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2. Woolf et als GWAS by subtraction is not useful for cross-generational Mendelian randomization studies

Author

Evans, David M, Smith, George Davey, and Moen, Gunn-Helen

Subjects
Quantitative Biology - Quantitative Methods
Abstract

Mendelian randomization (MR) is an epidemiological method that can be used to strengthen causal inference regarding the relationship between a modifiable environmental exposure and a medically relevant trait and to estimate the magnitude of this relationship1. Recently, there has been considerable interest in using MR to examine potential causal relationships between parental phenotypes and outcomes amongst their offspring. In a recent issue of BMC Research Notes, Woolf et al (2023) present a new method, GWAS by subtraction, to derive genome-wide summary statistics for paternal smoking and other paternal phenotypes with the goal that these estimates can then be used in downstream (including two sample) MR studies. Whilst a potentially useful goal, Woolf et al. (2023) focus on the wrong parameter of interest for useful genome-wide association studies (GWAS) and downstream cross-generational MR studies, and the estimator that they derive is neither efficient nor appropriate for such use., Comment: 8 pages, 0 figures

Published
2023

3. The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Author

Faber, Benjamin G, Frysz, Monika, Boer, Cindy G, Evans, Daniel S, Ebsim, Raja, Flynn, Kaitlyn A, Lundberg, Mischa, Southam, Lorraine, Hartley, April, Saunders, Fiona R, Lindner, Claudia, Gregory, Jennifer S, Aspden, Richard M, Lane, Nancy E, Harvey, Nicholas C, Evans, David M, Zeggini, Eleftheria, Davey Smith, George, Cootes, Timothy, Van Meurs, Joyce, Kemp, John P, and Tobias, Jonathan H

Subjects
Arthritis, Clinical Research, Genetics, Aging, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Cartilage, Genome-wide association study, Mendelian randomisation, Osteoarthritis, Clinical Sciences, Public Health and Health Services, Clinical sciences, Epidemiology
Abstract

BackgroundHip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest.MethodsGWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA.Findings50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life.InterpretationsOne group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism.FundingPrimarily funded by the Medical Research Council and Wellcome Trust.

Published
2023

4. A genome-wide association study provides insights into the genetic etiology of 57 essential and non-essential trace elements in humans

Author

Moksnes, Marta R., Hansen, Ailin F., Wolford, Brooke N., Thomas, Laurent F., Rasheed, Humaira, Simić, Anica, Bhatta, Laxmi, Brantsæter, Anne Lise, Surakka, Ida, Zhou, Wei, Magnus, Per, Njølstad, Pål R., Andreassen, Ole A., Syversen, Tore, Zheng, Jie, Fritsche, Lars G., Evans, David M., Warrington, Nicole M., Nøst, Therese H., Åsvold, Bjørn Olav, Flaten, Trond Peder, Willer, Cristen J., Hveem, Kristian, and Brumpton, Ben M.

Published
2024
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5. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

Author

Beaumont, Robin N., Flatley, Christopher, Vaudel, Marc, Wu, Xiaoping, Chen, Jing, Moen, Gunn-Helen, Skotte, Line, Helgeland, Øyvind, Solé-Navais, Pol, Banasik, Karina, Albiñana, Clara, Ronkainen, Justiina, Fadista, João, Stinson, Sara Elizabeth, Trajanoska, Katerina, Wang, Carol A., Westergaard, David, Srinivasan, Sundararajan, Sánchez-Soriano, Carlos, Bilbao, Jose Ramon, Allard, Catherine, Groleau, Marika, Kuulasmaa, Teemu, Leirer, Daniel J., White, Frédérique, Jacques, Pierre-Étienne, Cheng, Haoxiang, Hao, Ke, Andreassen, Ole A., Åsvold, Bjørn Olav, Atalay, Mustafa, Bhatta, Laxmi, Bouchard, Luigi, Brumpton, Ben Michael, Brunak, Søren, Bybjerg-Grauholm, Jonas, Ebbing, Cathrine, Elliott, Paul, Engelbrechtsen, Line, Erikstrup, Christian, Estarlich, Marisa, Franks, Stephen, Gaillard, Romy, Geller, Frank, Grove, Jakob, Hougaard, David M., Kajantie, Eero, Morgen, Camilla S., Nohr, Ellen A., Nyegaard, Mette, Palmer, Colin N. A., Pedersen, Ole Birger, Rivadeneira, Fernando, Sebert, Sylvain, Shields, Beverley M., Stoltenberg, Camilla, Surakka, Ida, Thørner, Lise Wegner, Ullum, Henrik, Vaarasmaki, Marja, Vilhjalmsson, Bjarni J., Willer, Cristen J., Lakka, Timo A., Gybel-Brask, Dorte, Bustamante, Mariona, Hansen, Torben, Pearson, Ewan R., Reynolds, Rebecca M., Ostrowski, Sisse R., Pennell, Craig E., Jaddoe, Vincent W. V., Felix, Janine F., Hattersley, Andrew T., Melbye, Mads, Lawlor, Deborah A., Hveem, Kristian, Werge, Thomas, Nielsen, Henriette Svarre, Magnus, Per, Evans, David M., Jacobsson, Bo, Järvelin, Marjo-Riitta, Zhang, Ge, Hivert, Marie-France, Johansson, Stefan, Freathy, Rachel M., Feenstra, Bjarke, and Njølstad, Pål R.

