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1. Complex trait susceptibilities and population diversity in a sample of 4,145 Russians

Author: Dmitrii Usoltsev, Nikita Kolosov, Oxana Rotar, Alexander Loboda, Maria Boyarinova, Ekaterina Moguchaya, Ekaterina Kolesova, Anastasia Erina, Kristina Tolkunova, Valeriia Rezapova, Ivan Molotkov, Olesya Melnik, Olga Freylikhman, Nadezhda Paskar, Asiiat Alieva, Elena Baranova, Elena Bazhenova, Olga Beliaeva, Elena Vasilyeva, Sofia Kibkalo, Rostislav Skitchenko, Alina Babenko, Alexey Sergushichev, Alena Dushina, Ekaterina Lopina, Irina Basyrova, Roman Libis, Dmitrii Duplyakov, Natalya Cherepanova, Kati Donner, Paivi Laiho, Anna Kostareva, Alexandra Konradi, Evgeny Shlyakhto, Aarno Palotie, Mark J. Daly, and Mykyta Artomov
Subjects: Science
Abstract: Abstract The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ancestries. We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed genetic ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts. Finally, we provide access to a database of allele frequencies and GWAS results for 464 phenotypes.
Published: 2024
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2. Polygenic risk scores as a marker for epilepsy risk across lifetime and after unspecified seizure events

Author: Henrike O. Heyne, Fanny-Dhelia Pajuste, Julian Wanner, Jennifer I. Daniel Onwuchekwa, Reedik Mägi, Aarno Palotie, FinnGen, Estonian Biobank research team, Reetta Kälviainen, and Mark J. Daly
Subjects: Science
Abstract: Abstract A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence epilepsy risk in detailed longitudinal electronic health records (EHRs) of > 700k Finns and Estonians. We found that a high genetic generalized epilepsy PRS (PRSGGE) increased risk for genetic generalized epilepsy (GGE) (hazard ratio [HR] 1.73 per PRSGGE standard deviation [SD]) across lifetime and within 10 years after an unspecified seizure event. The effect of PRSGGE was significantly larger on idiopathic generalized epilepsies, in females and for earlier epilepsy onset. Analogously, we found significant but more modest focal epilepsy PRS burden associated with non-acquired focal epilepsy (NAFE). Here, we outline the potential of epilepsy specific PRSs to serve as biomarkers after a first seizure event.
Published: 2024
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3. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients

Author: Yiming Wu, Kyle Gettler, Meltem Ece Kars, Mamta Giri, Dalin Li, Cigdem Sevim Bayrak, Peng Zhang, Aayushee Jain, Patrick Maffucci, Ksenija Sabic, Tielman Van Vleck, Girish Nadkarni, Lee A. Denson, Harry Ostrer, Adam P. Levine, Elena R. Schiff, Anthony W. Segal, Subra Kugathasan, Peter D. Stenson, David N. Cooper, L. Philip Schumm, Scott Snapper, Mark J. Daly, Talin Haritunians, Richard H. Duerr, Mark S. Silverberg, John D. Rioux, Steven R. Brant, Dermot P. B. McGovern, Judy H. Cho, and Yuval Itan
Subjects: Science
Abstract: Abstract Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.
Published: 2023
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4. Mendelian Randomization Analysis reveals Inverse Genetic Risks between Skin Cancers and Vitiligo

Author: Sarem Rashid, Ivan Molotkov, Nikolai Klebanov, Michael Shaughnessy, Mark J. Daly, Mykyta Artomov, and Hensin Tsao
Subjects: Dermatology, RL1-803
Abstract: Several observational studies have demonstrated a consistent pattern of decreased melanoma risk among patients with vitiligo. More recently, this finding has been supported by a suggested genetic relationship between the two entities, with certain variants significantly associated with an increased risk of melanoma, basal cell carcinoma, and squamous cell carcinoma but a decreased risk of vitiligo. We compared 48 associated variants from a recently published GWAS and identified three variants—located in the TYR, MC1R-DEF8, and RALY-EIF2S2-ASIP-AHCY-ITCH loci— that correlated with an increased risk for melanoma, basal cell carcinoma, and squamous cell carcinoma and a decreased risk for vitiligo. We then used results of skin cancers and vitiligo GWAS to compare the shared genetic properties between these two traits through an unbiased Mendelian randomization analysis. Our results suggest that the inverse genetic relationship between common skin cancers and vitiligo is broader than previously reported owing to the influence of shared genome-wide significant associations.
Published: 2023
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5. Profiling the inflammatory bowel diseases using genetics, serum biomarkers, and smoking information

Author: Ruize Liu, Dalin Li, Talin Haritunians, Yunfeng Ruan, Mark J. Daly, Hailiang Huang, and Dermot P.B. McGovern
Subjects: Association analysis, Diagnostic technique in health technology, Gastroenterology, Human Genetics, Smoking, Science
Abstract: Summary: Crohn's disease (CD) and ulcerative colitis (UC) are two etiologically related yet distinctive subtypes of the inflammatory bowel diseases (IBD). Differentiating CD from UC can be challenging using conventional clinical approaches in a subset of patients. We designed and evaluated a novel molecular-based prediction model aggregating genetics, serum biomarkers, and tobacco smoking information to assist the diagnosis of CD and UC in over 30,000 samples. A joint model combining genetics, serum biomarkers and smoking explains 46% (42–50%, 95% CI) of phenotypic variation. Despite modest overlaps with serum biomarkers, genetics makes unique contributions to distinguishing IBD subtypes. Smoking status only explains 1% (0–6%, 95% CI) of the phenotypic variance suggesting it may not be an effective biomarker. This study reveals that molecular-based models combining genetics, serum biomarkers, and smoking information could complement current diagnostic strategies and help classify patients based on biologic state rather than imperfect clinical parameters.
Published: 2023
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6. Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure

Author: Joel T. Rämö, Tuomo Kiiskinen, Richard Seist, Kristi Krebs, Masahiro Kanai, Juha Karjalainen, Mitja Kurki, Eija Hämäläinen, Paavo Häppölä, Aki S. Havulinna, Heidi Hautakangas, FinnGen, Reedik Mägi, Priit Palta, Tõnu Esko, Andres Metspalu, Matti Pirinen, Konrad J. Karczewski, Samuli Ripatti, Lili Milani, Konstantina M. Stankovic, Antti Mäkitie, Mark J. Daly, and Aarno Palotie
Subjects: Science
Abstract: Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.
Published: 2023
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7. Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis

