nicholette D. Palmer, George J. Papanicolau, Raha Pazoki, Nancy L. Pedersen, Annette Peters, Patricia A. Peyser, Ozren Polasek, David J. Porteous, Alaitz Poveda, Olli T. Raitakari, Stephen S. Rich, Neil Risch, Jennifer G. Robinson, Lynda M. Rose, Igor Rudan, Pamela J. Schreiner, Robert A. Scott, Stephen S. Sidney, Mario Sims, Jennifer A. Smith, Harold Snieder, Tamar Sofer, John M. Starr, Barbara Sternfeld, Konstantin Strauch, Hua Tang, Kent D. Taylor, Michael Y. Tsai, Jaakko Tuomilehto, André G. Uitterlinden, M. Yldau van der Ende, Diana van Heemst, Trudy Voortman, Melanie Waldenberger, Patrik Wennberg, Gregory Wilson, Yong-Bing Xiang, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B. Zonderman, Diane M. Becker, Michael Boehnke, Donald W. Bowden, Ulf de Faire, Ian J. Deary, Paul Elliott, Tõnu Esko, Barry I. Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Norihiro Kato, Markku Laakso, Timo A. Lakka, Terho Lehtimäki, Patrik K. E. Magnusson, Albertine J. Oldehinkel, Brenda W. J. H. Penninx, Nilesh J. Samani, Xiao-Ou Shu, Pim van der Harst, Jana V. Van Vliet-Ostaptchouk, Peter Vollenweider, Lynne E. Wagenknecht, Ya X. Wang, Nicholas J. Wareham, David R. Weir, Tangchun Wu, Wei Zheng, Xiaofeng Zhu, Michele K. Evans, Paul W. Franks, Vilmundur Gudnason, Caroline Hayward, Bernardo L. Horta, Tanika N. Kelly, Yongmei Liu, Kari E. North, Alexandre C. Pereira, Paul M. Ridker, E. Shyong Tai, Rob M. van Dam, Ervin R. Fox, Sharon L. R. Kardia, Ching-Ti Liu, Dennis O. Mook-Kanamori, Michael A. Province, Susan Redline, Cornelia M. van Duijn, Jerome I. Rotter, Charles B. Kooperberg, W. James Gauderman, Bruce M. Psaty, Kenneth Rice, Patricia B. Munroe, Myriam Fornage, L. Adrienne Cupples, Charles N. Rotimi, Alanna C. Morrison, Dabeeru C. Rao, and Ruth J. F. Loos
Subjects: Science
Abstract: GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.
Published: 2019
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38. Serum lipids in adults with late age-related macular degeneration: a case-control study

Author: Richard D. Semba, Ruin Moaddel, Mary Frances Cotch, Fridbert Jonasson, Gudny Eiriksdottir, Tamara B. Harris, Lenore J. Launer, Kai Sun, Ronald Klein, Debra A. Schaumberg, Pálmi Jónsson, Vilmundur Gudnason, and Luigi Ferrucci
Subjects: Age-related macular degeneration, Aging, Geographic atrophy, Lipids, Mass spectrometry, Neovascular AMD, Nutritional diseases. Deficiency diseases, RC620-627
Abstract: Abstract Background Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. Methods In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Results Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Conclusion Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy.
Published: 2019
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39. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan Sargurupremraj, Niina Pitkänen, Oscar Franzén, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih-Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, André G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Pasaniuc, Brenda W. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’Leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, Eric Boerwinkle, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline de Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. L. M. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimaki, Mike A. Nalls, Olle Melander, Olli Raitakari, Oscar H. Franco, Oscar L. Rueda-Ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, Reinhold Schmidt, Renée de Mutsert, Richard W. Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela McLachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf de Faire, Vincent Plagnol, Wayne D. Rosamond, Wendy Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, MEGASTROKE Consortium, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. van Duijn, Deborah A. Lawlor, Dennis O. Mook-Kanamori, Donald W. Bowden, Helena Schmidt, James F. Wilson, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo-Pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Gudnason, Aroon D. Hingorani, Johan L. M. Björkegren, Juan P. Casas, and Christopher J. O’Donnell
Subjects: Science
Abstract: Carotid intima-media thickness (cIMT) and plaque are associated with subclinical atherosclerosis and coronary heart disease (CHD). Here, the authors identify and prioritize genetic loci for cIMT and plaque by GWAS and colocalization approaches and further demonstrate genetic correlation with CHD and stroke.