Published
2023
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6. Higher amalgamation properties in measured structures

Author

Evans, David M.

Subjects
Mathematics - Logic, Primary 03C45, Secondary 03C13
Abstract

Using an infinitary version of the Hypergraph Removal Lemma due to Towsner, we prove a model-theoretic higher amalgamation result. In particular, we obtain an independent amalgamation property which holds in structures which are measurable in the sense of Macpherson and Steinhorn, but which is not generally true in structures which are supersimple of finite SU-rank. We use this to show that some of Hrushovski's non-locally-modular, supersimple $\omega$-categorical structures are not MS-measurable.

Published
2022
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7. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, Laurence J, Nivard, Michel G, Morris, Tim T, Hansen, Ailin F, Rasheed, Humaira, Cho, Yoonsu, Chittoor, Geetha, Ahlskog, Rafael, Lind, Penelope A, Palviainen, Teemu, van der Zee, Matthijs D, Cheesman, Rosa, Mangino, Massimo, Wang, Yunzhang, Li, Shuai, Klaric, Lucija, Ratliff, Scott M, Bielak, Lawrence F, Nygaard, Marianne, Giannelis, Alexandros, Willoughby, Emily A, Reynolds, Chandra A, Balbona, Jared V, Andreassen, Ole A, Ask, Helga, Baras, Aris, Bauer, Christopher R, Boomsma, Dorret I, Campbell, Archie, Campbell, Harry, Chen, Zhengming, Christofidou, Paraskevi, Corfield, Elizabeth, Dahm, Christina C, Dokuru, Deepika R, Evans, Luke M, de Geus, Eco JC, Giddaluru, Sudheer, Gordon, Scott D, Harden, K Paige, Hill, W David, Hughes, Amanda, Kerr, Shona M, Kim, Yongkang, Kweon, Hyeokmoon, Latvala, Antti, Lawlor, Deborah A, Li, Liming, Lin, Kuang, Magnus, Per, Magnusson, Patrik KE, Mallard, Travis T, Martikainen, Pekka, Mills, Melinda C, Njølstad, Pål Rasmus, Overton, John D, Pedersen, Nancy L, Porteous, David J, Reid, Jeffrey, Silventoinen, Karri, Southey, Melissa C, Stoltenberg, Camilla, Tucker-Drob, Elliot M, Wright, Margaret J, Hewitt, John K, Keller, Matthew C, Stallings, Michael C, Lee, James J, Christensen, Kaare, Kardia, Sharon LR, Peyser, Patricia A, Smith, Jennifer A, Wilson, James F, Hopper, John L, Hägg, Sara, Spector, Tim D, Pingault, Jean-Baptiste, Plomin, Robert, Havdahl, Alexandra, Bartels, Meike, Martin, Nicholas G, Oskarsson, Sven, Justice, Anne E, Millwood, Iona Y, Hveem, Kristian, Naess, Øyvind, Willer, Cristen J, Åsvold, Bjørn Olav, Koellinger, Philipp D, Kaprio, Jaakko, Medland, Sarah E, Walters, Robin G, Benjamin, Daniel J, Turley, Patrick, Evans, David M, Davey Smith, George, Hayward, Caroline, Brumpton, Ben, Hemani, Gibran, and Davies, Neil M

Subjects
Human Genome, Genetics, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Mental health, Generic health relevance, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Social Science Genetic Association Consortium, Within Family Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022

14. The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses

Author

Faber, Benjamin G., Frysz, Monika, Boer, Cindy G., Evans, Daniel S., Ebsim, Raja, Flynn, Kaitlyn A., Lundberg, Mischa, Southam, Lorraine, Hartley, April, Saunders, Fiona R., Lindner, Claudia, Gregory, Jennifer S., Aspden, Richard M., Lane, Nancy E., Harvey, Nicholas C., Evans, David M., Zeggini, Eleftheria, Davey Smith, George, Cootes, Timothy, Van Meurs, Joyce, Kemp, John P., and Tobias, Jonathan H.

