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1. Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture

Author: Haiko Schurz, Vivek Naranbhai, Tom A Yates, James J Gilchrist, Tom Parks, Peter J Dodd, Marlo Möller, Eileen G Hoal, Andrew P Morris, Adrian VS Hill, and International Tuberculosis Host Genetics Consortium
Subjects: tuberculosis, GWAS, multi-ancestry, meta-analysis, HLA, Medicine, Science, Biology (General), QH301-705.5
Abstract: The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h2 = 26.3%, 95% CI 23.7–29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p
Published: 2024
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2. Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues

Author: Nilufer Rahmioglu, Alexander W Drong, Helen Lockstone, Thomas Tapmeier, Karin Hellner, Merli Saare, Triin Laisk-Podar, Christine Dew, Emily Tough, George Nicholson, Maire Peters, Andrew P Morris, Cecilia M Lindgren, Christian M Becker, and Krina T Zondervan
Subjects: dna methylation, endometrium, endocrine, endometriosis, gene expression, reproductive, Genetics, QH426-470
Abstract: Genome-wide association studies in the fields of reproductive medicine and endocrinology are yielding robust genetic variants associated with disease. Integrated genomic, transcriptomic, and epigenomic molecular profiling studies are common methodologies used to understand the biologic pathways perturbed by these variants. However, molecular profiling resources do not include the tissue most relevant to many female reproductive traits, the endometrium, while the parameters influencing variability of results from its molecular profiling are unclear. We investigated the sources of DNA methylation and RNA expression profile variability in endometrium (n = 135), endometriotic disease tissue (endometriosis), and subcutaneous abdominal fat samples from 24 women, quantifying between-individual, within-tissue (cellular heterogeneity), and technical variation. DNA samples (n = 96) were analyzed using Illumina HumanMethlylation450 BeadChip arrays; RNA samples (n = 39) were analyzed using H12-expression arrays. Variance-component analyses showed that, for the top 10–50% variable DNA methylation/RNA expression sites, between-individual variation far exceeded within-tissue and technical variation. Menstrual-phase accounted for most variability in methylation/expression patterns in endometrium (Pm = 7.8 × 10−3, Pe = 8.4 × 10−5) but not in fat and endometriotic tissue; age was significantly associated with DNA methylation profile of endometrium (Pm = 9 × 10−5) and endometriotic disease tissue (Pm = 2.4 × 10−5); and smoking was significantly associated with DNA methylation in adipose tissue (Pm = 1.8 × 10−3). Hierarchical cluster analysis showed significantly different methylation signatures between endometrium and endometriotic tissue enriched for WNT signaling, angiogenesis, cadherin signaling, and gonadotropin-releasing-hormone-receptor pathways. Differential DNA methylation/expression analyses suggested detection of a limited number of sites with large fold changes (FC > 4), but power calculations accounting for different sources of variability showed that for robust detection >500 tissue samples are required. These results enable appropriate study design for large-scale expression and methylation tissue-based profiling relevant to many reproductive and endocrine traits.
Published: 2017
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3. Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing.

Author: James S Floyd, Katarzyna M Bloch, Jennifer A Brody, Cyrielle Maroteau, Moneeza K Siddiqui, Richard Gregory, Daniel F Carr, Mariam Molokhia, Xiaoming Liu, Joshua C Bis, Ammar Ahmed, Xuan Liu, Pär Hallberg, Qun-Ying Yue, Patrik K E Magnusson, Diane Brisson, Kerri L Wiggins, Alanna C Morrison, Etienne Khoury, Paul McKeigue, Bruno H Stricker, Maryse Lapeyre-Mestre, Susan R Heckbert, Arlene M Gallagher, Hector Chinoy, Richard A Gibbs, Emmanuelle Bondon-Guitton, Russell Tracy, Eric Boerwinkle, Daniel Gaudet, Anita Conforti, Tjeerd van Staa, Colleen M Sitlani, Kenneth M Rice, Anke-Hilse Maitland-van der Zee, Mia Wadelius, Andrew P Morris, Munir Pirmohamed, Colin A N Palmer, Bruce M Psaty, Ana Alfirevic, and PREDICTION-ADR Consortium and EUDRAGENE
Subjects: Medicine, Science
Abstract: AimsStatin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.Methods and resultsSRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.ConclusionsIn this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.
Published: 2019
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4. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

Author: Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, Audrey Y Chu, Weihua Zhang, Xu Wang, Peng Chen, Nisa M Maruthur, Bianca C Porneala, Stephen J Sharp, Yucheng Jia, Edmond K Kabagambe, Li-Ching Chang, Wei-Min Chen, Cathy E Elks, Daniel S Evans, Qiao Fan, Franco Giulianini, Min Jin Go, Jouke-Jan Hottenga, Yao Hu, Anne U Jackson, Stavroula Kanoni, Young Jin Kim, Marcus E Kleber, Claes Ladenvall, Cecile Lecoeur, Sing-Hui Lim, Yingchang Lu, Anubha Mahajan, Carola Marzi, Mike A Nalls, Pau Navarro, Ilja M Nolte, Lynda M Rose, Denis V Rybin, Serena Sanna, Yuan Shi, Daniel O Stram, Fumihiko Takeuchi, Shu Pei Tan, Peter J van der Most, Jana V Van Vliet-Ostaptchouk, Andrew Wong, Loic Yengo, Wanting Zhao, Anuj Goel, Maria Teresa Martinez Larrad, Dörte Radke, Perttu Salo, Toshiko Tanaka, Erik P A van Iperen, Goncalo Abecasis, Saima Afaq, Behrooz Z Alizadeh, Alain G Bertoni, Amelie Bonnefond, Yvonne Böttcher, Erwin P Bottinger, Harry Campbell, Olga D Carlson, Chien-Hsiun Chen, Yoon Shin Cho, W Timothy Garvey, Christian Gieger, Mark O Goodarzi, Harald Grallert, Anders Hamsten, Catharina A Hartman, Christian Herder, Chao Agnes Hsiung, Jie Huang, Michiya Igase, Masato Isono, Tomohiro Katsuya, Chiea-Chuen Khor, Wieland Kiess, Katsuhiko Kohara, Peter Kovacs, Juyoung Lee, Wen-Jane Lee, Benjamin Lehne, Huaixing Li, Jianjun Liu, Stephane Lobbens, Jian'an Luan, Valeriya Lyssenko, Thomas Meitinger, Tetsuro Miki, Iva Miljkovic, Sanghoon Moon, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Matthias Nauck, James S Pankow, Ozren Polasek, Inga Prokopenko, Paula S Ramos, Laura Rasmussen-Torvik, Wolfgang Rathmann, Stephen S Rich, Neil R Robertson, Michael Roden, Ronan Roussel, Igor Rudan, Robert A Scott, William R Scott, Bengt Sennblad, David S Siscovick, Konstantin Strauch, Liang Sun, Morris Swertz, Salman M Tajuddin, Kent D Taylor, Yik-Ying Teo, Yih Chung Tham, Anke Tönjes, Nicholas J Wareham, Gonneke Willemsen, Tom Wilsgaard, Aroon D Hingorani, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Josephine Egan, Luigi Ferrucci, G Kees Hovingh, Antti Jula, Mika Kivimaki, Meena Kumari, Inger Njølstad, Colin N A Palmer, Manuel Serrano Ríos, Michael Stumvoll, Hugh Watkins, Tin Aung, Matthias Blüher, Michael Boehnke, Dorret I Boomsma, Stefan R Bornstein, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Yduan-Tsong Chen, Ching-Yu Cheng, Francesco Cucca, Eco J C de Geus, Panos Deloukas, Michele K Evans, Myriam Fornage, Yechiel Friedlander, Philippe Froguel, Leif Groop, Myron D Gross, Tamara B Harris, Caroline Hayward, Chew-Kiat Heng, Erik Ingelsson, Norihiro Kato, Bong-Jo Kim, Woon-Puay Koh, Jaspal S Kooner, Antje Körner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Xu Lin, Yongmei Liu, Ruth J F Loos, Patrik K E Magnusson, Winfried März, Mark I McCarthy, Albertine J Oldehinkel, Ken K Ong, Nancy L Pedersen, Mark A Pereira, Annette Peters, Paul M Ridker, Charumathi Sabanayagam, Michele Sale, Danish Saleheen, Juha Saltevo, Peter Eh Schwarz, Wayne H H Sheu, Harold Snieder, Timothy D Spector, Yasuharu Tabara, Jaakko Tuomilehto, Rob M van Dam, James G Wilson, James F Wilson, Bruce H R Wolffenbuttel, Tien Yin Wong, Jer-Yuarn Wu, Jian-Min Yuan, Alan B Zonderman, Nicole Soranzo, Xiuqing Guo, David J Roberts, Jose C Florez, Robert Sladek, Josée Dupuis, Andrew P Morris, E-Shyong Tai, Elizabeth Selvin, Jerome I Rotter, Claudia Langenberg, Inês Barroso, and James B Meigs
Subjects: Medicine
Abstract: BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
Published: 2017
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5. Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions.