Published: 2018
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40. The use of predictive models in dynamic treatment planning.

Author: Saemundur O. Haraldsson, Ragnheidur D. Brynjolfsdottir, John R. Woodward, Kristin Siggeirsdottir, and Vilmundur Gudnason
Published: 2017
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41. Genetic improvement of runtime and its fitness landscape in a bioinformatics application.

Author: Saemundur O. Haraldsson, John R. Woodward, Alexander E. I. Brownlee, Albert V. Smith, and Vilmundur Gudnason
Published: 2017
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42. Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Author: Daokun Sun, Melissa A. Richard, Solomon K. Musani, Yun Ju Sung, Thomas W. Winkler, Karen Schwander, Jin Fang Chai, Xiuqing Guo, Tuomas O. Kilpeläinen, Dina Vojinovic, Hugues Aschard, Traci M. Bartz, Lawrence F. Bielak, Michael R. Brown, Kumaraswamy Chitrala, Fernando P. Hartwig, Andrea R.V.R. Horimoto, Yongmei Liu, Alisa K. Manning, Raymond Noordam, Albert V. Smith, Sarah E. Harris, Brigitte Kühnel, Leo-Pekka Lyytikäinen, Ilja M. Nolte, Rainer Rauramaa, Peter J. van der Most, Rujia Wang, Erin B. Ware, Stefan Weiss, Wanqing Wen, Lisa R. Yanek, Dan E. Arking, Donna K. Arnett, Ana Barac, Eric Boerwinkle, Ulrich Broeckel, Aravinda Chakravarti, Yii-Der Ida Chen, L. Adrienne Cupples, Martha L. Davigulus, Lisa de las Fuentes, Renée de Mutsert, Paul S. de Vries, Joseph A.C. Delaney, Ana V. Diez Roux, Marcus Dörr, Jessica D. Faul, Amanda M. Fretts, Linda C. Gallo, Hans Jörgen Grabe, C. Charles Gu, Tamara B. Harris, Catharina C.A. Hartman, Sami Heikkinen, M. Arfan Ikram, Carmen Isasi, W. Craig Johnson, Jost Bruno Jonas, Robert C. Kaplan, Pirjo Komulainen, Jose E. Krieger, Daniel Levy, Jianjun Liu, Kurt Lohman, Annemarie I. Luik, Lisa W. Martin, Thomas Meitinger, Yuri Milaneschi, Jeff R. O’Connell, Walter R. Palmas, Annette Peters, Patricia A. Peyser, Laura Pulkki-Råback, Leslie J. Raffel, Alex P. Reiner, Kenneth Rice, Jennifer G. Robinson, Frits R. Rosendaal, Carsten Oliver Schmidt, Pamela J. Schreiner, Lars Schwettmann, James M. Shikany, Xiao-ou Shu, Stephen Sidney, Mario Sims, Jennifer A. Smith, Nona Sotoodehnia, Konstantin Strauch, E. Shyong Tai, Kent D. Taylor, André G. Uitterlinden, Cornelia M. van Duijn, Melanie Waldenberger, Hwee-Lin Wee, Wen-Bin Wei, Gregory Wilson, Deng Xuan, Jie Yao, Donglin Zeng, Wei Zhao, Xiaofeng Zhu, Alan B. Zonderman, Diane M. Becker, Ian J. Deary, Christian Gieger, Timo A. Lakka, Terho Lehtimäki, Kari E. North, Albertine J. Oldehinkel, Brenda W.J.H. Penninx, Harold Snieder, Ya-Xing Wang, David R. Weir, Wei Zheng, Michele K. Evans, W. James Gauderman, Vilmundur Gudnason, Bernardo L. Horta, Ching-Ti Liu, Dennis O. Mook-Kanamori, Alanna C. Morrison, Alexandre C. Pereira, Bruce M. Psaty, Najaf Amin, Ervin R. Fox, Charles Kooperberg, Xueling Sim, Laura Bierut, Jerome I. Rotter, Sharon L.R. Kardia, Nora Franceschini, Dabeeru C. Rao, and Myriam Fornage
Subjects: gene-environment interaction, genome-wide association study, blood pressure, hypertension, psychosocial factors, depressive symptoms, Genetics, QH426-470
Abstract: Summary: Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value < 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.