Author: Sanni E. Ruotsalainen, Ida Surakka, Nina Mars, Juha Karjalainen, Mitja Kurki, Masahiro Kanai, Kristi Krebs, Sarah Graham, Pashupati P. Mishra, Binisha H. Mishra, Juha Sinisalo, Priit Palta, Terho Lehtimäki, Olli Raitakari, Estonian Biobank Research Team, Lili Milani, The Biobank Japan Project, Yukinori Okada, FinnGen, Aarno Palotie, Elisabeth Widen, Mark J. Daly, and Samuli Ripatti
Subjects: Biology (General), QH301-705.5
Abstract: A genome-wide association study identifies MFGE8 as protective against coronary atherosclerosis in European and East Asian populations.
Published: 2022
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8. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author: Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, Stephan Ripke, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Jr., Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lönnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, F. Anthony O'Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Söderman, Srinivas Thirumalai, Draga Toncheva, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O'Donovan, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, and Makoto Kinoshita
Subjects: Molecular interaction, Developmental neuroscience, Cellular neuroscience, Proteomics, Science
Abstract: Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.
Published: 2023
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9. Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Author: Ying Wang, Shinichi Namba, Esteban Lopera, Sini Kerminen, Kristin Tsuo, Kristi Läll, Masahiro Kanai, Wei Zhou, Kuan-Han Wu, Marie-Julie Favé, Laxmi Bhatta, Philip Awadalla, Ben Brumpton, Patrick Deelen, Kristian Hveem, Valeria Lo Faro, Reedik Mägi, Yoshinori Murakami, Serena Sanna, Jordan W. Smoller, Jasmina Uzunovic, Brooke N. Wolford, Cristen Willer, Eric R. Gamazon, Nancy J. Cox, Ida Surakka, Yukinori Okada, Alicia R. Martin, Jibril Hirbo, Kuan-Han H. Wu, Humaira Rasheed, Jibril B. Hirbo, Arjun Bhattacharya, Huiling Zhao, Esteban A. Lopera-Maya, Sinéad B. Chapman, Juha Karjalainen, Mitja Kurki, Maasha Mutaamba, Juulia J. Partanen, Ben M. Brumpton, Sameer Chavan, Tzu-Ting Chen, Michelle Daya, Yi Ding, Yen-Chen A. Feng, Christopher R. Gignoux, Sarah E. Graham, Whitney E. Hornsby, Nathan Ingold, Ruth Johnson, Triin Laisk, Kuang Lin, Jun Lv, Iona Y. Millwood, Priit Palta, Anita Pandit, Michael H. Preuss, Unnur Thorsteinsdottir, Matthew Zawistowski, Xue Zhong, Archie Campbell, Kristy Crooks, Geertruida H. de Bock, Nicholas J. Douville, Sarah Finer, Lars G. Fritsche, Christopher J. Griffiths, Yu Guo, Karen A. Hunt, Takahiro Konuma, Riccardo E. Marioni, Jansonius Nomdo, Snehal Patil, Nicholas Rafaels, Anne Richmond, Jonathan A. Shortt, Peter Straub, Ran Tao, Brett Vanderwerff, Kathleen C. Barnes, Marike Boezen, Zhengming Chen, Chia-Yen Chen, Judy Cho, George Davey Smith, Hilary K. Finucane, Lude Franke, Andrea Ganna, Tom R. Gaunt, Tian Ge, Hailiang Huang, Jennifer Huffman, Jukka T. Koskela, Clara Lajonchere, Matthew H. Law, Liming Li, Cecilia M. Lindgren, Ruth J.F. Loos, Stuart MacGregor, Koichi Matsuda, Catherine M. Olsen, David J. Porteous, Jordan A. Shavit, Harold Snieder, Richard C. Trembath, Judith M. Vonk, David Whiteman, Stephen J. Wicks, Cisca Wijmenga, John Wright, Jie Zheng, Xiang Zhou, Michael Boehnke, Daniel H. Geschwind, Caroline Hayward, Eimear E. Kenny, Yen-Feng Lin, Hilary C. Martin, Sarah E. Medland, Aarno V. Palotie, Bogdan Pasaniuc, Kari Stefansson, David A. van Heel, Robin G. Walters, Sebastian Zöllner, Cristen J. Willer, Mark J. Daly, and Benjamin M. Neale
Subjects: Global-Biobank Meta-analysis Initiative, polygenic risk scores, multi-ancestry genetic prediction, accuracy heterogeneity, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract: Summary: Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.
Published: 2023
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10. Functional screen of inflammatory bowel disease genes reveals key epithelial functions

Author: Jessy Carol Ntunzwenimana, Gabrielle Boucher, Jean Paquette, Hugues Gosselin, Azadeh Alikashani, Nicolas Morin, Claudine Beauchamp, Louise Thauvette, Marie-Ève Rivard, Frédérique Dupuis, Sonia Deschênes, Sylvain Foisy, Frédéric Latour, Geneviève Lavallée, Mark J. Daly, Ramnik J. Xavier, the iGenoMed Consortium, Guy Charron, Philippe Goyette, and John D. Rioux
Subjects: Inflammatory bowel diseases, Type I interferon response, Mucosal immunity, Secretory immunoglobulins, Medicine, Genetics, QH426-470
Abstract: Abstract Background Genetic studies have been tremendously successful in identifying genomic regions associated with a wide variety of phenotypes, although the success of these studies in identifying causal genes, their variants, and their functional impacts has been more limited. Methods We identified 145 genes from IBD-associated genomic loci having endogenous expression within the intestinal epithelial cell compartment. We evaluated the impact of lentiviral transfer of the open reading frame (ORF) of these IBD genes into the HT-29 intestinal epithelial cell line via transcriptomic analyses. By comparing the genes in which expression was modulated by each ORF, as well as the functions enriched within these gene lists, we identified ORFs with shared impacts and their putative disease-relevant biological functions. Results Analysis of the transcriptomic data for cell lines expressing the ORFs for known causal genes such as HNF4a, IFIH1, and SMAD3 identified functions consistent with what is already known for these genes. These analyses also identified two major clusters of genes: Cluster 1 contained the known IBD causal genes IFIH1, SBNO2, NFKB1, and NOD2, as well as genes from other IBD loci (ZFP36L1, IRF1, GIGYF1, OTUD3, AIRE and PITX1), whereas Cluster 2 contained the known causal gene KSR1 and implicated DUSP16 from another IBD locus. Our analyses highlight how multiple IBD gene candidates can impact on epithelial structure and function, including the protection of the mucosa from intestinal microbiota, and demonstrate that DUSP16 acts a regulator of MAPK activity and contributes to mucosal defense, in part via its regulation of the polymeric immunoglobulin receptor, involved in the protection of the intestinal mucosa from enteric microbiota. Conclusions This functional screen, based on expressing IBD genes within an appropriate cellular context, in this instance intestinal epithelial cells, resulted in changes to the cell’s transcriptome that are relevant to their endogenous biological function(s). This not only helped in identifying likely causal genes within genetic loci but also provided insight into their biological functions. Furthermore, this work has highlighted the central role of intestinal epithelial cells in IBD pathophysiology, providing a scientific rationale for a drug development strategy that targets epithelial functions in addition to the current therapies targeting immune functions.
Published: 2021
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11. Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices

Author: Pradeep Natarajan, Akhil Pampana, Sarah E. Graham, Sanni E. Ruotsalainen, James A. Perry, Paul S. de Vries, Jai G. Broome, James P. Pirruccello, Michael C. Honigberg, Krishna Aragam, Brooke Wolford, Jennifer A. Brody, Lucinda Antonacci-Fulton, Moscati Arden, Stella Aslibekyan, Themistocles L. Assimes, Christie M. Ballantyne, Lawrence F. Bielak, Joshua C. Bis, Brian E. Cade, Ron Do, Harsha Doddapaneni, Leslie S. Emery, Yi-Jen Hung, Marguerite R. Irvin, Alyna T. Khan, Leslie Lange, Jiwon Lee, Rozenn N. Lemaitre, Lisa W. Martin, Ginger Metcalf, May E. Montasser, Jee-Young Moon, Donna Muzny, Jeffrey R. O’Connell, Nicholette D. Palmer, Juan M. Peralta, Patricia A. Peyser, Adrienne M. Stilp, Michael Tsai, Fei Fei Wang, Daniel E. Weeks, Lisa R. Yanek, James G. Wilson, Goncalo Abecasis, Donna K. Arnett, Lewis C. Becker, John Blangero, Eric Boerwinkle, Donald W. Bowden, Yi-Cheng Chang, Yii-Der I. Chen, Won Jung Choi, Adolfo Correa, Joanne E. Curran, Mark J. Daly, Susan K. Dutcher, Patrick T. Ellinor, Myriam Fornage, Barry I. Freedman, Stacey Gabriel, Soren Germer, Richard A. Gibbs, Jiang He, Kristian Hveem, Gail P. Jarvik, Robert C. Kaplan, Sharon L. R. Kardia, Eimear Kenny, Ryan W. Kim, Charles Kooperberg, Cathy C. Laurie, Seonwook Lee, Don M. Lloyd-Jones, Ruth J. F. Loos, Steven A. Lubitz, Rasika A. Mathias, Karine A. Viaud Martinez, Stephen T. McGarvey, Braxton D. Mitchell, Deborah A. Nickerson, Kari E. North, Aarno Palotie, Cheol Joo Park, Bruce M. Psaty, D. C. Rao, Susan Redline, Alexander P. Reiner, Daekwan Seo, Jeong-Sun Seo, Albert V. Smith, Russell P. Tracy, Ramachandran S. Vasan, Sekar Kathiresan, L. Adrienne Cupples, Jerome I. Rotter, Alanna C. Morrison, Stephen S. Rich, Samuli Ripatti, Cristen Willer, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, FinnGen, and Gina M. Peloso
Subjects: Science
Abstract: The influence of X chromosome genetic variation on blood lipids and coronary heart disease (CHD) is not well understood. Here, the authors analyse X chromosome sequencing data across 65,322 multi-ancestry individuals, identifying associations of the Xq23 locus with lipid changes and reduced risk of CHD and diabetes mellitus.
Published: 2021
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12. The female protective effect against autism spectrum disorder