Published
2023
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15. Simplicity of the automorphism groups of generalised metric spaces

Author

Evans, David M., Hubička, Jan, Konečný, Matěj, Li, Yibei, and Ziegler, Martin

Subjects
Mathematics - Group Theory, Mathematics - Combinatorics, Mathematics - Logic, 20B27
Abstract

Tent and Ziegler proved that the automorphism group of the Urysohn sphere is simple and that the automorphism group of the Urysohn space is simple modulo bounded automorphisms. A key component of their proof is the definition of a stationary independence relation (SIR). In this paper we prove that the existence of a SIR satisfying some extra axioms is enough to prove simplicity of the automorphism group of a countable structure. The extra axioms are chosen with applications in mind, namely homogeneous structures which admit a "metric-like amalgamation", for example all primitive 3-constrained metrically homogeneous graphs of finite diameter from Cherlin's list., Comment: Accepted to Journal of Algebra

Published
2019
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18. Higher amalgamation properties in stable theories

Author

Evans, David M., Kirby, Jonathan, and Zander, Tim

Subjects
Mathematics - Logic
Abstract

For a complete, stable theory $T$ we construct, in a reasonably canonical way, a related stable theory $T^*$ which has higher independent amalgamation properties over the algebraic closure of the empty-set. The theory $T^*$ is an algebraic cover of $T$ and we give an explicit description of the finite covers involved in the construction of $T^*$ from $T$. This follows an approach of E. Hrushovski. If $T$ is almost strongly minimal with a $0$-definable strongly minimal set, then we show that $T^*$ has higher amalgamation over any algebraically closed subset., Comment: 25 pages

Published
2018

19. Permutation monoids and MB-homogeneity for graphs and relational structures

Author

Coleman, Thomas D. H., Evans, David M., and Gray, Robert D.

Subjects
Mathematics - Group Theory, Mathematics - Combinatorics, 20M99, 03C15, 05C63
Abstract

In this paper, we investigate the connection between infinite permutation monoids and bimorphism monoids of first-order structures. Taking our lead from the study of automorphism groups of structures as infinite permutation groups and the more recent developments in the field of homomorphism-homogeneous structures, we establish a series of results that underline this connection. Of particular interest is the idea of MB-homogeneity; a relational structure $\mathcal{M}$ is MB-homogeneous if every monomorphism between finite substructures of $\mathcal{M}$ extends to a bimorphism of $\mathcal{M}$. The results in question include a characterisation of closed permutation monoids, a Fra\"{i}ss\'{e}-like theorem for MB-homogeneous structures, and the construction of $2^{\aleph_0}$ pairwise non-isomorphic countable MB-homogeneous graphs. We prove that any finite group arises as the automorphism group of some MB-homogeneous graph and use this to construct oligomorphic permutation monoids with any given finite group of units. We also consider MB-homogeneity for various well-known examples of homogeneous structures and in particular give a complete classification of countable homogeneous undirected graphs that are also MB-homogeneous., Comment: 34 pages, 12 figures; to appear in the European Journal of Combinatorics

Published
2018

20. Automorphism groups and Ramsey properties of sparse graphs

Author

Evans, David M., Hubička, Jan, and Nešetřil, Jaroslav

Subjects
Mathematics - Group Theory, Computer Science - Discrete Mathematics, Mathematics - Combinatorics, Mathematics - Dynamical Systems, Mathematics - Logic, 05D10, 20B27, 37B05 (Primary), 03C15, 05C55, 22F50, 54H20 (Secondary), G.2.2, F.4.1
Abstract

We study automorphism groups of sparse graphs from the viewpoint of topological dynamics and the Kechris, Pestov, Todor\v{c}evi\'c correspondence. We investigate amenable and extremely amenable subgroups of these groups using the space of orientations of the graph and results from structural Ramsey theory. Resolving one of the open questions in the area, we show that Hrushovski's example of an $\omega$-categorical sparse graph has no $\omega$-categorical expansion with extremely amenable automorphism group., Comment: 41 pages, 2 figures, minor revision

Published
2018
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21. Identification of Novel Loci Associated With Hip Shape: A Meta‐Analysis of Genomewide Association Studies

Author

Baird, Denis A, Evans, Daniel S, Kamanu, Frederick K, Gregory, Jennifer S, Saunders, Fiona R, Giuraniuc, Claudiu V, Barr, Rebecca J, Aspden, Richard M, Jenkins, Deborah, Kiel, Douglas P, Orwoll, Eric S, Cummings, Steven R, Lane, Nancy E, Mullin, Benjamin H, Williams, Frances MK, Richards, J Brent, Wilson, Scott G, Spector, Tim D, Faber, Benjamin G, Lawlor, Deborah A, Grundberg, Elin, Ohlsson, Claes, Pettersson‐Kymmer, Ulrika, Capellini, Terence D, Richard, Daniel, Beck, Thomas J, Evans, David M, Paternoster, Lavinia, Karasik, David, and Tobias, Jonathan H

Subjects
Prevention, Genetics, Osteoporosis, Arthritis, Aging, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Musculoskeletal, Animals, Bone Density, Femur Head, Genetic Loci, Genome-Wide Association Study, Hip Fractures, Humans, Linkage Disequilibrium, Longitudinal Studies, Mice, Osteoporotic Fractures, Polymorphism, Single Nucleotide, HIP SHAPE, OSTEOARTHRITIS, HIP FRACTURE RISK, DXA, GWAS, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology
Abstract