Author: Dmitry Shungin, Wei Q Deng, Tibor V Varga, Jian'an Luan, Evelin Mihailov, Andres Metspalu, GIANT Consortium, Andrew P Morris, Nita G Forouhi, Cecilia Lindgren, Patrik K E Magnusson, Nancy L Pedersen, Göran Hallmans, Audrey Y Chu, Anne E Justice, Mariaelisa Graff, Thomas W Winkler, Lynda M Rose, Claudia Langenberg, L Adrienne Cupples, Paul M Ridker, Nicholas J Wareham, Ken K Ong, Ruth J F Loos, Daniel I Chasman, Erik Ingelsson, Tuomas O Kilpeläinen, Robert A Scott, Reedik Mägi, Guillaume Paré, and Paul W Franks
Subjects: Genetics, QH426-470
Abstract: Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G×E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G×E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman's ρ = 0.401 for triglycerides, and ρ = 0.236 for BMI) compared to all SNPs. When Pv and Pm were compared for all pruned SNPs, only BMI was statistically significant (Spearman's ρ = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the Pv distribution (Pbinomial
Published: 2017
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6. Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease.

Author: Lasse Folkersen, Eric Fauman, Maria Sabater-Lleal, Rona J Strawbridge, Mattias Frånberg, Bengt Sennblad, Damiano Baldassarre, Fabrizio Veglia, Steve E Humphries, Rainer Rauramaa, Ulf de Faire, Andries J Smit, Philippe Giral, Sudhir Kurl, Elmo Mannarino, Stefan Enroth, Åsa Johansson, Sofia Bosdotter Enroth, Stefan Gustafsson, Lars Lind, Cecilia Lindgren, Andrew P Morris, Vilmantas Giedraitis, Angela Silveira, Anders Franco-Cereceda, Elena Tremoli, IMPROVE study group, Ulf Gyllensten, Erik Ingelsson, Søren Brunak, Per Eriksson, Daniel Ziemek, Anders Hamsten, and Anders Mälarstig
Subjects: Genetics, QH426-470
Abstract: Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p
Published: 2017
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7. Admixture mapping in two Mexican samples identifies significant associations of locus ancestry with triglyceride levels in the BUD13/ZNF259/APOA5 region and fine mapping points to rs964184 as the main driver of the association signal.

Author: Esteban J Parra, Andrew Mazurek, Christopher R Gignoux, Alexandra Sockell, Michael Agostino, Andrew P Morris, Lauren E Petty, Craig L Hanis, Nancy J Cox, Adan Valladares-Salgado, Jennifer E Below, and Miguel Cruz
Subjects: Medicine, Science
Abstract: We carried out an admixture mapping study of lipid traits in two samples from Mexico City. Native American locus ancestry was significantly associated with triglyceride levels in a broad region of chromosome 11 overlapping the BUD13, ZNF259 and APOA5 genes. In our fine-mapping analysis of this region using dense genome-wide data, rs964184 is the only marker included in the 99% credible set of SNPs, providing strong support for rs964184 as the causal variant within this region. The frequency of the allele associated with increased triglyceride concentrations (rs964184-G) is between 30-40% higher in Native American populations from Mexico than in European populations. The evidence currently available for this variant indicates that it may be exerting its effect through three potential mechanisms: 1) modification of enhancer activity, 2) regulation of the expression of several genes in cis and/or trans, or 3) modification of the methylation patterns of the promoter of the APOA5 gene.
Published: 2017
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8. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
Subjects: Genetics, QH426-470
Abstract: [This corrects the article DOI: 10.1371/journal.pgen.1005378.].
Published: 2016
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9. Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

Author: Bram P Prins, Ali Abbasi, Anson Wong, Ahmad Vaez, Ilja Nolte, Nora Franceschini, Philip E Stuart, Javier Guterriez Achury, Vanisha Mistry, Jonathan P Bradfield, Ana M Valdes, Jose Bras, Aleksey Shatunov, PAGE Consortium, International Stroke Genetics Consortium, Systemic Sclerosis consortium, Treat OA consortium, DIAGRAM Consortium, CARDIoGRAMplusC4D Consortium, ALS consortium, International Parkinson’s Disease Genomics Consortium, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, CKDGen consortium, GERAD1 Consortium, International Consortium for Blood Pressure, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Inflammation Working Group of the CHARGE Consortium, Chen Lu, Buhm Han, Soumya Raychaudhuri, Steve Bevan, Maureen D Mayes, Lam C Tsoi, Evangelos Evangelou, Rajan P Nair, Struan F A Grant, Constantin Polychronakos, Timothy R D Radstake, David A van Heel, Melanie L Dunstan, Nicholas W Wood, Ammar Al-Chalabi, Abbas Dehghan, Hakon Hakonarson, Hugh S Markus, James T Elder, Jo Knight, Dan E Arking, Timothy D Spector, Bobby P C Koeleman, Cornelia M van Duijn, Javier Martin, Andrew P Morris, Rinse K Weersma, Cisca Wijmenga, Patricia B Munroe, John R B Perry, Jennie G Pouget, Yalda Jamshidi, Harold Snieder, and Behrooz Z Alizadeh
Subjects: Medicine
Abstract: BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and findingsWe performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses.ConclusionsGenetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.
Published: 2016
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10. Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Author: Anubha Mahajan, Xueling Sim, Hui Jin Ng, Alisa Manning, Manuel A Rivas, Heather M Highland, Adam E Locke, Niels Grarup, Hae Kyung Im, Pablo Cingolani, Jason Flannick, Pierre Fontanillas, Christian Fuchsberger, Kyle J Gaulton, Tanya M Teslovich, N William Rayner, Neil R Robertson, Nicola L Beer, Jana K Rundle, Jette Bork-Jensen, Claes Ladenvall, Christine Blancher, David Buck, Gemma Buck, Noël P Burtt, Stacey Gabriel, Anette P Gjesing, Christopher J Groves, Mette Hollensted, Jeroen R Huyghe, Anne U Jackson, Goo Jun, Johanne Marie Justesen, Massimo Mangino, Jacquelyn Murphy, Matt Neville, Robert Onofrio, Kerrin S Small, Heather M Stringham, Ann-Christine Syvänen, Joseph Trakalo, Goncalo Abecasis, Graeme I Bell, John Blangero, Nancy J Cox, Ravindranath Duggirala, Craig L Hanis, Mark Seielstad, James G Wilson, Cramer Christensen, Ivan Brandslund, Rainer Rauramaa, Gabriela L Surdulescu, Alex S F Doney, Lars Lannfelt, Allan Linneberg, Bo Isomaa, Tiinamaija Tuomi, Marit E Jørgensen, Torben Jørgensen, Johanna Kuusisto, Matti Uusitupa, Veikko Salomaa, Timothy D Spector, Andrew D Morris, Colin N A Palmer, Francis S Collins, Karen L Mohlke, Richard N Bergman, Erik Ingelsson, Lars Lind, Jaakko Tuomilehto, Torben Hansen, Richard M Watanabe, Inga Prokopenko, Josee Dupuis, Fredrik Karpe, Leif Groop, Markku Laakso, Oluf Pedersen, Jose C Florez, Andrew P Morris, David Altshuler, James B Meigs, Michael Boehnke, Mark I McCarthy, Cecilia M Lindgren, Anna L Gloyn, and T2D-GENES consortium and GoT2D consortium
Subjects: Genetics, QH426-470
Abstract: Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P
Published: 2015
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11. The inheritance of resistance alleles in multiple sclerosis.

Author: Sreeram V Ramagopalan, Andrew P Morris, David A Dyment, Blanca M Herrera, Gabriele C DeLuca, Matthew R Lincoln, Sarah M Orton, Michael J Chao, A Dessa Sadovnick, and George C Ebers
Subjects: Genetics, QH426-470
Abstract: Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex-associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex-associated susceptibility.
Published: 2007
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12. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author: Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
Published: 2015
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13. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author: Momoko Horikoshi, Reedik Mӓgi, Martijn van de Bunt, Ida Surakka, Antti-Pekka Sarin, Anubha Mahajan, Letizia Marullo, Gudmar Thorleifsson, Sara Hӓgg, Jouke-Jan Hottenga, Claes Ladenvall, Janina S Ried, Thomas W Winkler, Sara M Willems, Natalia Pervjakova, Tõnu Esko, Marian Beekman, Christopher P Nelson, Christina Willenborg, Steven Wiltshire, Teresa Ferreira, Juan Fernandez, Kyle J Gaulton, Valgerdur Steinthorsdottir, Anders Hamsten, Patrik K E Magnusson, Gonneke Willemsen, Yuri Milaneschi, Neil R Robertson, Christopher J Groves, Amanda J Bennett, Terho Lehtimӓki, Jorma S Viikari, Johan Rung, Valeriya Lyssenko, Markus Perola, Iris M Heid, Christian Herder, Harald Grallert, Martina Müller-Nurasyid, Michael Roden, Elina Hypponen, Aaron Isaacs, Elisabeth M van Leeuwen, Lennart C Karssen, Evelin Mihailov, Jeanine J Houwing-Duistermaat, Anton J M de Craen, Joris Deelen, Aki S Havulinna, Matthew Blades, Christian Hengstenberg, Jeanette Erdmann, Heribert Schunkert, Jaakko Kaprio, Martin D Tobin, Nilesh J Samani, Lars Lind, Veikko Salomaa, Cecilia M Lindgren, P Eline Slagboom, Andres Metspalu, Cornelia M van Duijn, Johan G Eriksson, Annette Peters, Christian Gieger, Antti Jula, Leif Groop, Olli T Raitakari, Chris Power, Brenda W J H Penninx, Eco de Geus, Johannes H Smit, Dorret I Boomsma, Nancy L Pedersen, Erik Ingelsson, Unnur Thorsteinsdottir, Kari Stefansson, Samuli Ripatti, Inga Prokopenko, Mark I McCarthy, Andrew P Morris, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Published: 2015
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14. Evaluating the Performance of Fine-Mapping Strategies at Common Variant GWAS Loci.