Published: 2021
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43. Progression of traction bronchiectasis/bronchiolectasis in interstitial lung abnormalities is associated with increased all-cause mortality: Age Gene/Environment Susceptibility-Reykjavik Study

Author: Takuya Hino, Tomoyuki Hida, Mizuki Nishino, Junwei Lu, Rachel K. Putman, Elias F. Gudmundsson, Akinori Hata, Tetsuro Araki, Vladimir I. Valtchinov, Osamu Honda, Masahiro Yanagawa, Yoshitake Yamada, Takeshi Kamitani, Masahiro Jinzaki, Noriyuki Tomiyama, Kousei Ishigami, Hiroshi Honda, Raul San Jose Estepar, George R. Washko, Takeshi Johkoh, David C. Christiani, David A. Lynch, Vilmundur Gudnason, Gunnar Gudmundsson, Gary M. Hunninghake, and Hiroto Hatabu
Subjects: Interstitial lung abnormality, Usual interstitial pneumonia, Pulmonary fibrosis, Traction bronchiectasis, Age Gene/Environment Susceptibility-Reykjavik Study, Medical physics. Medical radiology. Nuclear medicine, R895-920
Abstract: Purpose: The aim of this study is to assess the role of traction bronchiectasis/bronchiolectasis and its progression as a predictor for early fibrosis in interstitial lung abnormalities (ILA). Methods: Three hundred twenty-seven ILA participants out of 5764 in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who had undergone chest CT twice with an interval of approximately five-years were enrolled in this study. Traction bronchiectasis/bronchiolectasis index (TBI) was classified on a four-point scale: 0, ILA without traction bronchiectasis/bronchiolectasis; 1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion; 2, ILA with mild to moderate traction bronchiectasis; 3, ILA and severe traction bronchiectasis and/or honeycombing. Traction bronchiectasis (TB) progression was classified on a five-point scale: 1, Improved; 2, Probably improved; 3, No change; 4, Probably progressed; 5, Progressed. Overall survival (OS) among participants with different TB Progression Score and between the TB progression group and No TB progression group was also investigated. Hazard radio (HR) was estimated with Cox proportional hazards model. Results: The higher the TBI at baseline, the higher TB Progression Score (P
Published: 2021
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44. Body weight changes and longitudinal associations with cognitive decline among community‐dwelling older adults

Author: Hrafnhildur Eymundsdottir, Alfons Ramel, Olof G. Geirsdottir, Sigrun S. Skuladottir, Larus S. Gudmundsson, Palmi V. Jonsson, Vilmundur Gudnason, Lenore Launer, Maria K. Jonsdottir, and Milan Chang
Subjects: APOE ε4, body weight changes, cognitive function, dementia, executive function, memory function, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction We aim to investigate the longitudinal associations between changes in body weight (BW) and declines in cognitive function and risk of mild cognitive impairment (MCI)/dementia among cognitively normal individuals 65 years or older. Methods Data from the Age Gene/Environment Susceptibility‐Reykjavik Study (AGES‐Reykjavik Study) including 2620 participants, were examined using multiple logistic regression models. Cognitive function included speed of processing (SP), executive function (EF), and memory function (MF). Changes in BW were classified as; weight loss (WL), weight gain (WG), and stable weight (SW). Results Mean follow‐up time was 5.2 years and 61.3% were stable weight. Participants who experienced WL (13.4%) were significantly more likely to have declines in MF and SP compared to the SW group. Weight changes were not associated with EF. WL was associated with a higher risk of MCI, while WG (25.3%) was associated with a higher dementia risk, when compared to SW. Discussion Significant BW changes in older adulthood may indicate impending changes in cognitive function.