Author: Emilie M. Wigdor, Daniel J. Weiner, Jakob Grove, Jack M. Fu, Wesley K. Thompson, Caitlin E. Carey, Nikolas Baya, Celia van der Merwe, Raymond K. Walters, F. Kyle Satterstrom, Duncan S. Palmer, Anders Rosengren, Jonas Bybjerg-Grauholm, David M. Hougaard, Preben Bo Mortensen, Mark J. Daly, Michael E. Talkowski, Stephan J. Sanders, Somer L. Bishop, Anders D. Børglum, and Elise B. Robinson
Subjects: ASD, autism, genetics, genomics, epidemiology, sex differences, Genetics, QH426-470, Internal medicine, RC31-1245
Abstract: Summary: Autism spectrum disorder (ASD) is diagnosed three to four times more frequently in males than in females. Genetic studies of rare variants support a female protective effect (FPE) against ASD. However, sex differences in common inherited genetic risk for ASD are less studied, particularly within families. Leveraging the Danish iPSYCH resource, we found siblings of female ASD cases (n = 1,707) had higher rates of ASD than siblings of male ASD cases (n = 6,270; p
Published: 2022
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13. Case Report: Supernormal Vascular Aging in Leningrad Siege Survivors

Author: Oxana Rotar, Maria Boyarinova, Ekaterina Moguchaya, Kristina Tolkunova, Nikita Kolosov, Valeriia Rezapova, Olga Freylikhman, Dmitrii Usoltsev, Olesya Melnik, Alexey Sergushichev, Vladislav Solntsev, Anna Kostareva, Elena Dubinina, Trudy Voortman, Christine Stevens, Mark J. Daly, Alexandra Konradi, Evgeny Shlyakhto, and Mykyta Artomov
Subjects: supernormal vascular aging, starvation, aging, deep phenotyping, pulse wave velocity (PWV), Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Age-related changes in the vascular system play an important role in the biological age and lifespan of a person and maybe affected from an early age onward. One of the indicators of changes in the vascular system is arterial wall stiffness and its main measure, i.e., carotid-femoral pulse wave velocity (cfPWV). We examined arterial wall stiffness in a sample of 305 Leningrad Siege survivors to assess how hunger and stressful conditions during fetal development and early childhood affected the state of the cardiovascular system at a later age and what factors may neutralize the negative impact sustained in early childhood. Here, we presented an evaluation of two unique patients with supernormal vascular aging (SUPERNOVA) phenotype from this cohort and described the details of congruence between hereditary resistance and practiced lifestyle yielding slower biological aging rate.
Published: 2022
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14. Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease

Author: Shixian Hu, Werna T. Uniken Venema, Harm-Jan Westra, Arnau Vich Vila, Ruggero Barbieri, Michiel D. Voskuil, Tjasso Blokzijl, Bernadien H. Jansen, Yanni Li, Mark J. Daly, Ramnik J. Xavier, Gerard Dijkstra, Eleonora A. Festen, and Rinse K. Weersma
Subjects: Science
Abstract: Inflammatory bowel diseases are heterogeneous, and little is known about how underlying genetic variation can affect their development. Here, the authors report that intestinal inflammation modulates the effect of host genetics on the gut mucosal expression of 190 genes in the context of inflammatory bowel diseases.
Published: 2021
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15. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author: Dennis Lal, Patrick May, Eduardo Perez-Palma, Kaitlin E. Samocha, Jack A. Kosmicki, Elise B. Robinson, Rikke S. Møller, Roland Krause, Peter Nürnberg, Sarah Weckhuysen, Peter De Jonghe, Renzo Guerrini, Lisa M. Niestroj, Juliana Du, Carla Marini, EuroEPINOMICS-RES Consortium, James S. Ware, Mitja Kurki, Padhraig Gormley, Sha Tang, Sitao Wu, Saskia Biskup, Annapurna Poduri, Bernd A. Neubauer, Bobby P. C. Koeleman, Katherine L. Helbig, Yvonne G. Weber, Ingo Helbig, Amit R. Majithia, Aarno Palotie, and Mark J. Daly
Subjects: Paralogs, Gene family, Conservation, Missense variants, Neurodevelopmental disorders, Medicine, Genetics, QH426-470
Abstract: Abstract Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
Published: 2020
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16. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Author: Caroline M. Nievergelt, Adam X. Maihofer, Torsten Klengel, Elizabeth G. Atkinson, Chia-Yen Chen, Karmel W. Choi, Jonathan R. I. Coleman, Shareefa Dalvie, Laramie E. Duncan, Joel Gelernter, Daniel F. Levey, Mark W. Logue, Renato Polimanti, Allison C. Provost, Andrew Ratanatharathorn, Murray B. Stein, Katy Torres, Allison E. Aiello, Lynn M. Almli, Ananda B. Amstadter, Søren B. Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley-Koch, S. Bryn Austin, Esmina Avdibegovic, Dragan Babić, Marie Bækvad-Hansen, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan I. Bisson, Marco P. Boks, Elizabeth A. Bolger, Anders D. Børglum, Bekh Bradley, Megan Brashear, Gerome Breen, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg-Grauholm, Joseph R. Calabrese, José M. Caldas- de- Almeida, Anders M. Dale, Mark J. Daly, Nikolaos P. Daskalakis, Jürgen Deckert, Douglas L. Delahanty, Michelle F. Dennis, Seth G. Disner, Katharina Domschke, Alma Dzubur-Kulenovic, Christopher R. Erbes, Alexandra Evans, Lindsay A. Farrer, Norah C. Feeny, Janine D. Flory, David Forbes, Carol E. Franz, Sandro Galea, Melanie E. Garrett, Bizu Gelaye, Elbert Geuze, Charles Gillespie, Aferdita Goci Uka, Scott D. Gordon, Guia Guffanti, Rasha Hammamieh, Supriya Harnal, Michael A. Hauser, Andrew C. Heath, Sian M. J. Hemmings, David Michael Hougaard, Miro Jakovljevic, Marti Jett, Eric Otto Johnson, Ian Jones, Tanja Jovanovic, Xue-Jun Qin, Angela G. Junglen, Karen-Inge Karstoft, Milissa L. Kaufman, Ronald C. Kessler, Alaptagin Khan, Nathan A. Kimbrel, Anthony P. King, Nastassja Koen, Henry R. Kranzler, William S. Kremen, Bruce R. Lawford, Lauren A. M. Lebois, Catrin E. Lewis, Sarah D. Linnstaedt, Adriana Lori, Bozo Lugonja, Jurjen J. Luykx, Michael J. Lyons, Jessica Maples-Keller, Charles Marmar, Alicia R. Martin, Nicholas G. Martin, Douglas Maurer, Matig R. Mavissakalian, Alexander McFarlane, Regina E. McGlinchey, Katie A. McLaughlin, Samuel A. McLean, Sarah McLeay, Divya Mehta, William P. Milberg, Mark W. Miller, Rajendra A. Morey, Charles Phillip Morris, Ole Mors, Preben B. Mortensen, Benjamin M. Neale, Elliot C. Nelson, Merete Nordentoft, Sonya B. Norman, Meaghan O’Donnell, Holly K. Orcutt, Matthew S. Panizzon, Edward S. Peters, Alan L. Peterson, Matthew Peverill, Robert H. Pietrzak, Melissa A. Polusny, John P. Rice, Stephan Ripke, Victoria B. Risbrough, Andrea L. Roberts, Alex O. Rothbaum, Barbara O. Rothbaum, Peter Roy-Byrne, Ken Ruggiero, Ariane Rung, Bart P. F. Rutten, Nancy L. Saccone, Sixto E. Sanchez, Dick Schijven, Soraya Seedat, Antonia V. Seligowski, Julia S. Seng, Christina M. Sheerin, Derrick Silove, Alicia K. Smith, Jordan W. Smoller, Scott R. Sponheim, Dan J. Stein, Jennifer S. Stevens, Jennifer A. Sumner, Martin H. Teicher, Wesley K. Thompson, Edward Trapido, Monica Uddin, Robert J. Ursano, Leigh Luella van den Heuvel, Miranda Van Hooff, Eric Vermetten, Christiaan H. Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Thomas Werge, Michelle A. Williams, Douglas E. Williamson, Sherry Winternitz, Christiane Wolf, Erika J. Wolf, Jonathan D. Wolff, Rachel Yehuda, Ross McD. Young, Keith A. Young, Hongyu Zhao, Lori A. Zoellner, Israel Liberzon, Kerry J. Ressler, Magali Haas, and Karestan C. Koenen
Subjects: Science
Abstract: Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.
Published: 2019
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17. Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Author: Rubina Tabassum, Joel T. Rämö, Pietari Ripatti, Jukka T. Koskela, Mitja Kurki, Juha Karjalainen, Priit Palta, Shabbeer Hassan, Javier Nunez-Fontarnau, Tuomo T. J. Kiiskinen, Sanni Söderlund, Niina Matikainen, Mathias J. Gerl, Michal A. Surma, Christian Klose, Nathan O. Stitziel, Hannele Laivuori, Aki S. Havulinna, Susan K. Service, Veikko Salomaa, Matti Pirinen, FinnGen Project, Matti Jauhiainen, Mark J. Daly, Nelson B. Freimer, Aarno Palotie, Marja-Riitta Taskinen, Kai Simons, and Samuli Ripatti
Subjects: Science
Abstract: Cardiovascular diseases (CVD) are associated with plasma lipid levels. Here, Tabassum et al. perform genome-wide association studies for lipidomic profiles with 141 (non-standard) lipid species which highlights shared genetic loci with CVD and that traditional lipids have low genetic correlation with other lipids.
Published: 2019
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18. Paternal-age-related de novo mutations and risk for five disorders