Author: Martijn van de Bunt, Adrian Cortes, IGAS Consortium, Matthew A Brown, Andrew P Morris, and Mark I McCarthy
Subjects: Genetics, QH426-470
Abstract: The growing availability of high-quality genomic annotation has increased the potential for mechanistic insights when the specific variants driving common genome-wide association signals are accurately localized. A range of fine-mapping strategies have been advocated, and specific successes reported, but the overall performance of such approaches, in the face of the extensive linkage disequilibrium that characterizes the human genome, is not well understood. Using simulations based on sequence data from the 1000 Genomes Project, we quantify the extent to which fine-mapping, here conducted using an approximate Bayesian approach, can be expected to lead to useful improvements in causal variant localization. We show that resolution is highly variable between loci, and that performance is severely degraded as the statistical power to detect association is reduced. We confirm that, where causal variants are shared between ancestry groups, further improvements in performance can be obtained in a trans-ethnic fine-mapping design. Finally, using empirical data from a recently published genome-wide association study for ankylosing spondylitis, we provide empirical confirmation of the behaviour of the approximate Bayesian approach and demonstrate that seven of twenty-six loci can be fine-mapped to fewer than ten variants.
Published: 2015
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15. Gene-lifestyle interaction and type 2 diabetes: the EPIC interact case-cohort study.

Author: Claudia Langenberg, Stephen J Sharp, Paul W Franks, Robert A Scott, Panos Deloukas, Nita G Forouhi, Philippe Froguel, Leif C Groop, Torben Hansen, Luigi Palla, Oluf Pedersen, Matthias B Schulze, Maria-Jose Tormo, Eleanor Wheeler, Claudia Agnoli, Larraitz Arriola, Aurelio Barricarte, Heiner Boeing, Geraldine M Clarke, Françoise Clavel-Chapelon, Eric J Duell, Guy Fagherazzi, Rudolf Kaaks, Nicola D Kerrison, Timothy J Key, Kay Tee Khaw, Janine Kröger, Martin Lajous, Andrew P Morris, Carmen Navarro, Peter M Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, María-José Sánchez, Nadia Slimani, Annemieke M W Spijkerman, Rosario Tumino, Daphne L van der A, Yvonne T van der Schouw, Inês Barroso, Mark I McCarthy, Elio Riboli, and Nicholas J Wareham
Subjects: Medicine
Abstract: BackgroundUnderstanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.Methods and findingsThe InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20×10-4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50×10-3) and waist circumference (p for interaction = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.ConclusionsThe relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Published: 2014
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16. Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

Author: Wenbo Tang, Matthew Kowgier, Daan W Loth, María Soler Artigas, Bonnie R Joubert, Emily Hodge, Sina A Gharib, Albert V Smith, Ingo Ruczinski, Vilmundur Gudnason, Rasika A Mathias, Tamara B Harris, Nadia N Hansel, Lenore J Launer, Kathleen C Barnes, Joyanna G Hansen, Eva Albrecht, Melinda C Aldrich, Michael Allerhand, R Graham Barr, Guy G Brusselle, David J Couper, Ivan Curjuric, Gail Davies, Ian J Deary, Josée Dupuis, Tove Fall, Millennia Foy, Nora Franceschini, Wei Gao, Sven Gläser, Xiangjun Gu, Dana B Hancock, Joachim Heinrich, Albert Hofman, Medea Imboden, Erik Ingelsson, Alan James, Stefan Karrasch, Beate Koch, Stephen B Kritchevsky, Ashish Kumar, Lies Lahousse, Guo Li, Lars Lind, Cecilia Lindgren, Yongmei Liu, Kurt Lohman, Thomas Lumley, Wendy L McArdle, Bernd Meibohm, Andrew P Morris, Alanna C Morrison, Bill Musk, Kari E North, Lyle J Palmer, Nicole M Probst-Hensch, Bruce M Psaty, Fernando Rivadeneira, Jerome I Rotter, Holger Schulz, Lewis J Smith, Akshay Sood, John M Starr, David P Strachan, Alexander Teumer, André G Uitterlinden, Henry Völzke, Arend Voorman, Louise V Wain, Martin T Wells, Jemma B Wilk, O Dale Williams, Susan R Heckbert, Bruno H Stricker, Stephanie J London, Myriam Fornage, Martin D Tobin, George T O'Connor, Ian P Hall, and Patricia A Cassano
Subjects: Medicine, Science
Abstract: BACKGROUND:Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS:We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS:The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS:In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
Published: 2014
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17. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.

Author: John R B Perry, Benjamin F Voight, Loïc Yengo, Najaf Amin, Josée Dupuis, Martha Ganser, Harald Grallert, Pau Navarro, Man Li, Lu Qi, Valgerdur Steinthorsdottir, Robert A Scott, Peter Almgren, Dan E Arking, Yurii Aulchenko, Beverley Balkau, Rafn Benediktsson, Richard N Bergman, Eric Boerwinkle, Lori Bonnycastle, Noël P Burtt, Harry Campbell, Guillaume Charpentier, Francis S Collins, Christian Gieger, Todd Green, Samy Hadjadj, Andrew T Hattersley, Christian Herder, Albert Hofman, Andrew D Johnson, Anna Kottgen, Peter Kraft, Yann Labrune, Claudia Langenberg, Alisa K Manning, Karen L Mohlke, Andrew P Morris, Ben Oostra, James Pankow, Ann-Kristin Petersen, Peter P Pramstaller, Inga Prokopenko, Wolfgang Rathmann, William Rayner, Michael Roden, Igor Rudan, Denis Rybin, Laura J Scott, Gunnar Sigurdsson, Rob Sladek, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Jaakko Tuomilehto, Andre G Uitterlinden, Sidonie Vivequin, Michael N Weedon, Alan F Wright, MAGIC, DIAGRAM Consortium, GIANT Consortium, Frank B Hu, Thomas Illig, Linda Kao, James B Meigs, James F Wilson, Kari Stefansson, Cornelia van Duijn, David Altschuler, Andrew D Morris, Michael Boehnke, Mark I McCarthy, Philippe Froguel, Colin N A Palmer, Nicholas J Wareham, Leif Groop, Timothy M Frayling, and Stéphane Cauchi
Subjects: Genetics, QH426-470
Abstract: Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI
Published: 2012
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18. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author: Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, and Sekar Kathiresan
Subjects: Genetics, QH426-470
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p
Published: 2012
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19. A genome-wide association search for type 2 diabetes genes in African Americans.

Author: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, DIAGRAM Consortium, MAGIC Investigators, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, and Robert Sladek
Subjects: Medicine, Science
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P
Published: 2012
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20. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

Author: Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, Wellcome Trust Case Control Consortium, Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Procardis Consortia, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy, and Giant Consortium
Subjects: Genetics, QH426-470
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Published: 2009
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21. A flexible approach for the analysis of rare variants allowing for a mixture of effects on binary or quantitative traits.

Author: Geraldine M Clarke, Manuel A Rivas, and Andrew P Morris
Subjects: Genetics, QH426-470
Abstract: Multiple rare variants either within or across genes have been hypothesised to collectively influence complex human traits. The increasing availability of high throughput sequencing technologies offers the opportunity to study the effect of rare variants on these traits. However, appropriate and computationally efficient analytical methods are required to account for collections of rare variants that display a combination of protective, deleterious and null effects on the trait. We have developed a novel method for the analysis of rare genetic variation in a gene, region or pathway that, by simply aggregating summary statistics at each variant, can: (i) test for the presence of a mixture of effects on a trait; (ii) be applied to both binary and quantitative traits in population-based and family-based data; (iii) adjust for covariates to allow for non-genetic risk factors and; (iv) incorporate imputed genetic variation. In addition, for preliminary identification of promising genes, the method can be applied to association summary statistics, available from meta-analysis of published data, for example, without the need for individual level genotype data. Through simulation, we show that our method is immune to the presence of bi-directional effects, with no apparent loss in power across a range of different mixtures, and can achieve greater power than existing approaches as long as summary statistics at each variant are robust. We apply our method to investigate association of type-1 diabetes with imputed rare variants within genes in the major histocompatibility complex using genotype data from the Wellcome Trust Case Control Consortium.
Published: 2013
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22. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.