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p  0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Published
2019

23. Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores

Author

Bond, Tom A., Richmond, Rebecca C., Karhunen, Ville, Cuellar-Partida, Gabriel, Borges, Maria Carolina, Zuber, Verena, Couto Alves, Alexessander, Mason, Dan, Yang, Tiffany C., Gunter, Marc J., Dehghan, Abbas, Tzoulaki, Ioanna, Sebert, Sylvain, Evans, David M., Lewin, Alex M., O’Reilly, Paul F., Lawlor, Deborah A., and Järvelin, Marjo-Riitta

Published
2022
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24. DNA methylation in peripheral tissues and left-handedness

Author

Odintsova, Veronika V., Suderman, Matthew, Hagenbeek, Fiona A., Caramaschi, Doretta, Hottenga, Jouke-Jan, Pool, René, Dolan, Conor V., Ligthart, Lannie, van Beijsterveldt, Catharina E. M., Willemsen, Gonneke, de Geus, Eco J. C., Beck, Jeffrey J., Ehli, Erik A., Cuellar-Partida, Gabriel, Evans, David M., Medland, Sarah E., Relton, Caroline L., Boomsma, Dorret I., and van Dongen, Jenny

Published
2022
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25. Algorithms determining finite simple images of finitely presented groups

Author

Bridson, Martin R., Evans, David M., Liebeck, Martin W., and Segal, Dan

Subjects
Mathematics - Group Theory, 20F10 (Primary), 20D05, 03D35, 03C60, 03C98, 20G25 (Secondary)
Abstract

We address the question: for which collections of finite simple groups does there exist an algorithm that determines the images of an arbitrary finitely presented group that lie in the collection? We prove both positive and negative results. For a collection of finite simple groups that contains infinitely many alternating groups, or contains classical groups of unbounded dimensions, we prove that there is no such algorithm. On the other hand, for families of simple groups of Lie type of bounded rank, we obtain positive results. For example, given any fixed untwisted Lie type $X$ there is an algorithm that determines whether or not an arbitrary finitely presented group has infinitely many simple images isomorphic to $X(q)$ for some $q$, and if there are finitely many, the algorithm determines them.

Published
2017

26. Ramsey properties and extending partial automorphisms for classes of finite structures

Author

Evans, David M., Hubička, Jan, and Nešetřil, Jaroslav

Subjects
Mathematics - Combinatorics, Computer Science - Discrete Mathematics, Mathematics - Group Theory, Mathematics - Logic, Primary: 05D10, 20B27, Secondary: 03C15, 22F50, 37B05, G.2.2, F.4.1
Abstract

We show that every free amalgamation class of finite structures with relations and (symmetric) partial functions is a Ramsey class when enriched by a free linear ordering of vertices. This is a common strengthening of the Ne\v{s}et\v{r}il-R\"odl Theorem and the second and third authors' Ramsey theorem for finite models (that is, structures with both relations and functions). We also find subclasses with the ordering property. For languages with relational symbols and unary functions we also show the extension property for partial automorphisms (EPPA) of free amalgamation classes. These general results solve several conjectures and provide an easy Ramseyness test for many classes of structures., Comment: 30 pages, 9 figures; corrections and presentation improvements suggested by the referee. Functions in structures are now set-valued

Published
2017
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27. Finite homogeneous geometries

Author

Evans, David M.

Subjects
Mathematics - Group Theory, Primary 05B25, 20B20, 20B25, Secondary 51A05, 51A15
Abstract

This paper reproduces the text of a part of the Author's DPhil thesis. It gives a proof of the classification of non-trivial, finite homogeneous geometries of sufficiently high dimension which does not depend on the classification of the finite simple groups., Comment: 7 pages

Published
2017

28. Understanding the Genetic Landscape of Gestational Diabetes: Insights into the Causes and Consequences of Elevated Glucose Levels in Pregnancy.

Author

Brito Nunes, Caroline, Borges, Maria Carolina, Freathy, Rachel M., Lawlor, Deborah A., Qvigstad, Elisabeth, Evans, David M., and Moen, Gunn-Helen

Subjects
SECOND trimester of pregnancy, THIRD trimester of pregnancy, GLUCOSE intolerance, EVIDENCE gaps, ETIOLOGY of diabetes, GESTATIONAL diabetes
Abstract