Author: Jacob L. Taylor, Jean-Christophe P. G. Debost, Sarah U. Morton, Emilie M. Wigdor, Henrike O. Heyne, Dennis Lal, Daniel P. Howrigan, Alex Bloemendal, Janne T. Larsen, Jack A. Kosmicki, Daniel J. Weiner, Jason Homsy, Jonathan G. Seidman, Christine E. Seidman, Esben Agerbo, John J. McGrath, Preben Bo Mortensen, Liselotte Petersen, Mark J. Daly, and Elise B. Robinson
Subjects: Science
Abstract: Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.
Published: 2019
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19. Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion

Author: Rossella Spataro, Maria Kousi, Sali M. K. Farhan, Jason R. Willer, Jay P. Ross, Patrick A. Dion, Guy A. Rouleau, Mark J. Daly, Benjamin M. Neale, Vincenzo La Bella, and Nicholas Katsanis
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Background Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. Results We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study. Conclusions We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.
Published: 2019
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20. Contribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland

Author: Mitja I. Kurki, Elmo Saarentaus, Olli Pietiläinen, Padhraig Gormley, Dennis Lal, Sini Kerminen, Minna Torniainen-Holm, Eija Hämäläinen, Elisa Rahikkala, Riikka Keski-Filppula, Merja Rauhala, Satu Korpi-Heikkilä, Jonna Komulainen–Ebrahim, Heli Helander, Päivi Vieira, Minna Männikkö, Markku Peltonen, Aki S. Havulinna, Veikko Salomaa, Matti Pirinen, Jaana Suvisaari, Jukka S. Moilanen, Jarmo Körkkö, Outi Kuismin, Mark J. Daly, and Aarno Palotie
Subjects: Science
Abstract: Various types of genetic variation contribute to the etiology of intellectual disability (ID). Here, the authors study a cohort of ID patients enriched for mild ID from Finland, to investigate contributions of rare and common variants associated with ID of different levels of severity.
Published: 2019
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21. Phenome-wide association studies across large population cohorts support drug target validation

Author: Dorothée Diogo, Chao Tian, Christopher S. Franklin, Mervi Alanne-Kinnunen, Michael March, Chris C. A. Spencer, Ciara Vangjeli, Michael E. Weale, Hannele Mattsson, Elina Kilpeläinen, Patrick M. A. Sleiman, Dermot F. Reilly, Joshua McElwee, Joseph C. Maranville, Arnaub K. Chatterjee, Aman Bhandari, Khanh-Dung H. Nguyen, Karol Estrada, Mary-Pat Reeve, Janna Hutz, Nan Bing, Sally John, Daniel G. MacArthur, Veikko Salomaa, Samuli Ripatti, Hakon Hakonarson, Mark J. Daly, Aarno Palotie, David A. Hinds, Peter Donnelly, Caroline S. Fox, Aaron G. Day-Williams, Robert M. Plenge, and Heiko Runz
Subjects: Science
Abstract: Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.
Published: 2018
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22. Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author: Seyedeh M. Zekavat, Sanni Ruotsalainen, Robert E. Handsaker, Maris Alver, Jonathan Bloom, Timothy Poterba, Cotton Seed, Jason Ernst, Mark Chaffin, Jesse Engreitz, Gina M. Peloso, Ani Manichaikul, Chaojie Yang, Kathleen A. Ryan, Mao Fu, W. Craig Johnson, Michael Tsai, Matthew Budoff, Ramachandran S. Vasan, L. Adrienne Cupples, Jerome I. Rotter, Stephen S. Rich, Wendy Post, Braxton D. Mitchell, Adolfo Correa, Andres Metspalu, James G. Wilson, Veikko Salomaa, Manolis Kellis, Mark J. Daly, Benjamin M. Neale, Steven McCarroll, Ida Surakka, Tonu Esko, Andrea Ganna, Samuli Ripatti, Sekar Kathiresan, Pradeep Natarajan, and NHLBI TOPMed Lipids Working Group
Subjects: Science
Abstract: Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.
Published: 2018
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23. Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study

Author: Christopher DeBoever, Yosuke Tanigawa, Malene E. Lindholm, Greg McInnes, Adam Lavertu, Erik Ingelsson, Chris Chang, Euan A. Ashley, Carlos D. Bustamante, Mark J. Daly, and Manuel A. Rivas
Subjects: Science
Abstract: Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.
Published: 2018
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24. Host genetic variation and its microbiome interactions within the Human Microbiome Project

Author: Raivo Kolde, Eric A. Franzosa, Gholamali Rahnavard, Andrew Brantley Hall, Hera Vlamakis, Christine Stevens, Mark J. Daly, Ramnik J. Xavier, and Curtis Huttenhower
Subjects: Human Microbiome Project, Microbiome and human genetics, Human genome sequence, Microbiome metagenome sequence, Association studies, Medicine, Genetics, QH426-470
Abstract: Abstract Background Despite the increasing recognition that microbial communities within the human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and microbiome characterization have been performed. Methods We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Results Taxonomic composition and functional potential of the microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling microbiome properties in the microbial communities from multiple body sites. Conclusions This study adds deep sequencing of host genomes to the body-wide microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the microbiome.
Published: 2018
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25. Fine-Scale Genetic Structure in Finland

