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1. Systematic Review of Breast-Q: A Tool to Evaluate Post-Mastectomy Breast Reconstruction

Author

Seth I, Seth N, Bulloch G, Rozen WM, and Hunter-Smith DJ

Subjects
breast-q, patient-reported outcomes, breast reconstruction surgery, mastectomy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Ishith Seth,1 Nimish Seth,2 Gabriella Bulloch,3 Warren M Rozen,4 David J Hunter-Smith4 1Department of Surgery, Bendigo Health, Bendigo, Victoria, 3550, Australia; 2Department of Surgery, The Alfred Hospital, Melbourne, Victoria, 3004, Australia; 3Faculty of Science, Medicine and Health, University of Melbourne, Melbourne, Victoria, 3010, Australia; 4Peninsula Clinical School, Central Clinical School at Monash University, The Alfred Centre, Melbourne, Victoria, 3004, AustraliaCorrespondence: David J Hunter-SmithPeninsula Clinical School, Central Clinical School at Monash University, The Alfred Centre, 99 Commercial Road, Melbourne, Victoria, 3004, AustraliaTel +610359763522Fax +610359763544Email dhuntersmith@mac.comPurpose: The aim of this systematic review is to update and synthesize new evidence on BREAST-Q questionnaire’s ability to reflect patient-reported outcomes in women who have undergone breast reconstruction surgery (BRS) following mastectomy.Methods: PubMed, Science Direct, Google Scholar, Cochrane CENTRAL, and Clincaltrial.gov were searched for relevant studies from January 2009 to September 2021. Any interventional or observational studies that used BREAST-Q to assess patient-reported outcomes in the assessment of BRS following mastectomy were included.Results: A total of 42 studies were eligible for inclusion in the review. Three were randomized controlled trials and 39 were observational studies. Compared with pre-operative scores, there was an improvement in all BREAST-Q outcome domains following BRS including ‘satisfaction with breasts’, “satisfaction with outcome” “psychosocial”, “physical”, and “sexual wellbeing”. Sexual well-being had the lowest BREAST-Q score both pre-and post-operatively (37.8– 80.0 and 39.0– 78.0, respectively). Autologous BRS reports higher satisfaction and overall wellbeing compared to implant-based BRS. BREAST-Q has a higher and narrow internal consistency of 0.81 to 0.96 compared with other patient-reported outcome measures (PROMs; EORTC-QLQ, FACT-B, BR-23, BCTOS). The BREAST-Q questionnaire is the only PROM which allows patients to reflect on their care, surgical outcomes, and satisfaction collectively.Conclusion: This review highlights the fact that BREAST-Q can effectively and reliably measure satisfaction and wellbeing of breast cancer patients after BRS. Comparatively, sexual wellbeing shows poorer outcomes following BRS and more longitudinal studies are necessary to understand the basis for these findings. Compared to other PROMs, BREAST-Q is reliable and specific to breast cancer surgery. Overall, BREAST-Q can help clinicians improve their quality of service, understand patient experiences, and may be used as an auditing tool for surgical outcomes.Keywords: BREAST-Q, patient-reported outcomes, breast reconstruction surgery, mastectomy

Published
2021

2. Genetic screening reveals a link between Wnt signaling and antitubulin drugs

Author

Khan, AH, Bloom, JS, Faridmoayer, E, and Smith, DJ

Subjects
Biotechnology, Genetics, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Antineoplastic Agents, Cell Line, Cell Survival, Colchicine, Cricetinae, Humans, Hybrid Cells, Paclitaxel, Quantitative Trait Loci, Signal Transduction, Tubulin Modulators, Ubiquitin-Protein Ligases, Wnt Proteins, Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy
Abstract

The antitubulin drugs, paclitaxel (PX) and colchicine (COL), inhibit cell growth and are therapeutically valuable. PX stabilizes microtubules, while COL promotes their depolymerization. But, the drug concentrations that alter tubulin polymerization are hundreds of times higher than their clinically useful levels. To map genetic targets for drug action at single-gene resolution, we used a human radiation hybrid panel. We identified loci that affected cell survival in the presence of five compounds of medical relevance. For PX and COL, the zinc and ring finger 3 (ZNRF3) gene dominated the genetic landscape at therapeutic concentrations. ZNRF3 encodes an R-spondin regulated receptor that inhibits Wingless/Int (Wnt) signaling. Overexpression of the ZNRF3 gene shielded cells from antitubulin drug action, while small interfering RNA knockdowns resulted in sensitization. Further a potent pharmacological inhibitor of Wnt signaling, Wnt-C59, protected cells from PX and COL. Our results suggest that the antitubulin drugs perturb microtubule dynamics, thereby influencing Wnt signaling.