Background/Objectives: During pregnancy, physiological changes in maternal circulating glucose levels and its metabolism are essential to meet maternal and fetal energy demands. Major changes in glucose metabolism occur throughout pregnancy and consist of higher insulin resistance and a compensatory increase in insulin secretion to maintain glucose homeostasis. For some women, this change is insufficient to maintain normoglycemia, leading to gestational diabetes mellitus (GDM), a condition characterized by maternal glucose intolerance and hyperglycaemia first diagnosed during the second or third trimester of pregnancy. GDM is diagnosed in approximately 14.0% of pregnancies globally, and it is often associated with short- and long-term adverse health outcomes in both mothers and offspring. Although recent studies have highlighted the role of genetic determinants in the development of GDM, research in this area is still lacking, hindering the development of prevention and treatment strategies. Methods: In this paper, we review recent advances in the understanding of genetic determinants of GDM and glycaemic traits during pregnancy. Results/Conclusions: Our review highlights the need for further collaborative efforts as well as larger and more diverse genotyped pregnancy cohorts to deepen our understanding of the genetic aetiology of GDM, address research gaps, and further improve diagnostic and treatment strategies. [ABSTRACT FROM AUTHOR]

Published
2024
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30. Higher maternal adiposity reduces offspring birthweight if associated with a metabolically favourable profile

Author

Thompson, William D., Beaumont, Robin N., Kuang, Alan, Warrington, Nicole M., Ji, Yingjie, Tyrrell, Jessica, Wood, Andrew R., Scholtens, Denise M., Knight, Bridget A., Evans, David M., Lowe, Jr, William L., Santorelli, Gillian, Azad, Rafaq, Mason, Dan, Hattersley, Andrew T., Frayling, Timothy M., Yaghootkar, Hanieh, Borges, Maria Carolina, Lawlor, Deborah A., and Freathy, Rachel M.

Published
2021
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31. Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects

Author

Medina-Gomez, Carolina, Kemp, John P, Trajanoska, Katerina, Luan, Jian’an, Chesi, Alessandra, Ahluwalia, Tarunveer S, Mook-Kanamori, Dennis O, Ham, Annelies, Hartwig, Fernando P, Evans, Daniel S, Joro, Raimo, Nedeljkovic, Ivana, Zheng, Hou-Feng, Zhu, Kun, Atalay, Mustafa, Liu, Ching-Ti, Nethander, Maria, Broer, Linda, Porleifsson, Gudmar, Mullin, Benjamin H, Handelman, Samuel K, Nalls, Mike A, Jessen, Leon E, Heppe, Denise HM, Richards, J Brent, Wang, Carol, Chawes, Bo, Schraut, Katharina E, Amin, Najaf, Wareham, Nick, Karasik, David, Van der Velde, Nathalie, Ikram, M Arfan, Zemel, Babette S, Zhou, Yanhua, Carlsson, Christian J, Liu, Yongmei, McGuigan, Fiona E, Boer, Cindy G, Bønnelykke, Klaus, Ralston, Stuart H, Robbins, John A, Walsh, John P, Zillikens, M Carola, Langenberg, Claudia, Li-Gao, Ruifang, Williams, Frances MK, Harris, Tamara B, Akesson, Kristina, Jackson, Rebecca D, Sigurdsson, Gunnar, Heijer, Martin den, van der Eerden, Bram CJ, van de Peppel, Jeroen, Spector, Timothy D, Pennell, Craig, Horta, Bernardo L, Felix, Janine F, Zhao, Jing Hua, Wilson, Scott G, de Mutsert, Renée, Bisgaard, Hans, Styrkársdóttir, Unnur, Jaddoe, Vincent W, Orwoll, Eric, Lakka, Timo A, Scott, Robert, Grant, Struan FA, Lorentzon, Mattias, van Duijn, Cornelia M, Wilson, James F, Stefansson, Kari, Psaty, Bruce M, Kiel, Douglas P, Ohlsson, Claes, Ntzani, Evangelia, van Wijnen, Andre J, Forgetta, Vincenzo, Ghanbari, Mohsen, Logan, John G, Williams, Graham R, Bassett, JH Duncan, Croucher, Peter I, Evangelou, Evangelos, Uitterlinden, Andre G, Ackert-Bicknell, Cheryl L, Tobias, Jonathan H, Evans, David M, and Rivadeneira, Fernando

Subjects
Rare Diseases, Aging, Human Genome, Osteoporosis, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Good Health and Well Being, Adolescent, Age Factors, Animals, Bone Density, Child, Child, Preschool, Genetic Loci, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Mice, Knockout, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Regression Analysis, BMD, CREB3L1, ESR1, GWASs, RANKL, age-dependent effects, bone mineral density, fracture, genetic correlation, genome-wide association studies, meta-regression, total-body DXA, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Published
2018

33. The relationship between adrenocortical candidate gene expression and clinical response to hydrocortisone in patients with septic shock

Author

Cohen, Jeremy, Blumenthal, Antje, Cuellar-Partida, Gabriel, Evans, David M., Finfer, Simon, Li, Qiang, and Ljungberg, Johanna