Author: Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud
Subjects: Genetics, QH426-470
Abstract: Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Published: 2013
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23. Genetic associations of type 2 diabetes with islet amyloid polypeptide processing and degrading pathways in asian populations.

Author: Vincent Kwok Lim Lam, Ronald Ching Wan Ma, Heung Man Lee, Cheng Hu, Kyong Soo Park, Hiroto Furuta, Ying Wang, Claudia Ha Ting Tam, Xueling Sim, Daniel Peng-Keat Ng, Jianjun Liu, Tien-Yin Wong, E Shyong Tai, Andrew P Morris, DIAGRAM Consortium, Nelson Leung Sang Tang, Jean Woo, Ping Chung Leung, Alice Pik Shan Kong, Risa Ozaki, Wei Ping Jia, Hong Kyu Lee, Kishio Nanjo, Gang Xu, Maggie Chor Yin Ng, Wing-Yee So, and Juliana Chung Ngor Chan
Subjects: Medicine, Science
Abstract: Type 2 diabetes (T2D) is a complex disease characterized by beta cell dysfunctions. Islet amyloid polypeptide (IAPP) is highly conserved and co-secreted with insulin with over 40% of autopsy cases of T2D showing islet amyloid formation due to IAPP aggregation. Dysregulation in IAPP processing, stabilization and degradation can cause excessive oligomerization with beta cell toxicity. Previous studies examining genetic associations of pathways implicated in IAPP metabolism have yielded conflicting results due to small sample size, insufficient interrogation of gene structure and gene-gene interactions. In this multi-staged study, we screened 89 tag single nucleotide polymorphisms (SNPs) in 6 candidate genes implicated in IAPP metabolism and tested for independent and joint associations with T2D and beta cell dysfunctions. Positive signals in the stage-1 were confirmed by de novo and in silico analysis in a multi-centre unrelated case-control cohort. We examined the association of significant SNPs with quantitative traits in a subset of controls and performed bioinformatics and relevant functional analyses. Amongst the tag SNPs, rs1583645 in carboxypeptidase E (CPE) and rs6583813 in insulin degrading enzyme (IDE) were associated with 1.09 to 1.28 fold increased risk of T2D (P Meta = 9.4×10(-3) and 0.02 respectively) in a meta-analysis of East Asians. Using genetic risk scores (GRS) with each risk variant scoring 1, subjects with GRS≥3 (8.2% of the cohort) had 56% higher risk of T2D than those with GRS = 0 (P = 0.01). In a subcohort of control subjects, plasma IAPP increased and beta cell function index declined with GRS (P = 0.008 and 0.03 respectively). Bioinformatics and functional analyses of CPE rs1583645 predicted regulatory elements for chromatin modification and transcription factors, suggesting differential DNA-protein interactions and gene expression. Taken together, these results support the importance of dysregulation of IAPP metabolism in T2D in East Asians.
Published: 2013
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24. Common variants in left/right asymmetry genes and pathways are associated with relative hand skill.

Author: William M Brandler, Andrew P Morris, David M Evans, Thomas S Scerri, John P Kemp, Nicholas J Timpson, Beate St Pourcain, George Davey Smith, Susan M Ring, John Stein, Anthony P Monaco, Joel B Talcott, Simon E Fisher, Caleb Webber, and Silvia Paracchini
Subjects: Genetics, QH426-470
Abstract: Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Published: 2013
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25. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits.

Author: Benjamin F Voight, Hyun Min Kang, Jun Ding, Cameron D Palmer, Carlo Sidore, Peter S Chines, Noël P Burtt, Christian Fuchsberger, Yanming Li, Jeanette Erdmann, Timothy M Frayling, Iris M Heid, Anne U Jackson, Toby Johnson, Tuomas O Kilpeläinen, Cecilia M Lindgren, Andrew P Morris, Inga Prokopenko, Joshua C Randall, Richa Saxena, Nicole Soranzo, Elizabeth K Speliotes, Tanya M Teslovich, Eleanor Wheeler, Jared Maguire, Melissa Parkin, Simon Potter, N William Rayner, Neil Robertson, Kathleen Stirrups, Wendy Winckler, Serena Sanna, Antonella Mulas, Ramaiah Nagaraja, Francesco Cucca, Inês Barroso, Panos Deloukas, Ruth J F Loos, Sekar Kathiresan, Patricia B Munroe, Christopher Newton-Cheh, Arne Pfeufer, Nilesh J Samani, Heribert Schunkert, Joel N Hirschhorn, David Altshuler, Mark I McCarthy, Gonçalo R Abecasis, and Michael Boehnke
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
Published: 2012
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26. The dyslexia candidate locus on 2p12 is associated with general cognitive ability and white matter structure.

Author: Thomas S Scerri, Fahimeh Darki, Dianne F Newbury, Andrew J O Whitehouse, Myriam Peyrard-Janvid, Hans Matsson, Qi W Ang, Craig E Pennell, Susan Ring, John Stein, Andrew P Morris, Anthony P Monaco, Juha Kere, Joel B Talcott, Torkel Klingberg, and Silvia Paracchini
Subjects: Medicine, Science
Abstract: Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions.
Published: 2012
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27. The use of genome-wide eQTL associations in lymphoblastoid cell lines to identify novel genetic pathways involved in complex traits.

Author: Josine L Min, Jennifer M Taylor, J Brent Richards, Tim Watts, Fredrik H Pettersson, John Broxholme, Kourosh R Ahmadi, Gabriela L Surdulescu, Ernesto Lowy, Christian Gieger, Chris Newton-Cheh, Markus Perola, Nicole Soranzo, Ida Surakka, Cecilia M Lindgren, Jiannis Ragoussis, Andrew P Morris, Lon R Cardon, Tim D Spector, and Krina T Zondervan
Subjects: Medicine, Science
Abstract: The integrated analysis of genotypic and expression data for association with complex traits could identify novel genetic pathways involved in complex traits. We profiled 19,573 expression probes in Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) from 299 twins and correlated these with 44 quantitative traits (QTs). For 939 expressed probes correlating with more than one QT, we investigated the presence of eQTL associations in three datasets of 57 CEU HapMap founders and 86 unrelated twins. Genome-wide association analysis of these probes with 2.2 m SNPs revealed 131 potential eQTLs (1,989 eQTL SNPs) overlapping between the HapMap datasets, five of which were in cis (58 eQTL SNPs). We then tested 535 SNPs tagging the eQTL SNPs, for association with the relevant QT in 2,905 twins. We identified nine potential SNP-QT associations (P
Published: 2011
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28. Two-stage two-locus models in genome-wide association.

Author: David M Evans, Jonathan Marchini, Andrew P Morris, and Lon R Cardon
Subjects: Genetics, QH426-470
Abstract: Studies in model organisms suggest that epistasis may play an important role in the etiology of complex diseases and traits in humans. With the era of large-scale genome-wide association studies fast approaching, it is important to quantify whether it will be possible to detect interacting loci using realistic sample sizes in humans and to what extent undetected epistasis will adversely affect power to detect association when single-locus approaches are employed. We therefore investigated the power to detect association for an extensive range of two-locus quantitative trait models that incorporated varying degrees of epistasis. We compared the power to detect association using a single-locus model that ignored interaction effects, a full two-locus model that allowed for interactions, and, most important, two two-stage strategies whereby a subset of loci initially identified using single-locus tests were analyzed using the full two-locus model. Despite the penalty introduced by multiple testing, fitting the full two-locus model performed better than single-locus tests for many of the situations considered, particularly when compared with attempts to detect both individual loci. Using a two-stage strategy reduced the computational burden associated with performing an exhaustive two-locus search across the genome but was not as powerful as the exhaustive search when loci interacted. Two-stage approaches also increased the risk of missing interacting loci that contributed little effect at the margins. Based on our extensive simulations, our results suggest that an exhaustive search involving all pairwise combinations of markers across the genome might provide a useful complement to single-locus scans in identifying interacting loci that contribute to moderate proportions of the phenotypic variance.
Published: 2006
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29. snpQT: flexible, reproducible, and comprehensive quality control and imputation of genomic data [version 2; peer review: 1 approved, 2 approved with reservations]

Author: Christina Vasilopoulou, Benjamin Wingfield, Andrew P. Morris, and William Duddy
Subjects: Software Tool Article, Articles, GWAS, Quality Control, GWAS pipeline, Nextflow, Imputation, SNPs, Genomic Variants, BioContainers, QC, Population Stratification, Anaconda
Abstract: Quality control of genomic data is an essential but complicated multi-step procedure, often requiring separate installation and expert familiarity with a combination of different bioinformatics tools. Software incompatibilities, and inconsistencies across computing environments, are recurrent challenges, leading to poor reproducibility. Existing semi-automated or automated solutions lack comprehensive quality checks, flexible workflow architecture, and user control. To address these challenges, we have developed snpQT: a scalable, stand-alone software pipeline using nextflow and BioContainers, for comprehensive, reproducible and interactive quality control of human genomic data. snpQT offers some 36 discrete quality filters or correction steps in a complete standardised pipeline, producing graphical reports to demonstrate the state of data before and after each quality control procedure. This includes human genome build conversion, population stratification against data from the 1,000 Genomes Project, automated population outlier removal, and built-in imputation with its own pre- and post- quality controls. Common input formats are used, and a synthetic dataset and comprehensive online tutorial are provided for testing, educational purposes, and demonstration. The snpQT pipeline is designed to run with minimal user input and coding experience; quality control steps are implemented with numerous user-modifiable thresholds, and workflows can be flexibly combined in custom combinations. snpQT is open source and freely available at https://github.com/nebfield/snpQT. A comprehensive online tutorial and installation guide is provided through to GWAS (https://snpqt.readthedocs.io/en/latest/), introducing snpQT using a synthetic demonstration dataset and a real-world Amyotrophic Lateral Sclerosis SNP-array dataset.
Published: 2021
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30. snpQT: flexible, reproducible, and comprehensive quality control and imputation of genomic data [version 1; peer review: 3 approved with reservations]