Published: 2021
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45. Correction: Association of low-frequency and rare coding variants with information processing speed

Author: Jan Bressler, Gail Davies, Albert V. Smith, Yasaman Saba, Joshua C. Bis, Xueqiu Jian, Caroline Hayward, Lisa Yanek, Jennifer A. Smith, Saira S. Mirza, Ruiqi Wang, Hieab H. H. Adams, Diane Becker, Eric Boerwinkle, Archie Campbell, Simon R. Cox, Gudny Eiriksdottir, Chloe Fawns-Ritchie, Rebecca F. Gottesman, Megan L. Grove, Xiuqing Guo, Edith Hofer, Sharon L. R. Kardia, Maria J. Knol, Marisa Koini, Oscar L. Lopez, Riccardo E. Marioni, Paul Nyquist, Alison Pattie, Ozren Polasek, David J. Porteous, Igor Rudan, Claudia L. Satizabal, Helena Schmidt, Reinhold Schmidt, Stephen Sidney, Jeannette Simino, Blair H. Smith, Stephen T. Turner, Sven J. van der Lee, Erin B. Ware, Rachel A. Whitmer, Kristine Yaffe, Qiong Yang, Wei Zhao, Vilmundur Gudnason, Lenore J. Launer, Annette L. Fitzpatrick, Bruce M. Psaty, Myriam Fornage, M. Arfan Ikram, Cornelia M. van Duijn, Sudha Seshadri, Thomas H. Mosley, and Ian J. Deary
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published: 2022
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46. Fatty acids in the de novo lipogenesis pathway and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies.

Author: Fumiaki Imamura, Amanda M Fretts, Matti Marklund, Andres V Ardisson Korat, Wei-Sin Yang, Maria Lankinen, Waqas Qureshi, Catherine Helmer, Tzu-An Chen, Jyrki K Virtanen, Kerry Wong, Julie K Bassett, Rachel Murphy, Nathan Tintle, Chaoyu Ian Yu, Ingeborg A Brouwer, Kuo-Liong Chien, Yun-Yu Chen, Alexis C Wood, Liana C Del Gobbo, Luc Djousse, Johanna M Geleijnse, Graham G Giles, Janette de Goede, Vilmundur Gudnason, William S Harris, Allison Hodge, Frank Hu, InterAct Consortium, Albert Koulman, Markku Laakso, Lars Lind, Hung-Ju Lin, Barbara McKnight, Kalina Rajaobelina, Ulf Riserus, Jennifer G Robinson, Cecilia Samieri, Mackenzie Senn, David S Siscovick, Sabita S Soedamah-Muthu, Nona Sotoodehnia, Qi Sun, Michael Y Tsai, Tomi-Pekka Tuomainen, Matti Uusitupa, Lynne E Wagenknecht, Nick J Wareham, Jason H Y Wu, Renata Micha, Rozenn N Lemaitre, Dariush Mozaffarian, and Nita G Forouhi
Subjects: Medicine
Abstract: BackgroundDe novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).Methods and findingsSeventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.ConclusionsConcentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.