Subjects
Corticosteroids -- Physiological aspects -- Genetic aspects, Gene expression -- Physiological aspects -- Genetic aspects, RNA sequencing -- Genetic aspects -- Physiological aspects, Mortality -- Australia, Genes -- Physiological aspects -- Genetic aspects, Proteins -- Genetic aspects -- Physiological aspects, Septic shock -- Genetic aspects -- Care and treatment, Health care industry
Abstract

Purpose To determine if adrenocortical gene expression is associated with clinical outcomes or response to corticosteroid treatment in septic shock. Methods A pre-specified nested cohort study of a randomised controlled trial of hydrocortisone compared to placebo in septic shock. Blood was collected for RNAseq analysis prior to treatment with hydrocortisone or placebo. The expression of adrenocortical candidate genes related to pituitary releasing hormones, mineralocorticoid and glucocorticoid receptors, intracellular glucocorticoid metabolism and transport proteins was measured. Results From May 2014 to April 2017, 671 patients were enrolled in the nested cohort study, from which 494 samples were available for analysis. We found no evidence of an association between candidate gene expression levels and either 90-day mortality, 28-day mortality or time to shock reversal. We observed evidence of a significant interaction between expression and treatment group for time to shock reversal in two genes; GLCCI1 (HR 3.81, 95%CI 0.57-25.47 vs. HR 0.64, 95%CI 0.13-3.07 for hydrocortisone and placebo respectively, p for interaction 0.008) and BHSD1 (HR 0.55, 95%CI 0.28-1.09 vs. HR 1.32 95%CI 0.67-2.60, p for interaction 0.01). Conclusions In patients with septic shock, there is no association between adrenocortical candidate gene expression and mortality. Patients with higher expression of GLCCI1 who received hydrocortisone achieved shock resolution faster than those receiving placebo; conversely, patients who had higher expression of BHSD1 who received hydrocortisone achieved shock resolution slower than those who received placebo. Variation in gene expression may be a mechanism for heterogeneity of treatment response to corticosteroids in septic shock., Author(s): Jeremy Cohen [sup.1] [sup.2] [sup.3] [sup.4], Antje Blumenthal [sup.5], Gabriel Cuellar-Partida [sup.5], David M. Evans [sup.5] [sup.6], Simon Finfer [sup.1] [sup.7] [sup.8] [sup.9], Qiang Li [sup.1], Johanna Ljungberg [sup.5], [...]

Published
2021
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35. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study

Author

Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O’Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t’Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, Woo, Daniel, and Rosand, Jonathan

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Cancer, Prevention, Genetics, Aetiology, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis, Telomeres Mendelian Randomization Collaboration, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

36. Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Author

Telomeres Mendelian Randomization Collaboration, Haycock, Philip C, Burgess, Stephen, Nounu, Aayah, Zheng, Jie, Okoli, George N, Bowden, Jack, Wade, Kaitlin Hazel, Timpson, Nicholas J, Evans, David M, Willeit, Peter, Aviv, Abraham, Gaunt, Tom R, Hemani, Gibran, Mangino, Massimo, Ellis, Hayley Patricia, Kurian, Kathreena M, Pooley, Karen A, Eeles, Rosalind A, Lee, Jeffrey E, Fang, Shenying, Chen, Wei V, Law, Matthew H, Bowdler, Lisa M, Iles, Mark M, Yang, Qiong, Worrall, Bradford B, Markus, Hugh Stephen, Hung, Rayjean J, Amos, Chris I, Spurdle, Amanda B, Thompson, Deborah J, O'Mara, Tracy A, Wolpin, Brian, Amundadottir, Laufey, Stolzenberg-Solomon, Rachael, Trichopoulou, Antonia, Onland-Moret, N Charlotte, Lund, Eiliv, Duell, Eric J, Canzian, Federico, Severi, Gianluca, Overvad, Kim, Gunter, Marc J, Tumino, Rosario, Svenson, Ulrika, van Rij, Andre, Baas, Annette F, Bown, Matthew J, Samani, Nilesh J, van t'Hof, Femke NG, Tromp, Gerard, Jones, Gregory T, Kuivaniemi, Helena, Elmore, James R, Johansson, Mattias, Mckay, James, Scelo, Ghislaine, Carreras-Torres, Robert, Gaborieau, Valerie, Brennan, Paul, Bracci, Paige M, Neale, Rachel E, Olson, Sara H, Gallinger, Steven, Li, Donghui, Petersen, Gloria M, Risch, Harvey A, Klein, Alison P, Han, Jiali, Abnet, Christian C, Freedman, Neal D, Taylor, Philip R, Maris, John M, Aben, Katja K, Kiemeney, Lambertus A, Vermeulen, Sita H, Wiencke, John K, Walsh, Kyle M, Wrensch, Margaret, Rice, Terri, Turnbull, Clare, Litchfield, Kevin, Paternoster, Lavinia, Standl, Marie, Abecasis, Gonçalo R, SanGiovanni, John Paul, Li, Yong, Mijatovic, Vladan, Sapkota, Yadav, Low, Siew-Kee, Zondervan, Krina T, Montgomery, Grant W, Nyholt, Dale R, van Heel, David A, Hunt, Karen, Arking, Dan E, Ashar, Foram N, Sotoodehnia, Nona, and Woo, Daniel