Author: Christina Vasilopoulou, Benjamin Wingfield, Andrew P. Morris, and William Duddy
Subjects: Software Tool Article, Articles, GWAS, Quality Control, GWAS pipeline, Nextflow, Imputation, SNPs, Genomic Variants, BioContainers, QC, Population Stratification, Anaconda
Abstract: Quality control of genomic data is an essential but complicated multi-step procedure, often requiring separate installation and expert familiarity with a combination of different bioinformatics tools. Dependency hell and reproducibility are recurrent challenges. Existing semi-automated or automated solutions lack comprehensive quality checks, flexible workflow architecture, and user control. To address these challenges, we have developed snpQT: a scalable, stand-alone software pipeline using nextflow and BioContainers, for comprehensive, reproducible and interactive quality control of human genomic data. snpQT offers some 36 discrete quality filters or correction steps in a complete standardised pipeline, producing graphical reports to demonstrate the state of data before and after each quality control procedure. This includes human genome build conversion, population stratification against data from the 1,000 Genomes Project, automated population outlier removal, and built-in imputation with its own pre- and post- quality controls. Common input formats are used, and a synthetic dataset and comprehensive online tutorial are provided for testing, educational purposes, and demonstration. The snpQT pipeline is designed to run with minimal user input and coding experience; quality control steps are implemented with default thresholds which can be modified by the user, and workflows can be flexibly combined in custom combinations. snpQT is open source and freely available at https://github.com/nebfield/snpQT. A comprehensive online tutorial and installation guide is provided through to GWAS (https://snpqt.readthedocs.io/en/latest/), introducing snpQT using a synthetic demonstration dataset and a real-world Amyotrophic Lateral Sclerosis SNP-array dataset.
Published: 2021
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31. 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

32. Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Author: K. Alaine Broadaway, Xianyong Yin, Alice Williamson, Victoria A. Parsons, Emma P. Wilson, Anne H. Moxley, Swarooparani Vadlamudi, Arushi Varshney, Anne U. Jackson, Vasudha Ahuja, Stefan R. Bornstein, Laura J. Corbin, Graciela E. Delgado, Om P. Dwivedi, Lilian Fernandes Silva, Timothy M. Frayling, Harald Grallert, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Christian Herder, Sandra Herrmann, Kurt Højlund, David A. Hughes, Marcus E. Kleber, Cecilia M. Lindgren, Ching-Ti Liu, Jian’an Luan, Anni Malmberg, Angela P. Moissl, Andrew P. Morris, Nikolaos Perakakis, Annette Peters, John R. Petrie, Michael Roden, Peter E.H. Schwarz, Sapna Sharma, Angela Silveira, Rona J. Strawbridge, Tiinamaija Tuomi, Andrew R. Wood, Peitao Wu, Björn Zethelius, Damiano Baldassarre, Johan G. Eriksson, Tove Fall, Jose C. Florez, Andreas Fritsche, Bruna Gigante, Anders Hamsten, Eero Kajantie, Markku Laakso, Jari Lahti, Deborah A. Lawlor, Lars Lind, Winfried März, James B. Meigs, Johan Sundström, Nicholas J. Timpson, Robert Wagner, Mark Walker, Nicholas J. Wareham, Hugh Watkins, Inês Barroso, Stephen O’Rahilly, Niels Grarup, Stephen CJ. Parker, Michael Boehnke, Claudia Langenberg, Eleanor Wheeler, and Karen L. Mohlke
Subjects: Genetics, ALSPAC, Genetics (clinical)
Abstract: Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p-value < 5x10-8), which validated 12 previously reported loci for proinsulin and 10 additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher vs. lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait loci (eQTL) data, suggesting candidate genes including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal, but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms predisposing to disease.
Published: 2023

33. Dog ownership in infancy is protective for persistent wheeze in 17q21 asthma-risk carriers

Author: Mauro Tutino, Raquel Granell, John A. Curtin, Sadia Haider, Sara Fontanella, Clare S. Murray, Graham Roberts, S. Hasan Arshad, Stephen Turner, Andrew P. Morris, Adnan Custovic, and Angela Simpson
Subjects: longitudinal, LCA, 17q, Immunology, cat, ownership, birth cohort, ALSPAC, asthma, UNICORN, Gene-environment interaction, meta-analysis, wheeze, dog, Immunology and Allergy, STELAR
Abstract: BackgroundAsthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.ObjectivesWe sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze.MethodsWheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed.Resultsrs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10−4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed.ConclusionsAmong dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.
Published: 2023

34. Do genetics contribute to TNF inhibitor response prediction in Psoriatic Arthritis?

Author: Philippa D. K. Curry, Andrew P. Morris, Anne Barton, and James Bluett
Subjects: Pharmacology, Genetics, Molecular Medicine
Abstract: Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to ‘trial and error’ drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.
Published: 2022

35. Investigating the prediction of CpG methylation levels from SNP genotype data to help elucidate relationships between methylation, gene expression and complex traits

Author: James J. Fryett, Andrew P. Morris, and Heather J. Cordell
Subjects: Multifactorial Inheritance, Models, Genetic, Genotype, Epidemiology, Humans, CpG Islands, DNA Methylation, Transcriptome, Polymorphism, Single Nucleotide, Genetics (clinical), Genome-Wide Association Study
Abstract: As popularised by PrediXcan (and related methods), transcriptome-wide association studies (TWAS), in which gene expression is imputed from single-nucleotide polymorphism (SNP) genotypes and tested for association with a phenotype, are a popular approach for investigating the role of gene expression in complex traits. Like gene expression, DNA methylation is an important biological process and, being under genetic regulation, may be imputable from SNP genotypes. Here, we investigate prediction of CpG methylation levels from SNP genotype data to help elucidate relationships between methylation, gene expression and complex traits. We start by examining how well CpG methylation can be predicted from SNP genotypes, comparing three penalised regression approaches and examining whether changing the window size improves prediction accuracy. Although methylation at most CpG sites cannot be accurately predicted from SNP genotypes, for a subset it can be predicted well. We next apply our methylation prediction models (trained using the optimal method and window size) to carry out a methylome-wide association study (MWAS) of primary biliary cholangitis. We intersect the regions identified via MWAS with those identified via TWAS, providing insight into the interplay between CpG methylation, gene expression and disease status. We conclude that MWAS has the potential to improve understanding of biological mechanisms in complex traits.
Published: 2022

36. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Author: Richard A. Jensen, Denis Rybin, Jaakko Tuomilehto, Reedik Mägi, Inga Prokopenko, Jeffrey R. O'Connell, Marcus E. Kleber, Han Chen, Geoffrey A. Walford, Allan Linnenberg, Anke Tönjes, Francis S. Collins, Sonsoles Morcillo, Gemma Rojo-Martínez, Kenneth Rice, Jose C. Florez, Leif Groop, Manuel Serrano-Ríos, Josée Dupuis, Alisa K. Manning, Peter Kovacs, Torben Jørgensen, Graciela E. Delgado, Alena Stančáková, Hans-Ulrich Häring, Claudia Langenberg, Joshua P. Lewis, Norbert Stefan, Markku Laakso, Torben Hansen, Bruce M. Psaty, Jian'an Luan, Michael Stumvoll, Mark O. Goodarzi, Robert A. Scott, Oluf Pedersen, Ching-Ti Liu, Michael N. Weedon, Michael Boehnke, Ulf Smith, David S. Siscovick, Aaron Leong, Weijia Xie, James B. Meigs, Claes Landenvall, Anne U. Jackson, Joseph M. Zmuda, Mary L. Biggs, Jerome I. Rotter, Federico Soriguer, Winfried März, Zhongyang Zhang, May E. Montasser, Arturo Corbatón-Anchuelo, J M Gómez-Zumaquero, Günther Silbernagel, Kristine Færch, Karen L. Mohlke, Heikki A. Koistinen, Yii-Der Ida Chen, Jaeyoung Hong, Gracia María Martín-Núñez, María Teresa Martínez-Larrad, Emil V. R. Appel, Niels Grarup, Harald Staiger, Johanna Kuusisto, Lars Lind, Nicholas J. Wareham, Andreas Fritsche, Stefan Gustafsson, Andrew P. Morris, Richard N. Bergman, Mark Walker, Cecilia M. Lindgren, Erik Ingelsson, Jorge R. Kizer, Timothy M. Frayling, and Fausto Machicao
Subjects: 0301 basic medicine, Male, Insulin Receptor Substrate Proteins, Endocrinology, Diabetes and Metabolism, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endocrinology & Metabolism, Insulin resistance, Genotype, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic association, Genetics, business.industry, Insulin sensitivity, Genetics/Genomes/Proteomics/Metabolomics, 11 Medical And Health Sciences, medicine.disease, IRS1, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Chemokines, CC, Female, Insulin Resistance, business, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
Published: 2023
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37. P084 The relationship between self-reported adherence, drug levels and tumour necrosis factor inhibitor response in psoriatic arthritis