Published
2016

3. Special Issue: Population and Development: Comparative Anthropological Perspectives

Author

Smith, DJ and Johnson-Hanks, JA

Subjects
Political Science & Public Administration, Studies in Human Society
Abstract

In this introduction, we do five things. First, we briefly review some of the contributions that anthropology has made in recent decades to the study of development. Second, we discuss the overall importance of population processes in development. Third, we provide an introduction to the field of anthropological demography. While each of these sections is necessarily brief, they are meant to situate the articles in this issue, placing them in a broad framework that suggests the contributions that anthropology can make to the study of comparative international development in general, and to the relationship between population and development in particular. To this end, the fourth aim of this introduction is to consider how anthropology approaches the social science task of comparison. Familiarizing readers with this engagement will, we hope, help in thinking about the contributions of the papers in this issue. The final section provides a brief introduction to each article, suggesting some of the ways they intersect with and illuminate themes we have raised here.

Published
2015

4. Using structural disorder to enhance the magnetism and spin-polarization in FexSi1-x thin films for spintronics

Author

Karel, J, Zhang, YN, Bordel, C, Stone, KH, Chen, TY, Jenkins, CA, Smith, DJ, Hu, J, Wu, RQ, Heald, SM, Kortright, JB, and Hellman, F

Subjects
amorphous, thin film magnetism, spintronics, x-ray absorption, x-ray magnetic circular dichroism, density functional theory, Materials Engineering
Abstract

Amorphous FexSi1-x thin films exhibit a striking enhancement in magnetization compared to crystalline films with the same composition (0.45 < x < 0.75), and xray magnetic circular dichroism reveals an enhancement in both spin and orbital moments in the amorphous films. Density functional theory (DFT) calculations reproduce this enhanced magnetization and also show a relatively large spinpolarization at the Fermi energy, also seen experimentally in Andreev reflection. Theory and experiment show that the amorphous materials have a decreased number of nearest neighbors and reduced number density relative to the crystalline samples of the same composition; the associated decrease in Fe-Si neighbors reduces the hybridization of Fe orbitals, leading to the enhanced moment.

Published
2014

6. Effects of genome-wide copy number variation on expression in mammalian cells

Author

Wang, RT, Ahn, S, Park, CC, Khan, AH, Lange, K, and Smith, DJ

Abstract

Background: There is only a limited understanding of the relation between copy number and expression for mammalian genes. We fine mapped cis and trans regulatory loci due to copy number change for essentially all genes using a human-hamster radiation hybrid (RH) panel. These loci are called copy number expression quantitative trait loci (ceQTLs).Results: Unexpected findings from a previous study of a mouse-hamster RH panel were replicated. These findings included decreased expression as a result of increased copy number for 30% of genes and an attenuated relationship between expression and copy number on the X chromosome suggesting an Xist independent form of dosage compensation. In a separate glioblastoma dataset, we found conservation of genes in which dosage was negatively correlated with gene expression. These genes were enriched in signaling and receptor activities. The observation of attenuated X-linked gene expression in response to increased gene number was also replicated in the glioblastoma dataset. Of 523 gene deserts of size > 600 kb in the human RH panel, 325 contained trans ceQTLs with -log10P > 4.1. Recently discovered genes, ultra conserved regions, noncoding RNAs and microRNAs explained only a small fraction of the results, suggesting a substantial portion of gene deserts harbor as yet unidentified functional elements.Conclusion: Radiation hybrids are a useful tool for high resolution mapping of cis and trans loci capable of affecting gene expression due to copy number change. Analysis of two independent radiation hybrid panels show agreement in their findings and may serve as a discovery source for novel regulatory loci in noncoding regions of the genome. © 2011 Wang et al; licensee BioMed Central Ltd.

Published
2011

7. Gene networks associated with conditional fear in mice identified using a systems genetics approach

Author

Park, CC, Gale, GD, de Jong, S, Ghazalpour, A, Bennett, BJ, Farber, CR, Langfelder, P, Lin, A, Khan, AH, Eskin, E, Horvath, S, Lusis, AJ, Ophoff, RA, and Smith, DJ

Abstract

Background: Our understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution.Results: A total of 27 behavioral quantitative trait loci were mapped with a false discovery rate of 5%. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and also genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. In addition, we surveyed the architecture of brain transcript regulation and demonstrated preservation of gene co-expression modules in hippocampus and striatum, while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance were strongly associated with fear phenotypes.Conclusion: Application of our multi-faceted mapping strategy permits an increasingly detailed characterization of the genetic networks underlying behavior. © 2011 Park et al; licensee BioMed Central Ltd.