Subjects
Telomeres Mendelian Randomization Collaboration, Telomere, Humans, Neoplasms, Cardiovascular Diseases, Genetic Predisposition to Disease, Risk Assessment, Germ-Line Mutation, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Mendelian Randomization Analysis, Telomere Homeostasis, Polymorphism, Single Nucleotide, and over, Prevention, Clinical Research, Cancer, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

Published
2017

43. Codelivery of TGFβ and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors

Author

Kim, Wookhyun, primary, Ye, Zhou, additional, Simonenko, Vera, additional, Shahi, Aashirwad, additional, Malikzay, Asra, additional, Long, Steven Z, additional, Xu, John J, additional, Lu, Alan, additional, Horng, Jau-Hau, additional, Wu, Chang-Ru, additional, Chen, Pei-Jer, additional, Lu, Patrick Y, additional, and Evans, David M, additional

Published
2024
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44. Genome-wide association study identifies 48 common genetic variants associated with handedness

Author

Cuellar-Partida, Gabriel, Tung, Joyce Y., Eriksson, Nicholas, Albrecht, Eva, Aliev, Fazil, Andreassen, Ole A., Barroso, Inês, Beckmann, Jacques S., Boks, Marco P., Boomsma, Dorret I., Boyd, Heather A., Breteler, Monique M. B., Campbell, Harry, Chasman, Daniel I., Cherkas, Lynn F., Davies, Gail, de Geus, Eco J. C., Deary, Ian J., Deloukas, Panos, Dick, Danielle M., Duffy, David L., Eriksson, Johan G., Esko, Tõnu, Feenstra, Bjarke, Geller, Frank, Gieger, Christian, Giegling, Ina, Gordon, Scott D., Han, Jiali, Hansen, Thomas F., Hartmann, Annette M., Hayward, Caroline, Heikkilä, Kauko, Hicks, Andrew A., Hirschhorn, Joel N., Hottenga, Jouke-Jan, Huffman, Jennifer E., Hwang, Liang-Dar, Ikram, M. Arfan, Kaprio, Jaakko, Kemp, John P., Khaw, Kay-Tee, Klopp, Norman, Konte, Bettina, Kutalik, Zoltan, Lahti, Jari, Li, Xin, Loos, Ruth J. F., Luciano, Michelle, Magnusson, Sigurdur H., Mangino, Massimo, Marques-Vidal, Pedro, Martin, Nicholas G., McArdle, Wendy L., McCarthy, Mark I., Medina-Gomez, Carolina, Melbye, Mads, Melville, Scott A., Metspalu, Andres, Milani, Lili, Mooser, Vincent, Nelis, Mari, Nyholt, Dale R., O’Connell, Kevin S., Ophoff, Roel A., Palmer, Cameron, Palotie, Aarno, Palviainen, Teemu, Pare, Guillaume, Paternoster, Lavinia, Peltonen, Leena, Penninx, Brenda W. J. H., Polasek, Ozren, Pramstaller, Peter P., Prokopenko, Inga, Raikkonen, Katri, Ripatti, Samuli, Rivadeneira, Fernando, Rudan, Igor, Rujescu, Dan, Smit, Johannes H., Smith, George Davey, Smoller, Jordan W., Soranzo, Nicole, Spector, Tim D., Pourcain, Beate St, Starr, John M., Stefánsson, Hreinn, Steinberg, Stacy, Teder-Laving, Maris, Thorleifsson, Gudmar, Stefánsson, Kári, Timpson, Nicholas J., Uitterlinden, André G., van Duijn, Cornelia M., van Rooij, Frank J. A., Vink, Jaqueline M., Vollenweider, Peter, Vuoksimaa, Eero, Waeber, Gérard, Wareham, Nicholas J., Warrington, Nicole, Waterworth, Dawn, Werge, Thomas, Wichmann, H.-Erich, Widen, Elisabeth, Willemsen, Gonneke, Wright, Alan F., Wright, Margaret J., Xu, Mousheng, Zhao, Jing Hua, Kraft, Peter, Hinds, David A., Lindgren, Cecilia M., Mägi, Reedik, Neale, Benjamin M., Evans, David M., and Medland, Sarah E.