Published: 2020
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47. Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

Author: Julie Hahn, Yi-Ping Fu, Michael R Brown, Joshua C Bis, Paul S de Vries, Mary F Feitosa, Lisa R Yanek, Stefan Weiss, Franco Giulianini, Albert Vernon Smith, Xiuqing Guo, Traci M Bartz, Diane M Becker, Lewis C Becker, Eric Boerwinkle, Jennifer A Brody, Yii-Der Ida Chen, Oscar H Franco, Megan Grove, Tamara B Harris, Albert Hofman, Shih-Jen Hwang, Brian G Kral, Lenore J Launer, Marcello R P Markus, Kenneth M Rice, Stephen S Rich, Paul M Ridker, Fernando Rivadeneira, Jerome I Rotter, Nona Sotoodehnia, Kent D Taylor, André G Uitterlinden, Uwe Völker, Henry Völzke, Jie Yao, Daniel I Chasman, Marcus Dörr, Vilmundur Gudnason, Rasika A Mathias, Wendy Post, Bruce M Psaty, Abbas Dehghan, Christopher J O'Donnell, and Alanna C Morrison
Subjects: Medicine, Science
Abstract: BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.Methods and resultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.ConclusionThis study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.
Published: 2020
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48. Smoking-by-genotype interaction in type 2 diabetes risk and fasting glucose.

Author: Peitao Wu, Denis Rybin, Lawrence F Bielak, Mary F Feitosa, Nora Franceschini, Yize Li, Yingchang Lu, Jonathan Marten, Solomon K Musani, Raymond Noordam, Sridharan Raghavan, Lynda M Rose, Karen Schwander, Albert V Smith, Salman M Tajuddin, Dina Vojinovic, Najaf Amin, Donna K Arnett, Erwin P Bottinger, Ayse Demirkan, Jose C Florez, Mohsen Ghanbari, Tamara B Harris, Lenore J Launer, Jingmin Liu, Jun Liu, Dennis O Mook-Kanamori, Alison D Murray, Mike A Nalls, Patricia A Peyser, André G Uitterlinden, Trudy Voortman, Claude Bouchard, Daniel Chasman, Adolfo Correa, Renée de Mutsert, Michele K Evans, Vilmundur Gudnason, Caroline Hayward, Linda Kao, Sharon L R Kardia, Charles Kooperberg, Ruth J F Loos, Michael M Province, Tuomo Rankinen, Susan Redline, Paul M Ridker, Jerome I Rotter, David Siscovick, Blair H Smith, Cornelia van Duijn, Alan B Zonderman, D C Rao, James G Wilson, Josée Dupuis, James B Meigs, Ching-Ti Liu, and Jason L Vassy
Subjects: Medicine, Science
Abstract: Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p
Published: 2020
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49. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Author: Dina Vojinovic, Hieab H. Adams, Xueqiu Jian, Qiong Yang, Albert Vernon Smith, Joshua C. Bis, Alexander Teumer, Markus Scholz, Nicola J. Armstrong, Edith Hofer, Yasaman Saba, Michelle Luciano, Manon Bernard, Stella Trompet, Jingyun Yang, Nathan A. Gillespie, Sven J. van der Lee, Alexander Neumann, Shahzad Ahmad, Ole A. Andreassen, David Ames, Najaf Amin, Konstantinos Arfanakis, Mark E. Bastin, Diane M. Becker, Alexa S. Beiser, Frauke Beyer, Henry Brodaty, R. Nick Bryan, Robin Bülow, Anders M. Dale, Philip L. De Jager, Ian J. Deary, Charles DeCarli, Debra A. Fleischman, Rebecca F. Gottesman, Jeroen van der Grond, Vilmundur Gudnason, Tamara B. Harris, Georg Homuth, David S. Knopman, John B. Kwok, Cora E. Lewis, Shuo Li, Markus Loeffler, Oscar L. Lopez, Pauline Maillard, Hanan El Marroun, Karen A. Mather, Thomas H. Mosley, Ryan L. Muetzel, Matthias Nauck, Paul A. Nyquist, Matthew S. Panizzon, Zdenka Pausova, Bruce M. Psaty, Ken Rice, Jerome I. Rotter, Natalie Royle, Claudia L. Satizabal, Reinhold Schmidt, Peter R. Schofield, Pamela J. Schreiner, Stephen Sidney, David J. Stott, Anbupalam Thalamuthu, Andre G. Uitterlinden, Maria C. Valdés Hernández, Meike W. Vernooij, Wei Wen, Tonya White, A. Veronica Witte, Katharina Wittfeld, Margaret J. Wright, Lisa R. Yanek, Henning Tiemeier, William S. Kremen, David A. Bennett, J. Wouter Jukema, Tomas Paus, Joanna M. Wardlaw, Helena Schmidt, Perminder S. Sachdev, Arno Villringer, Hans Jörgen Grabe, W T Longstreth, Cornelia M. van Duijn, Lenore J. Launer, Sudha Seshadri, M Arfan Ikram, and Myriam Fornage
Subjects: Science
Abstract: An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.