Author: Philippa D K Curry, Andrew P Morris, Meghna Jani, Hector Chinoy, Anne Barton, and James Bluett
Subjects: Rheumatology, Pharmacology (medical)
Abstract: Background/Aims It is not currently possible to accurately predict tumour necrosis factor inhibitor (TNF-i) response in psoriatic arthritis (PsA). In rheumatoid arthritis, suboptimal adherence to TNF-i and reduced drug levels have been associated with decreased response. Suboptimal treatment adherence (16%-81%) has been reported in PsA although little is known about the impact on TNF-i response. Self-reported adherence may be biased, but direct drug measurements offer an objective adherence evaluation. The objective of this study is to assess the relationship between self-reported adherence, drug levels, and drug response to TNF-i in PsA. Methods Blood samples and adherence questionnaires were collected at 3, 6 and 12 months for PsA patients prescribed biologic or targeted synthetic anti-rheumatic drugs in a UK multi-centre observational study (OUTPASS). Self-reported adherence was measured using two previously validated questionnaires (MARS5 and Treatment). Adherence was classified as self-reporting never missing or delaying a dose, unless medically advised. Adalimumab (ADA) and etanercept (ETN) drug levels were measured at 3 and 6 months using commercially available ELISAs. Clinical response was assessed using PsARC and ΔDAS28 between baseline and 3, 6 and 12 months. Univariate regression and general estimating equations were used to assess associations across timepoints. Results In the OUTPASS cohort (46% ADA, 40% ETN), 42% of patients self-reported non-adherence within the first 12 months of treatment. Patients with self-reported non-adherence at 6 months using the MARS5 questionnaire were significantly less likely to achieve a PsARC response at 6 months [odds ratio (OR)=0.40, P = 0.047] in univariate regression. Non-adherence, reported using the Treatment questionnaire, was associated with decreased PsARC response over 12 months [OR = 0.52, P = 0.031]. There was no association (P > 0.05) between whether a patient returned a self-reported adherence questionnaire and response. Drug levels at 3 months (n = 70 (ADA), 73 (ETN)) were associated with drug levels at 6 months (n = 61 (ADA), 67 (ETN)) for both ADA [β = 0.47, P = 0.001] and ETN [β = 0.41, P = 0.018] paired samples. Higher 3-month ADA levels were associated with increased ΔDAS28 response at 3 months [β = 0.11, P = 0.036] and PsARC response at 12 months [OR = 1.39, P = 0.028]. Higher 3-month ETN levels were associated with increased PsARC response at 3 months [OR = 1.50, P = 0.026]. Increased ADA levels were associated with improved ΔDAS28 over 12 months [β = 0.07, P = 0.001] and higher ETN levels associated with enhanced PsARC response [OR = 1.17, P = 0.022] over 12 months. Levels of neither drug were associated (P > 0.05) with any self-reported adherence measures at any time point. Conclusion There was no association between self-reported adherence and TNF-i drug levels in ADA or ETN-treated PsA patients. Objectively measured adherence via drug level measurements were more strongly associated with drug response than self-reported measures, particularly using ΔDAS28 as the measure of response. Disclosure P.D.K. Curry: None. A.P. Morris: None. M. Jani: None. H. Chinoy: Grants/research support; HC received grant support from Eli Lilly and UCB. A. Barton: Grants/research support; AB has received fees/grant awards from Galapagos, Scipher Medicine, Roche-Chugai, Pfizer and BMS. J. Bluett: Grants/research support; JB has received a research grant award from Pfizer. Other; JB has received travel/conference fees from UCB, Pfizer and Eli Lilly.
Published: 2023

38. Insights into the comorbidity between type 2 diabetes and osteoarthritis

Author: Ana Luiza de S. V. Arruda, April Hartley, Georgia Katsoula, George Davey Smith, Andrew P. Morris, and Eleftheria Zeggini
Abstract: Multimorbidity is a rising public health challenge with important implications for health management and policy. The most common multimorbidity pattern is for the combination of cardiometabolic and osteoarticular diseases. Here, we study the genetic underpinning of the comorbidity between type 2 diabetes and osteoarthritis. We find genome-wide genetic correlation between the two diseases, and robust evidence for association signal colocalization at 18 genomic regions. We integrate multi-omics and functional information to resolve the colocalizing signals, and identify high-confidence effector genes, includingFTOandIRX3, which provide proof-of-concept insights into the epidemiologic link between obesity and both diseases. We find enrichment for lipid metabolism and skeletal formation pathways for signals underpinning the knee and hip osteoarthritis comorbidities with type 2 diabetes, respectively. Causal inference analysis identifies complex effects of tissue-specific gene expression on comorbidity outcomes. Our findings provide insights into the biological basis for the type 2 diabetes-osteoarthritis disease co-occurrence.
Published: 2023

39. Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS

Author: Christina Vasilopoulou, Sarah L. McDaid-McCloskey, Gavin McCluskey, Stephanie Duguez, Andrew P. Morris, and William Duddy
Subjects: Inorganic Chemistry, amyotrophic lateral sclerosis (ALS), Organic Chemistry, gene-set analysis, GWAS, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, functional genomics, Spectroscopy, Catalysis, ALS pathology, Computer Science Applications
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal late-onset motor neuron disease characterized by the loss of the upper and lower motor neurons. Our understanding of the molecular basis of ALS pathology remains elusive, complicating the development of efficient treatment. Gene-set analyses of genome-wide data have offered insight into the biological processes and pathways of complex diseases and can suggest new hypotheses regarding causal mechanisms. Our aim in this study was to identify and explore biological pathways and other gene sets having genomic association to ALS. Two cohorts of genomic data from the dbGaP repository were combined: (a) the largest available ALS individual-level genotype dataset (N = 12,319), and (b) a similarly sized control cohort (N = 13,210). Following comprehensive quality control pipelines, imputation and meta-analysis, we assembled a large European descent ALS-control cohort of 9244 ALS cases and 12,795 healthy controls represented by genetic variants of 19,242 genes. Multi-marker analysis of genomic annotation (MAGMA) gene-set analysis was applied to an extensive collection of 31,454 gene sets from the molecular signatures database (MSigDB). Statistically significant associations were observed for gene sets related to immune response, apoptosis, lipid metabolism, neuron differentiation, muscle cell function, synaptic plasticity and development. We also report novel interactions between gene sets, suggestive of mechanistic overlaps. A manual meta-categorization and enrichment mapping approach is used to explore the overlap of gene membership between significant gene sets, revealing a number of shared mechanisms.
Published: 2023
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40. Atopic Polygenic Risk Score Is Associated with Paradoxical Eczema Developing in Patients with Psoriasis Treated with Biologics

Author: Ali Al-Janabi, Steve Eyre, Amy C. Foulkes, Adnan R. Khan, Nick Dand, Ekaterina Burova, Bernadette DeSilva, Areti Makrygeorgou, Emily Davies, Catherine H. Smith, Christopher E.M. Griffiths, Andrew P. Morris, and Richard B. Warren
Subjects: Cell Biology, Dermatology, Molecular Biology, Biochemistry
Published: 2023

41. The Use of Class Imbalanced Learning Methods on ULSAM Data to Predict the Case-Control Status in Genome-Wide Association Studies

Author: R. Onur Öztornaci, Hamzah Syed, Andrew P. Morris, and Bahar Taşdelen
Abstract: Machine learning (ML) methods for uncovering single nucleotide polymorphisms (SNPs) in genome-wide association study (GWAS) data that can be used to predict disease outcomes are becoming increasingly used in genetic research. Two issues with the use of ML models are finding the correct method for dealing with imbalanced data and data training. This article compares three ML models to identify SNPs that predict type 2 diabetes (T2D) status using the Support vector machine SMOTE (SVM SMOTE), The Adaptive Synthetic Sampling Approach (ADASYN), Random under sampling (RUS) on GWAS data from elderly male participants (165 cases and 951 controls) from the Uppsala Longitudinal Study of Adult Men (ULSAM). It was also applied to SNPs selected by the SMOTE, SVM SMOTE, ADASYN, and RUS clumping method. The analysis was performed using three different ML models: (i) support vector machine (SVM), (ii) multilayer perceptron (MLP) and (iii) random forests (RF). The accuracy of the case-control classification was compared between these three methods. The best classification algorithm was a combination of MLP and SMOTE (97% accuracy). Both RF and SVM achieved good accuracy results of over 90%. Overall, methods used against unbalanced data, all three ML algorithms were found to improve prediction accuracy.
Published: 2023

42. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author: Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M
Subjects: Genome-wide association study, Medizin, Polymorphism, Single Nucleotide, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Sex Characteristics, Phenotype, Lipids/genetics, Genetic Pleiotropy, Cholesterol, GWAS, Genetics, Lipids, Genetic, SDG 3 - Good Health and Well-being, Medicine [Science], 112 Statistics and probability, Medicinsk genetik, Genome-wide Association Study, Gwas, 1184 Genetics, developmental biology, physiology, 3126 Surgery, anesthesiology, intensive care, radiology, 3142 Public health care science, environmental and occupational health, 3141 Health care science, FOS: Biological sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 3111 Biomedicine, Medical Genetics
Abstract: Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756
Published: 2022

43. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

Author: William J. Young, Najim Lahrouchi, Aaron Isaacs, ThuyVy Duong, Luisa Foco, Farah Ahmed, Jennifer A. Brody, Reem Salman, Raymond Noordam, Jan-Walter Benjamins, Jeffrey Haessler, Leo-Pekka Lyytikäinen, Linda Repetto, Maria Pina Concas, Marten E. van den Berg, Stefan Weiss, Antoine R. Baldassari, Traci M. Bartz, James P. Cook, Daniel S. Evans, Rebecca Freudling, Oliver Hines, Jonas L. Isaksen, Honghuang Lin, Hao Mei, Arden Moscati, Martina Müller-Nurasyid, Casia Nursyifa, Yong Qian, Anne Richmond, Carolina Roselli, Kathleen A. Ryan, Eduardo Tarazona-Santos, Sébastien Thériault, Stefan van Duijvenboden, Helen R. Warren, Jie Yao, Dania Raza, Stefanie Aeschbacher, Gustav Ahlberg, Alvaro Alonso, Laura Andreasen, Joshua C. Bis, Eric Boerwinkle, Archie Campbell, Eulalia Catamo, Massimiliano Cocca, Michael J. Cutler, Dawood Darbar, Alessandro De Grandi, Antonio De Luca, Jun Ding, Christina Ellervik, Patrick T. Ellinor, Stephan B. Felix, Philippe Froguel, Christian Fuchsberger, Martin Gögele, Claus Graff, Mariaelisa Graff, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Paul L. Huang, Heikki V. Huikuri, Nina Hutri-Kähönen, M. Arfan Ikram, Rebecca D. Jackson, Juhani Junttila, Maryam Kavousi, Jan A. Kors, Thiago P. Leal, Rozenn N. Lemaitre, Henry J. Lin, Lars Lind, Allan Linneberg, Simin Liu, Peter W. MacFarlane, Massimo Mangino, Thomas Meitinger, Massimo Mezzavilla, Pashupati P. Mishra, Rebecca N. Mitchell, Nina Mononen, May E. Montasser, Alanna C. Morrison, Matthias Nauck, Victor Nauffal, Pau Navarro, Kjell Nikus, Guillaume Pare, Kristen K. Patton, Giulia Pelliccione, Alan Pittman, David J. Porteous, Peter P. Pramstaller, Michael H. Preuss, Olli T. Raitakari, Alexander P. Reiner, Antonio Luiz P. Ribeiro, Kenneth M. Rice, Lorenz Risch, David Schlessinger, Ulrich Schotten, Claudia Schurmann, Xia Shen, M. Benjamin Shoemaker, Gianfranco Sinagra, Moritz F. Sinner, Elsayed Z. Soliman, Monika Stoll, Konstantin Strauch, Kirill Tarasov, Kent D. Taylor, Andrew Tinker, Stella Trompet, André Uitterlinden, Uwe Völker, Henry Völzke, Melanie Waldenberger, Lu-Chen Weng, Eric A. Whitsel, James G. Wilson, Christy L. Avery, David Conen, Adolfo Correa, Francesco Cucca, Marcus Dörr, Sina A. Gharib, Giorgia Girotto, Niels Grarup, Caroline Hayward, Yalda Jamshidi, Marjo-Riitta Järvelin, J. Wouter Jukema, Stefan Kääb, Mika Kähönen, Jørgen K. Kanters, Charles Kooperberg, Terho Lehtimäki, Maria Fernanda Lima-Costa, Yongmei Liu, Ruth J. F. Loos, Steven A. Lubitz, Dennis O. Mook-Kanamori, Andrew P. Morris, Jeffrey R. O’Connell, Morten Salling Olesen, Michele Orini, Sandosh Padmanabhan, Cristian Pattaro, Annette Peters, Bruce M. Psaty, Jerome I. Rotter, Bruno Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James F. Wilson, Dan E. Arking, Julia Ramirez, Pier D. Lambiase, Nona Sotoodehnia, Borbala Mifsud, Christopher Newton-Cheh, Patricia B. Munroe, Cardiology, ACS - Heart failure & arrhythmias, Epidemiology, Radiology & Nuclear Medicine, Medical Informatics, Internal Medicine, Young, William J, Lahrouchi, Najim, Isaacs, Aaron, Duong, Thuyvy, Foco, Luisa, Ahmed, Farah, Brody, Jennifer A, Salman, Reem, Noordam, Raymond, Benjamins, Jan-Walter, Haessler, Jeffrey, Lyytikäinen, Leo-Pekka, Repetto, Linda, Concas, Maria Pina, van den Berg, Marten E, Weiss, Stefan, Baldassari, Antoine R, Bartz, Traci M, Cook, James P, Evans, Daniel S, Freudling, Rebecca, Hines, Oliver, Isaksen, Jonas L, Lin, Honghuang, Mei, Hao, Moscati, Arden, Müller-Nurasyid, Martina, Nursyifa, Casia, Qian, Yong, Richmond, Anne, Roselli, Carolina, Ryan, Kathleen A, Tarazona-Santos, Eduardo, Thériault, Sébastien, van Duijvenboden, Stefan, Warren, Helen R, Yao, Jie, Raza, Dania, Aeschbacher, Stefanie, Ahlberg, Gustav, Alonso, Alvaro, Andreasen, Laura, Bis, Joshua C, Boerwinkle, Eric, Campbell, Archie, Catamo, Eulalia, Cocca, Massimiliano, Cutler, Michael J, Darbar, Dawood, De Grandi, Alessandro, De Luca, Antonio, Ding, Jun, Ellervik, Christina, Ellinor, Patrick T, Felix, Stephan B, Froguel, Philippe, Fuchsberger, Christian, Gögele, Martin, Graff, Clau, Graff, Mariaelisa, Guo, Xiuqing, Hansen, Torben, Heckbert, Susan R, Huang, Paul L, Huikuri, Heikki V, Hutri-Kähönen, Nina, Ikram, M Arfan, Jackson, Rebecca D, Junttila, Juhani, Kavousi, Maryam, Kors, Jan A, Leal, Thiago P, Lemaitre, Rozenn N, Lin, Henry J, Lind, Lar, Linneberg, Allan, Liu, Simin, Macfarlane, Peter W, Mangino, Massimo, Meitinger, Thoma, Mezzavilla, Massimo, Mishra, Pashupati P, Mitchell, Rebecca N, Mononen, Nina, Montasser, May E, Morrison, Alanna C, Nauck, Matthia, Nauffal, Victor, Navarro, Pau, Nikus, Kjell, Pare, Guillaume, Patton, Kristen K, Pelliccione, Giulia, Pittman, Alan, Porteous, David J, Pramstaller, Peter P, Preuss, Michael H, Raitakari, Olli T, Reiner, Alexander P, Ribeiro, Antonio Luiz P, Rice, Kenneth M, Risch, Lorenz, Schlessinger, David, Schotten, Ulrich, Schurmann, Claudia, Shen, Xia, Shoemaker, M Benjamin, Sinagra, Gianfranco, Sinner, Moritz F, Soliman, Elsayed Z, Stoll, Monika, Strauch, Konstantin, Tarasov, Kirill, Taylor, Kent D, Tinker, Andrew, Trompet, Stella, Uitterlinden, André, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Weng, Lu-Chen, Whitsel, Eric A, Wilson, James G, Avery, Christy L, Conen, David, Correa, Adolfo, Cucca, Francesco, Dörr, Marcu, Gharib, Sina A, Girotto, Giorgia, Grarup, Niel, Hayward, Caroline, Jamshidi, Yalda, Järvelin, Marjo-Riitta, Jukema, J Wouter, Kääb, Stefan, Kähönen, Mika, Kanters, Jørgen K, Kooperberg, Charle, Lehtimäki, Terho, Lima-Costa, Maria Fernanda, Liu, Yongmei, Loos, Ruth J F, Lubitz, Steven A, Mook-Kanamori, Dennis O, Morris, Andrew P, O'Connell, Jeffrey R, Olesen, Morten Salling, Orini, Michele, Padmanabhan, Sandosh, Pattaro, Cristian, Peters, Annette, Psaty, Bruce M, Rotter, Jerome I, Stricker, Bruno, van der Harst, Pim, van Duijn, Cornelia M, Verweij, Niek, Wilson, James F, Arking, Dan E, Ramirez, Julia, Lambiase, Pier D, Sotoodehnia, Nona, Mifsud, Borbala, Newton-Cheh, Christopher, Munroe, Patricia B, Cardiovascular Centre (CVC), Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Paediatrics, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Fysiologie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - H08 Experimental atrial fibrillation, and Biochemie
Subjects: Male, Electrocardiography/methods, General Physics and Astronomy, 610 Medicine & health, Arrhythmias, 3121 Internal medicine, Genome-wide association studies, General Biochemistry, Genetics and Molecular Biology, Electrocardiography, Humans, Arrhythmias, Cardiac/genetics, Genetic Testing, Medicinsk genetik, Multidisciplinary, Death, Sudden, Cardiac, Arrhythmias, Cardiac, General Chemistry, Sudden, Electrocardiogram, Death, Genetic markers, 3111 Biomedicine, 610 Medizin und Gesundheit, Cardiac, Medical Genetics
Abstract: The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
Published: 2022