Published
2021
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45. Genome-wide association study identifies 74 loci associated with educational attainment

Author

Okbay, Aysu, Beauchamp, Jonathan P, Fontana, Mark Alan, Lee, James J, Pers, Tune H, Rietveld, Cornelius A, Turley, Patrick, Chen, Guo-Bo, Emilsson, Valur, Meddens, S Fleur W, Oskarsson, Sven, Pickrell, Joseph K, Thom, Kevin, Timshel, Pascal, de Vlaming, Ronald, Abdellaoui, Abdel, Ahluwalia, Tarunveer S, Bacelis, Jonas, Baumbach, Clemens, Bjornsdottir, Gyda, Brandsma, Johannes H, Pina Concas, Maria, Derringer, Jaime, Furlotte, Nicholas A, Galesloot, Tessel E, Girotto, Giorgia, Gupta, Richa, Hall, Leanne M, Harris, Sarah E, Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E, Kaasik, Kadri, Kalafati, Ioanna P, Karlsson, Robert, Kong, Augustine, Lahti, Jari, Lee, Sven J van der, deLeeuw, Christiaan, Lind, Penelope A, Lindgren, Karl-Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B, van der Most, Peter J, Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J, Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E, Shi, Jianxin, Smith, Albert V, Poot, Raymond A, St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm-Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z, Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E, Biino, Ginevra, Bønnelykke, Klaus, Boyle, Patricia A, Campbell, Harry, Cappuccio, Francesco P, Davies, Gail, De Neve, Jan-Emmanuel, Deloukas, Panos, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M, Faul, Jessica D, Feitosa, Mary F, Forstner, Andreas J, Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V, Harris, Tamara B, Heath, Andrew C, Hocking, Lynne J, Holliday, Elizabeth G, Homuth, Georg, and Horan, Michael A

Subjects
Biological Sciences, Genetics, Epidemiology, Health Sciences, Statistics, Mathematical Sciences, Human Genome, Clinical Research, Alzheimer Disease, Bipolar Disorder, Brain, Cognition, Computational Biology, Educational Status, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Genome-Wide Association Study, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia, United Kingdom, LifeLines Cohort Study, General Science & Technology
Abstract

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Published
2016

46. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author

Minelli, Cosetta, Dean, Charlotte H, Hind, Matthew, Alves, Alexessander Couto, Amaral, André FS, Siroux, Valerie, Huikari, Ville, Soler Artigas, María, Evans, David M, Loth, Daan W, Bossé, Yohan, Postma, Dirkje S, Sin, Don, Thompson, John, Demenais, Florence, Henderson, John, Bouzigon, Emmanuelle, Jarvis, Deborah, Järvelin, Marjo-Riitta, and Burney, Peter

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Lung, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Respiratory, Adult, Aged, Female, Forced Expiratory Volume, Gene Expression Profiling, Genes, Developmental, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Nuclear Receptor Co-Repressor 2, Organogenesis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Young Adult, SpiroMeta consortium, CHARGE consortium, General Science & Technology
Abstract

BackgroundForced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes.MethodsPer-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p

Published
2016

47. Infinite primitive and distance transitive directed graphs of finite out-valency

Author

Amato, Daniela and Evans, David M.

Subjects
Mathematics - Combinatorics, Mathematics - Group Theory, 05C20, 05E18, 20B07, 20B15
Abstract

We give certain properties which are satisfied by the descendant set of a vertex in an infinite, primitive, distance transitive digraph of finite out-valency and provide a strong structure theory for digraphs satisfying these properties. In particular, we show that there are only countably many possibilities for the isomorphism type of such a descendant set, thereby confirming a conjecture of the first Author. As a partial converse, we show that certain related conditions on a countable digraph are sufficient for it to occur as the descendant set of a primitive, distance transitive digraph., Comment: 18 pages

Published
2014
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49. Free actions of free groups on countable structures and property (T)

Author

Evans, David M. and Tsankov, Todor

Subjects
Mathematics - Group Theory, Mathematics - Logic, Primary 22A25, 20B27, Secondary 03C15
Abstract

We show that if $G$ is a non-archimedean, Roelcke precompact, Polish group, then $G$ has Kazhdan's property (T). Moreover, if $G$ has a smallest open subgroup of finite index, then $G$ has a finite Kazhdan set. Examples of such $G$ include automorphism groups of countable $\omega$-categorical structures, that is, the closed, oligomorphic permutation groups on a countable set. The proof uses work of the second author on the unitary representations of such groups, together with a separation result for infinite permutation groups. The latter allows the construction of a non-abelian free subgroup of $G$ acting freely in all infinite transitive permutation representations of $G$., Comment: 14 pages. Minor changes to original version

Published
2013

50. Simplicity of the automorphism groups of some Hrushovski constructions

Author

Evans, David M., Ghadernezhad, Zaniar, and Tent, Katrin

Subjects
Mathematics - Logic, Mathematics - Group Theory, 03C15, 20B07, 20B27
Abstract

We show that the automorphism groups of certain countable structures obtained using the Hrushovski amalgamation method are simple groups. The structures we consider are the 'uncollapsed' structures of infinite Morley rank obtained by the ab initio construction and the (unstable) omega-categorical pseudoplanes. The simplicity of the automorphism groups of these follows from results which generalize work of Lascar and of Tent and Ziegler., Comment: 35 pages

Published
2013

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