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

Author: Mykyta Artomov, Manuel A. Rivas, Giulio Genovese, and Mark J. Daly
Subjects: Medicine, Genetics, QH426-470
Abstract: Cancer: Blood mutations linked to solid tumor risk Increased risk for solid tumors linked to mutations detected in blood samples that shorten the coding sequence of their genes. Mark Daly and colleagues from the Broad Institute in Cambridge, Massachusetts, USA, used large genomic databases to test whether having blood cells both with and without genetic variants predicted to shorten the encoded protein—a phenomenon known as mosaic protein-truncating variants (PTVs)—was associated with developing a range of solid-tumor cancers. They studied DNA from around 8,000 people with cancer and 6,000 healthy controls. Other studies have shown that mosaic PTVs precede and predict the development of leukemia. In this study, the scientists not only confirmed previous reports linking these variants to breast and ovarian cancer but also extended the association to include tumors of the brain, skin and lungs. These results broadly connect cancer to blood DNA changes.
Published: 2017
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27. Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author: Seyedeh M. Zekavat, Sanni Ruotsalainen, Robert E. Handsaker, Maris Alver, Jonathan Bloom, Timothy Poterba, Cotton Seed, Jason Ernst, Mark Chaffin, Jesse Engreitz, Gina M. Peloso, Ani Manichaikul, Chaojie Yang, Kathleen A. Ryan, Mao Fu, W. Craig Johnson, Michael Tsai, Matthew Budoff, Ramachandran S. Vasan, L. Adrienne Cupples, Jerome I. Rotter, Stephen S. Rich, Wendy Post, Braxton D. Mitchell, Adolfo Correa, Andres Metspalu, James G. Wilson, Veikko Salomaa, Manolis Kellis, Mark J. Daly, Benjamin M. Neale, Steven McCarroll, Ida Surakka, Tonu Esko, Andrea Ganna, Samuli Ripatti, Sekar Kathiresan, Pradeep Natarajan, and NHLBI TOPMed Lipids Working Group
Subjects: Science
Abstract: The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article.
Published: 2018
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28. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author: Manuel A. Rivas, Daniel Graham, Patrick Sulem, Christine Stevens, A. Nicole Desch, Philippe Goyette, Daniel Gudbjartsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Frauke Degenhardt, Sören Mucha, Mitja I. Kurki, Dalin Li, Mauro D’Amato, Vito Annese, Severine Vermeire, Rinse K. Weersma, Jonas Halfvarson, Paulina Paavola-Sakki, Maarit Lappalainen, Monkol Lek, Beryl Cummings, Taru Tukiainen, Talin Haritunians, Leena Halme, Lotta L. E. Koskinen, Ashwin N. Ananthakrishnan, Yang Luo, Graham A. Heap, Marijn C. Visschedijk, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Daniel G. MacArthur, Benjamin M. Neale, Tariq Ahmad, Carl A. Anderson, Steven R. Brant, Richard H. Duerr, Mark S. Silverberg, Judy H Cho, Aarno Palotie, Päivi Saavalainen, Kimmo Kontula, Martti Färkkilä, Dermot P. B. McGovern, Andre Franke, Kari Stefansson, John D. Rioux, Ramnik J. Xavier, and Mark J. Daly
Subjects: Science
Abstract: While hundreds of loci are linked with inflammatory bowel diseases (IBDs), the functional consequences of the associated variants remain unclear. Here, the authors screened in ulcerative colitis (UC) patients’ genomes for protein-truncating variants near IBD loci, and identify a protein truncating variant in RNF186to be protective against UC.
Published: 2016
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29. Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Author: Seyedeh M. Zekavat, Sanni Ruotsalainen, Robert E. Handsaker, Maris Alver, Jonathan Bloom, Timothy Poterba, Cotton Seed, Jason Ernst, Mark Chaffin, Jesse Engreitz, Gina M. Peloso, Ani Manichaikul, Chaojie Yang, Kathleen A. Ryan, Mao Fu, W. Craig Johnson, Michael Tsai, Matthew Budoff, Ramachandran S. Vasan, L. Adrienne Cupples, Jerome I. Rotter, Stephen S. Rich, Wendy Post, Braxton D. Mitchell, Adolfo Correa, Andres Metspalu, James G. Wilson, Veikko Salomaa, Manolis Kellis, Mark J. Daly, Benjamin M. Neale, Steven McCarroll, Ida Surakka, Tonu Esko, Andrea Ganna, Samuli Ripatti, Sekar Kathiresan, Pradeep Natarajan, and NHLBI TOPMed Lipids Working Group
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020
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30. Integrated Genomics of Crohn’s Disease Risk Variant Identifies a Role for CLEC12A in Antibacterial Autophagy

Author: Jakob Begun, Kara G. Lassen, Humberto B. Jijon, Leigh A. Baxt, Gautam Goel, Robert J. Heath, Aylwin Ng, Jenny M. Tam, Szu-Yu Kuo, Eduardo J. Villablanca, Lola Fagbami, Marije Oosting, Vinod Kumar, Monica Schenone, Steven A. Carr, Leo A.B. Joosten, Jatin M. Vyas, Mark J. Daly, Mihai G. Netea, Gordon D. Brown, Cisca Wijmenga, and Ramnik J. Xavier
Subjects: Biology (General), QH301-705.5
Abstract: The polymorphism ATG16L1 T300A, associated with increased risk of Crohn’s disease, impairs pathogen defense mechanisms including selective autophagy, but specific pathway interactions altered by the risk allele remain unknown. Here, we use perturbational profiling of human peripheral blood cells to reveal that CLEC12A is regulated in an ATG16L1-T300A-dependent manner. Antibacterial autophagy is impaired in CLEC12A-deficient cells, and this effect is exacerbated in the presence of the ATG16L1∗300A risk allele. Clec12a−/− mice are more susceptible to Salmonella infection, supporting a role for CLEC12A in antibacterial defense pathways in vivo. CLEC12A is recruited to sites of bacterial entry, bacteria-autophagosome complexes, and sites of sterile membrane damage. Integrated genomics identified a functional interaction between CLEC12A and an E3-ubiquitin ligase complex that functions in antibacterial autophagy. These data identify CLEC12A as early adaptor molecule for antibacterial autophagy and highlight perturbational profiling as a method to elucidate defense pathways in complex genetic disease.
Published: 2015
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31. Erratum: A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author: Manuel A. Rivas, Daniel Graham, Patrick Sulem, Christine Stevens, A. Nicole Desch, Philippe Goyette, Daniel Gudbjartsson, Ingileif Jonsdottir, Unnur Thorsteinsdottir, Frauke Degenhardt, Sören Mucha, Mitja I. Kurki, Dalin Li, Mauro D’Amato, Vito Annese, Severine Vermeire, Rinse K. Weersma, Jonas Halfvarson, Paulina Paavola-Sakki, Maarit Lappalainen, Monkol Lek, Beryl Cummings, Taru Tukiainen, Talin Haritunians, Leena Halme, Lotta L. E. Koskinen, Ashwin N. Ananthakrishnan, Yang Luo, Graham A. Heap, Marijn C. Visschedijk, UK IBD Genetics Consortium, NIDDK IBD Genetics Consortium, Daniel G. MacArthur, Benjamin M. Neale, Tariq Ahmad, Carl A. Anderson, Steven R. Brant, Richard H. Duerr, Mark S. Silverberg, Judy H. Cho, Aarno Palotie, Päivi Saavalainen, Kimmo Kontula, Martti Färkkilä, Dermot P. B. McGovern, Andre Franke, Kari Stefansson, John D. Rioux, Ramnik J. Xavier, and Mark J. Daly
Subjects: Science
Abstract: Nature Communications 7 Article number: 12342 (2016); Published 9 August 2016; Updated 13 September 2016 The HTML version of this Article incorrectly listed the authors of the UK IBD Genetics Consortium and the NIDDK IBD Genetics Consortium individually in the main author list. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication.
Published: 2016
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32. Correction: Common Genetic Variants and Modification of Penetrance of -Associated Breast Cancer.

Author: Mia M. Gaudet, Tomas Kirchhoff, Todd Green, Joseph Vijai, Joshua M. Korn, Candace Guiducci, Ayellet V. Segrè, Kate McGee, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Marion Gauthier-Villars, Hagay Sobol, Michel Longy, Marc Frenay, GEMO Study Collaborators, Frans B. L. Hogervorst, Matti A. Rookus, J. Margriet Collée, Nicoline Hoogerbrugge, Kees E. P. van Roozendaal, Marion Piedmonte, Wendy Rubinstein, Stacy Nerenstone, Linda Van Le, Stephanie V. Blank, Trinidad Caldés, Miguel de la Hoya, Heli Nevanlinna, Kristiina Aittomäki, Conxi Lazaro, Ignacio Blanco, Adalgeir Arason, Oskar T. Johannsson, Rosa B. Barkardottir, Peter Devilee, Olofunmilayo I. Olopade, Susan L. Neuhausen, Xianshu Wang, Zachary S. Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Alessandra Viel, Paolo Radice, Catherine M. Phelan, Steven Narod, Gad Rennert, Flavio Lejbkowicz, Anath Flugelman, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Amanda E. Toland, Marco Montagna, Emma D'Andrea, Eitan Friedman, Yael Laitman, Ake Borg, Mary Beattie, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Tim Rebbeck, Amanda B. Spurdle, Xiaoqing Chen, Helene Holland, Esther M. John, John L. Hopper, Saundra S. Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V. Overeem Hansen, Finn C. Nielsen, Mark H. Greene, Phuong L. Mai, Ana Osorio, Mercedes Durán, Raquel Andres, Javier Benítez, Jeffrey N. Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Lisa Walker, Jacqueline Eason, Julian Barwell, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Stefanie Engert, Norbert Arnold, Dorothea Gadzicki, Michael Dean, Bert Gold, Robert J. Klein, Fergus J. Couch, Georgia Chenevix-Trench, Douglas F. Easton, Mark J. Daly, Antonis C. Antoniou, David M. Altshuler, and Kenneth Offit
Subjects: Genetics, QH426-470
Published: 2010
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33. RICOPILI: Rapid Imputation for COnsortias PIpeLIne.