44. S-22-3: UNCOVERING NEW GENES, TISSUES AND THERAPEUTIC TARGETS FOR BLOOD PRESSURE THROUGH LARGE-SCALE TRANSCRIPTOME-WIDE ASSOCIATION STUDIES

Author: Xiaoguang Xu, Chachrit Khunsriraksakul, James M Eales, Havell Markus, Lida Wang, Sushant Saluja, Abigail Lay, Tomasz J Guzik, Andrew P Morris, Dajiang J Liu, Fadi J Charchar, and Maciej Tomaszewski
Subjects: Physiology, Internal Medicine, Cardiology and Cardiovascular Medicine
Published: 2023

45. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
Subjects: Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022

46. Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Author: Nicholas J. Timpson, Jackie F. Price, Henning Tiemeier, Caroline Hayward, Stephan J. L. Bakker, Christian Gieger, Tom Michoel, Catriona L. K. Barnes, Ville Karhunen, Peter K. Joshi, Katyayani Sukhavasi, Anubha Mahajan, Carol A. Wang, Igor Rudan, Maik Pietzner, Andrew P. Morris, Craig E. Pennell, Andrew A Crawford, Marjo-Riitta Järvelin, Henry Völzke, Harry Campbell, Johan L.M. Björkegren, Pim van der Harst, David W. Clark, Massimo Mangino, Claes Ohlsson, Tim D. Spector, Jari Lahti, Elisabeth Altmaier, Johan G. Eriksson, Alexander Neumann, Raili Ermel, Maria Nethander, Arno Ruusalepp, James R M Wilson, George Davey Smith, Nele Friedrich, Sean Bankier, Brian R. Walker, Stela McLachlan, Department of Psychology and Logopedics, University of Helsinki, Clinicum, Diabetes and Obesity Research Program, Research Programs Unit, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Male, STRESS, LD SCORE REGRESSION, Myocardial Infarction, Adipose tissue, BLOOD-PRESSURE, 0302 clinical medicine, Transcortin, Adrenal Cortex Hormones, LOW-BIRTH-WEIGHT, Genetics (clinical), Morning, Biological Specimen Banks, education.field_of_study, biology, HERITABILITY, Middle Aged, INSULIN, 3142 Public health care science, environmental and occupational health, 3. Good health, Liver, Cardiovascular Diseases, Female, Adult, medicine.medical_specialty, 515 Psychology, Population, Quantitative Trait Loci, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, education, METAANALYSIS, Genetic association, business.industry, Mendelian Randomization Analysis, United Kingdom, 030104 developmental biology, Endocrinology, Gene Expression Regulation, alpha 1-Antitrypsin, Expression quantitative trait loci, biology.protein, VISUALIZATION, business, RESPONSES, Genome-Wide Association Study
Abstract: The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
Published: 2021

47. Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Author: Nick Shrine, Abril G Izquierdo, Jing Chen, Richard Packer, Robert J Hall, Anna L Guyatt, Chiara Batini, Rebecca J Thompson, Chandan Pavuluri, Vidhi Malik, Brian D Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y Millwood, Zhengming Chen, Liming Li, Sara RA Wielscher, Lies Lahousse, Guy Brusselle, Andre G Uitterlinden, Ani Manichaikul, Elizabeth C Oelsner, Stephen S Rich, R. Graham Barr, Shona M Kerr, Veronique Vitart, Michael R Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M Bartz, Sina A Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E Ortega, Deborah A Meyers, Eugene R Bleecker, Stacey B Gabriel, Namrata Gupta, Albert Vernon Smith, Jian’an Luan, Jing-Hua Zhao, Ailin F Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T O’Connor, Gaurav Thareja, Omar M E., Hamdi Mbarek, Karsten Suhre, Raquel Granell, Tariq O Faquih, Pieter S Hiemstra, Annelies M Slats, Benjamin H Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T Koskela, Annah B Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A Kentistou, Peter K Joshi, Paul RHJ Timmers, Alexander T Williams, Robert C Free, Xueyang Wang, John L Morrison, Frank D Gilliland, Zhanghua Chen, Carol A Wang, Rachel E Foong, Sarah E Harris, Adele Taylor, Paul Redmond, James P Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H Pietiläinen, Simon R Cox, Craig E Pennell, Graham L Hall, W. James Gauderman, Chris Brightling, James F Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O Mook-Kanamori, Nicholas J Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo-Riitta Jarvelin, Alanna C Morrison, Ozren Polasek, Igor Rudan, Joo-Hyeon Lee, Ian Sayers, Emma L Rawlins, Frank Dudbridge, Edwin K Silverman, David P Strachan, Robin G Walters, Andrew P Morris, Stephanie J London, Michael H Cho, Louise V Wain, Ian P Hall, and Martin D Tobin
Abstract: Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Published: 2022

48. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Author: Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, and John C. Chambers
Subjects: Medicine (miscellaneous), General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Published: 2022

49. Pre-defined gene co-expression modules in rheumatoid arthritis transition towards molecular health following anti-TNF therapy

Author: Megan Sutcliffe, Nisha Nair, James Oliver, Ann W Morgan, John D Isaacs, Anthony G Wilson, Suzanne M M Verstappen, Sebastien Viatte, Kimme L Hyrich, Andrew P Morris, Anne Barton, and Darren Plant
Subjects: Arthritis, Rheumatoid, Biological therapies, Biomarkers, Rheumatoid arthritis, TNFi, genetics, inflammation, transcriptomics, treatment response, Methotrexate, Treatment Outcome, Rheumatology, Tumor Necrosis Factor-alpha, Antirheumatic Agents, Adalimumab, Humans, Tumor Necrosis Factor Inhibitors, Pharmacology (medical), skin and connective tissue diseases
Abstract: Background No reliable biomarkers to predict response to TNF inhibitors (TNFi) in RA patients currently exist. The aims of this study were to replicate changes in gene co-expression modules that were previously reported in response to TNFi therapy in RA; to test if changes in module expression are specific to TNFi therapy; and to determine whether module expression transitions towards a disease-free state in responding patients. Method Published transcriptomic data from the whole blood of disease-free controls (n = 10) and RA patients, treated with the TNFi adalimumab (n = 70) or methotrexate (n = 85), were studied. Treatment response was assessed using the EULAR response criteria following 3 or 6 months of treatment. Change in transcript expression between pre- and post-treatment was recorded for previously defined modules. Linear mixed models tested whether modular expression after treatment transitioned towards a disease-free state. Results For 25 of the 27 modules, change in expression between pre- and post-treatment in the adalimumab cohort replicated published findings. Of these 25 modules, six transitioned towards a disease-free state by 3 months (P Conclusion This study provides independent validation of changes in module expression in response to therapy in RA. However, these effects are not specific to TNFi. Further studies are required to determine whether specific modules could assist molecular classification of therapeutic response.
Published: 2022

50. Pharmacogenetics of TNF inhibitor response in rheumatoid arthritis utilizing the two-component disease activity score

Author: John D. Isaacs, Darren Plant, Anne Barton, Syed Gilani, Kimme L. Hyrich, Nisha Nair, Anthony G. Wilson, James Bluett, Andrew P. Morris, and Ann W. Morgan
Subjects: Male, rheumatoid arthritis, 0301 basic medicine, Oncology, medicine.medical_treatment, Severity of Illness Index, Arthritis, Rheumatoid, TNF inhibitors, 0302 clinical medicine, single nucleotide polymorphism, Treatment Failure, skin and connective tissue diseases, education.field_of_study, Middle Aged, TNF inhibitor, Treatment Outcome, Rheumatoid arthritis, biomarker, Molecular Medicine, Biomarker (medicine), Female, Research Article, Adult, musculoskeletal diseases, medicine.medical_specialty, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Disease activity, 03 medical and health sciences, Internal medicine, Linear regression, Genetics, medicine, Humans, education, Aged, 030203 arthritis & rheumatology, Pharmacology, Tumor Necrosis Factor-alpha, business.industry, treatment response, medicine.disease, United Kingdom, 030104 developmental biology, Pharmacogenetics, Tumor Necrosis Factor Inhibitors, business, Biomarkers, Genome-Wide Association Study
Abstract: Aim: TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. Materials & methods: A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Results: Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Conclusion: Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.
Published: 2020

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