Published: 2018
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50. PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Author: Jessica van Setten, Jennifer A. Brody, Yalda Jamshidi, Brenton R. Swenson, Anne M. Butler, Harry Campbell, Fabiola M. Del Greco, Daniel S. Evans, Quince Gibson, Daniel F. Gudbjartsson, Kathleen F. Kerr, Bouwe P. Krijthe, Leo-Pekka Lyytikäinen, Christian Müller, Martina Müller-Nurasyid, Ilja M. Nolte, Sandosh Padmanabhan, Marylyn D. Ritchie, Antonietta Robino, Albert V. Smith, Maristella Steri, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sheila Ulivi, Niek Verweij, Xiaoyan Yin, David O. Arnar, Folkert W. Asselbergs, Joel S. Bader, John Barnard, Josh Bis, Stefan Blankenberg, Eric Boerwinkle, Yuki Bradford, Brendan M. Buckley, Mina K. Chung, Dana Crawford, Marcel den Hoed, Josh C. Denny, Anna F. Dominiczak, Georg B. Ehret, Mark Eijgelsheim, Patrick T. Ellinor, Stephan B. Felix, Oscar H. Franco, Lude Franke, Tamara B. Harris, Hilma Holm, Gandin Ilaria, Annamaria Iorio, Mika Kähönen, Ivana Kolcic, Jan A. Kors, Edward G. Lakatta, Lenore J. Launer, Honghuang Lin, Henry J. Lin, Ruth J. F. Loos, Steven A. Lubitz, Peter W. Macfarlane, Jared W. Magnani, Irene Mateo Leach, Thomas Meitinger, Braxton D. Mitchell, Thomas Munzel, George J. Papanicolaou, Annette Peters, Arne Pfeufer, Peter P. Pramstaller, Olli T. Raitakari, Jerome I. Rotter, Igor Rudan, Nilesh J. Samani, David Schlessinger, Claudia T. Silva Aldana, Moritz F. Sinner, Jonathan D. Smith, Harold Snieder, Elsayed Z. Soliman, Timothy D. Spector, David J. Stott, Konstantin Strauch, Kirill V. Tarasov, Unnur Thorsteinsdottir, Andre G. Uitterlinden, David R. Van Wagoner, Uwe Völker, Henry Völzke, Melanie Waldenberger, Harm Jan Westra, Philipp S. Wild, Tanja Zeller, Alvaro Alonso, Christy L. Avery, Stefania Bandinelli, Emelia J. Benjamin, Francesco Cucca, Marcus Dörr, Luigi Ferrucci, Paolo Gasparini, Vilmundur Gudnason, Caroline Hayward, Susan R. Heckbert, Andrew A. Hicks, J. Wouter Jukema, Stefan Kääb, Terho Lehtimäki, Yongmei Liu, Patricia B. Munroe, Afshin Parsa, Ozren Polasek, Bruce M. Psaty, Dan M. Roden, Renate B. Schnabel, Gianfranco Sinagra, Kari Stefansson, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, James F. Wilson, Sina A. Gharib, Paul I. W. de Bakker, Aaron Isaacs, Dan E. Arking, and Nona Sotoodehnia
Subjects: Science
Abstract: Abnormal PR interval duration is associated with risk for atrial fibrillation and heart block. Here, van Setten et al. identify 44 PR interval loci in a genome-wide association study of over 92,000 individuals and find genetic overlap with QRS duration, heart rate and atrial fibrillation.
Published: 2018
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