Author: Max Lam, Swapnil Awasthi, Hunna J. Watson, Jackie Goldstein, Georgia Panagiotaropoulou, Vassily Trubetskoy, Robert Karlsson, Oleksander Frei, Chun-Chieh Fan, Ward De Witte, Nina R. Mota, Niamh Mullins, Kim Brügger, Sang Hong Lee, Naomi R. Wray, Nora Skarabis, Hailiang Huang, Benjamin M. Neale, Mark J. Daly, Manuel Mattheisen, Raymond Walters, and Stephan Ripke
Published: 2020
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34. MISCAST: MIssense variant to protein StruCture Analysis web SuiTe.

Author: Sumaiya Iqbal, David Hoksza, Eduardo Pérez-Palma, Patrick May, Jakob B. Jespersen, Shehab S. Ahmed, Zaara T. Rifat, Henrike O. Heyne, Mohammad Sohel Rahman, Jeffrey R. Cottrell, Florence F. Wagner, Mark J. Daly, Arthur J. Campbell, and Dennis Lal
Published: 2020
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35. A structural variation reference for medical and population genetics.

Author: Ryan L. Collins, Harrison Brand, Konrad J. Karczewski, Xuefang Zhao, Jessica Alföldi, Laurent C. Francioli, Amit V. Khera, Chelsea Lowther, Laura D. Gauthier, Harold Wang, Nicholas A. Watts, Matthew Solomonson, Alexander Baumann, Ruchi Munshi, Mark Walker, Christopher W. Whelan, Yongqing Huang, Ted Brookings, Ted Sharpe, Matthew R. Stone, Elise Valkanas, Jack Fu, Grace Tiao, Kristen M. Laricchia, Valentín Ruano-Rubio, Christine Stevens, Namrata Gupta, Caroline Cusick, Lauren Margolin, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Beryl B. Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Eric V. Minikel, Benjamin M. Neale, Sam Novod, Anne H. O'Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, José Soto, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S. Ware, Ben Weisburd, Nicola Whiffin, Carlos A. Aguilar Salinas, Tariq Ahmad 0003, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W. Bowden, Matthew J. Bown, John C. Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher A. Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J. F. Loos, Steven A. Lubitz, Ronald C. W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven A. McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Peter M. Nilsson, Michael C. O'Donovan, Dost öngür, Lorena Orozco, Michael J. Owen, Colin N. A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Sokol, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E. Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Hugh Watkins, Rinse K. Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, Kent D. Taylor, Henry J. Lin, Stephen S. Rich, Wendy S. Post, Yii-Der Ida Chen, Jerome I. Rotter, Chad Nusbaum, Anthony A. Philippakis, Eric S. Lander, and Michael E. Talkowski
Published: 2020
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36. 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

37. The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder

Author: Frank R. Wendt, Miguel Garcia-Argibay, Brenda Cabrera-Mendoza, Unnur A. Valdimarsdóttir, Joel Gelernter, Murray B. Stein, Michel G. Nivard, Adam X. Maihofer, Caroline M. Nievergelt, Henrik Larsson, Manuel Mattheisen, Renato Polimanti, Sandra M. Meier, Karmel W. Choi, Jonathan R.I. Coleman, Nikolaos P. Daskalakis, Christy A. Denckla, Elizabeth Ketema, Rajendra A. Morey, Andrew Ratanatharathorn, Katy Torres, Aliza P. Wingo, Clement C. Zai, Allison E. Aiello, Lynn M. Almli, Ananda B. Amstadter, Soren B. Andersen, Ole A. Andreassen, Paul A. Arbisi, Allison E. Ashley-Koch, S. Bryn Austin, Esmina Avdibegovic, Anders D. Borglum, Dragan Babic, Marie Bækvad-Hansen, Dewleen G. Baker, Jean C. Beckham, Laura J. Bierut, Jonathan I. Bisson, Marco P. Boks, Elizabeth A. Bolger, Bekh Bradley, Meghan Brashear, Gerome Breen, Richard A. Bryant, Angela C. Bustamante, Jonas Bybjerg-Grauholm, Joseph R. Calabrese, Jose Miguel Caldas-de-Almeida, Chia-Yen Chen, Anders M. Dale, Shareefa Dalvie, Jürgen Deckert, Douglas L. Delahanty, Michelle F. Dennis, Seth G. Disner, Katharina Domschke, Laramie E. Duncan, Alma Dzubur Kulenovic, Christopher R. Erbes, Alexandra Evans, Lindsay A. Farrer, Norah C. Feeny, Janine D. Flory, David Forbes, Carol E. Franz, Sandro Galea, Melanie E. Garrett, Aarti Gautam, Bizu Gelaye, Elbert Geuze, Charles F. Gillespie, Aferdita Goci Uka, Scott D. Gordon, Guia Guffanti, Rasha Hammamieh, Michael A. Hauser, Andrew C. Heath, Sian M.J. Hemmings, David Michael Hougaard, Miro Jakovljevic, Marti Jett, Eric Otto Johnson, Ian Jones, Tanja Jovanovic, Xue-Jun Qin, Karen-Inge Karstoft, Milissa L. Kaufman, Ronald C. Kessler, Alaptagin Khan, Nathan A. Kimbrel, Anthony P. King, Nastassja Koen, Henry R. Kranzler, William S. Kremen, Bruce R. Lawford, Lauren A.M. Lebois, Catrin Lewis, Israel Liberzon, Sarah D. Linnstaedt, Mark W. Logue, Adriana Lori, Bozo Lugonja, Jurjen J. Luykx, Michael J. Lyons, Jessica L. Maples-Keller, Charles Marmar, Nicholas G. Martin, Douglas Maurer, Matig R. Mavissakalian, Alexander McFarlane, Regina E. McGlinchey, Katie A. McLaughlin, Samuel A. McLean, Divya Mehta, Rebecca Mellor, Vasiliki Michopoulos, William Milberg, Mark W. Miller, Charles Phillip Morris, Ole Mors, Preben Bo Mortensen, Elliot C. Nelson, Merete Nordentoft, Sonya B. Norman, Meaghan O’Donnell, Holly K. Orcutt, Matthew S. Panizzon, Edward S. Peters, Alan L. Peterson, Matthew Peverill, Robert H. Pietrzak, Melissa A. Polusny, John P. Rice, Victoria B. Risbrough, Andrea L. Roberts, Alex O. Rothbaum, Barbara O. Rothbaum, Peter Roy-Byrne, Kenneth J. Ruggiero, Ariane Rung, Bart P.F. Rutten, Nancy L. Saccone, Sixto E. Sanchez, Dick Schijven, Soraya Seedat, Antonia V. Seligowski, Julia S. Seng, Christina M. Sheerin, Derrick Silove, Alicia K. Smith, Jordan W. Smoller, Scott R. Sponheim, Dan J. Stein, Jennifer S. Stevens, Martin H. Teicher, Wesley K. Thompson, Edward Trapido, Monica Uddin, Robert J. Ursano, Leigh Luella van den Heuvel, Miranda Van Hooff, Eric Vermetten, Christiaan Vinkers, Joanne Voisey, Yunpeng Wang, Zhewu Wang, Thomas Werge, Michelle A. Williams, Douglas E. Williamson, Sherry Winternitz, Christiane Wolf, Erika J. Wolf, Rachel Yehuda, Keith A. Young, Ross McD. Young, Hongyu Zhao, Lori A. Zoellner, Magali Haas, Heather Lasseter, Allison C. Provost, Rany M. Salem, Jonathan Sebat, Richard Shaffer, Tianying Wu, Stephan Ripke, Mark J. Daly, Kerry J. Ressler, Karestan C. Koenen, Biological Psychology, APH - Mental Health, APH - Methodology, Anatomy and neurosciences, Psychiatry, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: Genome-wide association study, Epidemiology, Siblings, PTSD, Mendelian Randomization Analysis, Comorbidities, SDG 3 - Good Health and Well-being, Humans, ADHD, Attention Deficit Disorder with Hyperactivity/epidemiology, Stress Disorders, Post-Traumatic/genetics, Biological Psychiatry, Causal inference
Abstract: Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.
Published: 2023

38. Delineation of functionally essential protein regions for 242 neurodevelopmental genes

Author: Sumaiya Iqbal, Tobias Brünger, Eduardo Pérez-Palma, Marie Macnee, Andreas Brunklaus, Mark J Daly, Arthur J Campbell, David Hoksza, Patrick May, Dennis Lal, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Fonds National de la Recherche - FnR [sponsor], DFG [sponsor], BMBF [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Neurologie [D14] [Sciences de la santé humaine], Neurodevelopmental disorder, Bioinformatics, Neurology [D14] [Human health sciences], Genetics, 3112 Neurosciences, Neurodevelopmental diseases, genetics, bioinformatics, Genetics & genetic processes [F10] [Life sciences], Neurology (clinical), Génétique & processus génétiques [F10] [Sciences du vivant], 3124 Neurology and psychiatry
Abstract: Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients. In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.
Published: 2022

39. Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa

Author: Nastassja Koen, Wilfred E. Injera, Roxanne James, Edith Kwobah, Dan J. Stein, Sohini Ramachandran, Abebaw Fekadu, Anne Stevenson, Alicia R. Martin, Karestan C. Koenen, Rocky E. Stroud, Solomon Teferra, Gabriel Kigen, Zukiswa Zingela, Elizabeth G. Atkinson, Henry Musinguzi, Linnet Ongeri, Allan Kalungi, Charles R. Newton, Fred K. Ashaba, Yakov Pichkar, NeuroGAP-Psychosis Study Team, Welelta Shiferaw, Bizu Gelaye, Melkam Alemayehu, Rehema M. Mwema, Benjamin M. Neale, Mark Baker, Carter P. Newman, Nicole Creanza, Tamrat Abebe, Joseph Kyebuzibwa, Zan Koenig, Shareefa Dalvie, Lori B. Chibnik, Mark J. Daly, Raj Ramesar, Lerato Majara, Lukoye Atwoli, Dickens Akena, Symon M. Kariuki, Stella Gichuru, and Team, NeuroGAP-Psychosis Study
Subjects: Genetic diversity, medicine.medical_specialty, Genetic Structures, media_common.quotation_subject, Black People, Genetic Variation, Genealogy, Africa, Southern, Geography, Variation (linguistics), Genetics, Population, Genetic variation, Genetic structure, medicine, Genetics, Medical genetics, Humans, Three generations, Genetics (clinical), Diversity (politics), media_common
Abstract: SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.
Published: 2022

40. The ExAC browser: displaying reference data information from over 60 000 exomes.

Author: Konrad J. Karczewski, Ben Weisburd, Brett Thomas, Matthew Solomonson, Douglas M. Ruderfer, David Kavanagh, Tymor Hamamsy, Monkol Lek, Kaitlin E. Samocha, Beryl B. Cummings, Daniel Birnbaum, The Exome Aggregation Consortium, Mark J. Daly, and Daniel G. MacArthur
Published: 2017
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41. Fine-mapping inflammatory bowel disease loci to single-variant resolution.

Author: Hailiang Huang, Ming Fang, Luke Jostins, Masa Umicevic Mirkov, Gabrielle Boucher, Carl A. Anderson, Vibeke Andersen, Isabelle Cleynen, Adrian Cortes, François Crins, Mauro D'Amato, Valérie Deffontaine, Julia Dmitrieva, Elisa Docampo, Mahmoud Elansary, Kyle Kai-How Farh, Andre Franke, Ann-Stephan Gori, Philippe Goyette, Jonas Halfvarson, Talin Haritunians, Jo Knight, Ian C. Lawrance, Charlie W. Lees, Edouard Louis, Rob Mariman, Theo H. E. Meuwissen, Myriam Mni, Yukihide Momozawa, Miles Parkes, Sarah L. Spain, Emilie Théâtre, Gosia Trynka, Jack Satsangi, Suzanne van Sommeren, Severine Vermeire, Ramnik J. Xavier, Rinse K. Weersma, Richard H. Duerr, Christopher G. P. Mathew, John D. Rioux, Dermot P. B. McGovern, Judy H. Cho, Michel Georges, Mark J. Daly, and Jeffrey C. Barrett
Published: 2017
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42. Supplementary Figures 1 - 6, Tables 1 - 2 from A Recurrent ERCC3 Truncating Mutation Confers Moderate Risk for Breast Cancer

Author: Kenneth Offit, Gad Rennert, Larry Norton, Katherine L. Nathanson, Fergus J. Couch, Mark J. Daly, Jeffrey N. Weitzel, Mark Robson, Zsofia K. Stadler, Hedy Rennert, Flavio Lejbkowicz, Liying Zhang, Michael F. Walsh, Susan L. Neuhausen, Steve M. Lipkin, Steven N. Hart, Kasmintan A. Schrader, Shai Carmi, Brandon Wenz, Sarah Kazzaz, Anne Lincoln, Pragna Gaddam, Tinu Thomas, Ann Maria, Kara N. Maxwell, Vignesh Ravichandran, Danylo Villano, Sabine Topka, and Joseph Vijai
Abstract: Supplementary Figure 1. Electropherogram. Supplementary Figure 2. Ramachandran plot. Supplementary Figure 3. Modeling ERCC3 R109X via CRISPR/Cas9 genome editing. Supplementary Figure 4. Haplotype analyses from the TAGC heterozygote carriers. Supplementary Figure 5. ERCC3 mutations present in the cBioPortal (MSKCC) datasets. Supplementary Figure 6. ERCC3 transcript levels in patient derived whole blood. Supplementary Table 1. Family history and pathology information on R109X carriers. Supplementary Table 2. Identity of mutations in HMLE cell lines generated by CRISPR/Cas9.
Published: 2023

43. Supplementary Table S1 from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma

Author: Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
Abstract: Clinical characteristics of familial myeloma probands who were studied with germline whole exome sequencing.
Published: 2023

44. Supplementary Figure S1 from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma

Author: Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
Abstract: PCA and gene based rare synonymous variant comparison analyses of European ancestry Multiple Myeloma cases and controls
Published: 2023

45. Data from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma

Author: Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
Abstract: Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.
Published: 2023

46. Supplementary Data from Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma

Author: Steven M. Lipkin, Leandro Cerchietti, Haiyuan Yu, Robert J. Klein, Kenneth Offit, Nicola J. Camp, Charles G. Mullighan, Henry T. Lynch, Charles Dumontet, Robert G. Roeder, Mark J. Daly, Kenneth C. Anderson, Judy E. Garber, Jane Churpek, Lucy A. Godley, Susan L. Slager, Ola Landgren, Ruben Niesvizky, Djordje Atanackovic, Mohamed Salama, Karen Curtin, Selina Chen-Kiang, Jude Phillip, Jayeshkumar Patel, Agnes Viale, Mykyta Artomov, Rosalie G. Waller, Dina Becirovic, Lauren M. Jacobs, David S. Jayabalan, Shu-Ping Wang, James D. McKay, Celine M. Vachon, Carrie Snyder, Vijai Joseph, Kim E. Nichols, Michael F. Walsh, Jinghui Zhang, Jian Sun, Maria V. Revuelta, Gang Wu, Siwei Chen, M. Nieves Calvo-Vidal, and Xiaomu Wei
Abstract: Additional methods, statistical and resource information to assist readers about how experiments and analyses were conducted.
Published: 2023

47. Understanding Complex Trait Susceptibilities and Ethnical Diversity in a Sample of 4,145 Russians Through Analysis of Clinical and Genetic Data

Author: Dmitrii Usoltsev, Nikita Kolosov, Oxana Rotar, Alexander Loboda, Maria Boyarinova, Ekaterina Moguchaya, Ekaterina Kolesova, Anastasia Erina, Kristina Tolkunova, Valeriia Rezapova, Olesya Melnik, Olga Freylikhman, Nadezhda Paskar, Asiiat Alieva, Elena Baranova, Elena Bazhenova, Olga Beliaeva, Elena Vasilyeva, Sofia Kibkalo, Rostislav Skitchenko, Alina Babenko, Alexey Sergushichev, Alena Dushina, Ekaterina Lopina, Irina Basyrova, Roman Libis, Dmitrii Duplyakov, Natalya Cherepanova, Kati Donner, Paivi Laiho, Anna Kostareva, Alexandra Konradi, Evgeny Shlyakhto, Aarno Palotie, Mark J. Daly, and Mykyta Artomov
Abstract: The population of Russia consists of more than 150 local ethnicities. The ethnic diversity and geographic origins, which extend from eastern Europe to Asia, make the population uniquely positioned to investigate the shared properties of inherited disease risks between European and Asian ethnicities.We present the analysis of genetic and phenotypic data from a cohort of 4,145 individuals collected in three metro areas in western Russia. We show the presence of multiple admixed ancestry clusters spanning from primarily European to Asian and high identity-by-descent sharing with the Finnish population. As a result, there was notable enrichment of Finnish-specific variants in Russia. We illustrate the utility of Russian-descent cohorts for discovery of novel population-specific genetic associations, as well as replication of previously identified associations that were thought to be population-specific in other cohorts.Finally, we provide access to a database of GWAS results for 465 unique phenotypes and allele frequencies.
Published: 2023

48. Differences in the Commonly used Genotype Imputation Algorithms and Their Imputation Accuracy Estimates.

Author: Kalle Parn, Matti Pirinen, Mart Kals, Reedik Mägi, Veikko Salomaa, Michael Boehnke, Ira Hall, Nathan Stitziel, Nelson Freimer, Mark J. Daly, Aarno Palotie, Samuli Ripatti, and Priit Palta
Published: 2018
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49. Variant Score Ranker - a web application for intuitive missense variant prioritization.

Author: Juanjiangmeng Du, Monica Sudarsanam, Eduardo Pérez-Palma, Andrea Ganna, Laurent C. Francioli, Sumaiya Iqbal, Lisa-Marie Niestroj, Costin Leu, Ben Weisburd, Timothy Poterba, Peter Nürnberg, Mark J. Daly, Aarno Palotie, Patrick May, and Dennis Lal
Published: 2019
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50. Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Author: Masahiro Kanai, Roy Elzur, Wei Zhou, Mark J. Daly, Hilary K. Finucane, Kuan-Han H. Wu, Humaira Rasheed, Kristin Tsuo, Jibril B. Hirbo, Ying Wang, Arjun Bhattacharya, Huiling Zhao, Shinichi Namba, Ida Surakka, Brooke N. Wolford, Valeria Lo Faro, Esteban A. Lopera-Maya, Kristi Läll, Marie-Julie Favé, Juulia J. Partanen, Sinéad B. Chapman, Juha Karjalainen, Mitja Kurki, Mutaamba Maasha, Ben M. Brumpton, Sameer Chavan, Tzu-Ting Chen, Michelle Daya, Yi Ding, Yen-Chen A. Feng, Lindsay A. Guare, Christopher R. Gignoux, Sarah E. Graham, Whitney E. Hornsby, Nathan Ingold, Said I. Ismail, Ruth Johnson, Triin Laisk, Kuang Lin, Jun Lv, Iona Y. Millwood, Sonia Moreno-Grau, Kisung Nam, Priit Palta, Anita Pandit, Michael H. Preuss, Chadi Saad, Shefali Setia-Verma, Unnur Thorsteinsdottir, Jasmina Uzunovic, Anurag Verma, Matthew Zawistowski, Xue Zhong, Nahla Afifi, Kawthar M. Al-Dabhani, Asma Al Thani, Yuki Bradford, Archie Campbell, Kristy Crooks, Geertruida H. de Bock, Scott M. Damrauer, Nicholas J. Douville, Sarah Finer, Lars G. Fritsche, Eleni Fthenou, Gilberto Gonzalez-Arroyo, Christopher J. Griffiths, Yu Guo, Karen A. Hunt, Alexander Ioannidis, Nomdo M. Jansonius, Takahiro Konuma, Ming Ta Michael Lee, Arturo Lopez-Pineda, Yuta Matsuda, Riccardo E. Marioni, Babak Moatamed, Marco A. Nava-Aguilar, Kensuke Numakura, Snehal Patil, Nicholas Rafaels, Anne Richmond, Agustin Rojas-Muñoz, Jonathan A. Shortt, Peter Straub, Ran Tao, Brett Vanderwerff, Manvi Vernekar, Yogasudha Veturi, Kathleen C. Barnes, Marike Boezen, Zhengming Chen, Chia-Yen Chen, Judy Cho, George Davey Smith, Lude Franke, Eric R. Gamazon, Andrea Ganna, Tom R. Gaunt, Tian Ge, Hailiang Huang, Jennifer Huffman, Nicholas Katsanis, Jukka T. Koskela, Clara Lajonchere, Matthew H. Law, Liming Li, Cecilia M. Lindgren, Ruth J.F. Loos, Stuart MacGregor, Koichi Matsuda, Catherine M. Olsen, David J. Porteous, Jordan A. Shavit, Harold Snieder, Tomohiro Takano, Richard C. Trembath, Judith M. Vonk, David C. Whiteman, Stephen J. Wicks, Cisca Wijmenga, John Wright, Jie Zheng, Xiang Zhou, Philip Awadalla, Michael Boehnke, Carlos D. Bustamante, Nancy J. Cox, Segun Fatumo, Daniel H. Geschwind, Caroline Hayward, Kristian Hveem, Eimear E. Kenny, Seunggeun Lee, Yen-Feng Lin, Hamdi Mbarek, Reedik Mägi, Hilary C. Martin, Sarah E. Medland, Yukinori Okada, Aarno V. Palotie, Bogdan Pasaniuc, Daniel J. Rader, Marylyn D. Ritchie, Serena Sanna, Jordan W. Smoller, Kari Stefansson, David A. van Heel, Robin G. Walters, Sebastian Zöllner, null Biobank of the Americas, null Biobank Japan Project, null BioMe, null BioVU, null CanPath - Ontario Health Study, null China Kadoorie Biobank Collaborative Group, null Colorado Center for Personalized Medicine, null deCODE Genetics, null Estonian Biobank, FinnGen, null Generation Scotland, null Genes & Health Research Team, null LifeLines, null Mass General Brigham Biobank, null Michigan Genomics Initiative, null National Biobank of Korea, null Penn Medicine BioBank, null Qatar Biobank, null The Qskin Sun and Health Study, null Taiwan Biobank, null The Hunt Study, null Ucla Atlas Community Health Initiative, null Uganda Genome Resource, null Uk Biobank, Alicia R. Martin, Cristen J. Willer, Benjamin M. Neale, Institute for Molecular Medicine Finland, Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Data Science Genetic Epidemiology Lab, Research Programs Unit, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and University of Helsinki
Subjects: biobank, meta-analysis, genome-wide association study, fine-mapping, Genetics, 1184 Genetics, developmental biology, physiology, GWAS, 3111 Biomedicine, heterogeneity, summary statistics, Biochemistry, Genetics and Molecular Biology (miscellaneous), linkage disequilibrium, miscalibration
Abstract: Funding Information: We acknowledge all the participants and researchers of the 23 biobanks that have contributed to the GBMI. Biobank-specific acknowledgments are included in the Data S3 . We thank H. Huang, A.R. Martin, B.M. Neale, Y. Okada, K. Tsuo, J.C. Ulirsch, Y. Wang, and all the members of Finucane and Daly labs for their helpful feedback. M.K. was supported by a Nakajima Foundation Fellowship and the Masason Foundation . H.K.F. was funded by NIH grant DP5 OD024582 . Publisher Copyright: © 2022 The Author(s) Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWASs). Fine-mapping of meta-analysis studies is typically performed as in a single-cohort study. Here, we first demonstrate that heterogeneity (e.g., of sample size, phenotyping, imputation) hurts calibration of meta-analysis fine-mapping. We propose a summary statistics-based quality-control (QC) method, suspicious loci analysis of meta-analysis summary statistics (SLALOM), that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics. We validate SLALOM in simulations and the GWAS Catalog. Applying SLALOM to 14 meta-analyses from the Global Biobank Meta-analysis Initiative (GBMI), we find that 67% of loci show suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci are significantly depleted for having nonsynonymous variants as lead variant (2.7×; Fisher's exact p = 7.3 × 10−4). We find limited evidence of fine-mapping improvement in the GBMI meta-analyses compared with individual biobanks. We urge extreme caution when interpreting fine-mapping results from meta-analysis of heterogeneous cohorts.
Published: 2022

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