Published
2011

8. A genome-wide panel of congenic mice reveals widespread epistasis of behavior quantitative trait loci

Author

Gale, GD, Yazdi, RD, Khan, AH, Lusis, AJ, Davis, RC, and Smith, DJ

Subjects
Biological Psychology, Psychology, Human Genome, Behavioral and Social Science, Genetics, Animals, Anxiety, Behavior, Animal, Chromosome Mapping, Conditioning, Psychological, Epistasis, Genetic, Exploratory Behavior, Fear, Genomics, Male, Maze Learning, Memory, Mice, Mice, Congenic, Mice, Inbred C57BL, Pain Threshold, Quantitative Trait Loci, fear, anxiety, learning, memory, mapping, gene, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Understanding the genetics of behavioral variation remains a fascinating but difficult problem with considerable theoretical and practical implications. We used the genome-tagged mice (GTM) and an extensive test battery of well-validated behavioral assays to scan the genome for behavioral quantitative trait loci (QTLs). The GTM are a panel of 'speed congenic' mice consisting of over 60 strains spanning the entire autosomal genome. Each strain harbors a small (approximately 23 cM) DBA/2J donor segment on a uniform C57BL/6J background. The panel allows for mapping to regions as small as 5 cM and provides a powerful new tool for increasing mapping power and replicability in the analysis of QTLs. A total of 97 loci were mapped for a variety of complex behavioral traits including hyperactivity, anxiety, prepulse inhibition, avoidance and conditional fear. A larger number of loci were recovered than generally attained from standard mapping crosses. In addition, a surprisingly high proportion of loci, 63%, showed phenotypes unlike either of the parental strains. These data suggest that epistasis decreases sensitivity of locus detection in traditional crosses and demonstrate the utility of the GTM for mapping complex behavioral traits with high sensitivity and precision.

Published
2009

9. Quenched magnetic moment in Mn-doped amorphous Si films

Author

Zeng, L, Helgren, E, Rahimi, M, Hellman, F, Islam, R, Wilkens, BJ, Culbertson, RJ, and Smith, DJ

Subjects
Fluids & Plasmas, Physical Sciences, Chemical Sciences
Abstract

The absence of a Mn local moment was observed in Mn-doped amorphous silicon (a- Mnx Si1-x) films. The magnetic susceptibility obeys the Curie-Weiss law for a wide range of x (5× 10-3 up to 0.175) but with extremely small moment. Magnetization measurements suggest that this behavior occurs because only a small percentage of Mn (Mn2+ states with J=S=5/2) contribute to the magnetization. Thus, the magnetic moments are quenched for the majority of Mn atoms, contrary to the general belief of the existence of a localized Mn moment in Si. X-ray absorption spectroscopy suggests that the quenching of Mn moments is attributed to the formation of an itinerant but Anderson-localized impurity band, forming at x as low as 5× 10-3. © 2008 The American Physical Society.

Published
2008

11. Squirmer hydrodynamics near a periodic surface topography

Author

Ishimoto, K, Gaffney, EA, and Smith, DJ

Subjects
Fluid Dynamics (physics.flu-dyn), Soft Condensed Matter (cond-mat.soft), FOS: Physical sciences, Physics - Fluid Dynamics, Cell Biology, Condensed Matter - Soft Condensed Matter, Developmental Biology
Abstract

The behaviour of microscopic swimmers has previously been explored near large scale confining geometries and in the presence of very small-scale surface roughness. Here we consider an intermediate case of how a simple microswimmer, the tangential spherical squirmer, behaves adjacent to singly- and doubly-periodic sinusoidal surface topographies that spatially oscillate with an amplitude that is an order of magnitude less than the swimmer size and wavelengths within an order of magnitude of this scale. The nearest neighbour regularised Stokeslet method is used for numerical explorations after validating its accuracy for a spherical tangential squirmer that swims stably near a flat surface. The same squirmer is then introduced to the different surface topographies. The key governing factor in the resulting swimming behaviour is the size of the squirmer relative to the surface topography wavelength. When the squirmer is much larger, or much smaller, than the surface topography wavelength then directional guidance is not observed. Once the squirmer size is on the scale of the topography wavelength limited guidance is possible, often with local capture in the topography troughs. However, complex dynamics can also emerge, especially when the initial configuration is not close to alignment along topography troughs or above topography crests. In contrast to sensitivity in alignment and the topography wavelength, reductions in the amplitude of the surface topography or variations in the shape of the periodic surface topography do not have extensive impacts on the squirmer behaviour. Our findings more generally highlight that detailed numerical explorations are necessary to determine how surface topographies may interact with a given swimmer that swims stably near a flat surface and whether surface topographies may be designed to provide such swimmers with directional guidance., Comment: 13 pages, 9 figures

Published
2023

12. Characterization of A/H7 influenza virus global antigenic diversity and key determinants in the hemagglutinin globular head mediating A/H7N9 antigenic evolution

Author

Kok, A, Scheuer, R, Bestebroer, TM, Burke, DF, Wilks, SH, Spronken, MI, de Meulder, D, Lexmond, P, Pronk, M, Smith, DJ, Herfst, S, Fouchier, RAM, Richard, M, Kok, A, Scheuer, R, Bestebroer, TM, Burke, DF, Wilks, SH, Spronken, MI, de Meulder, D, Lexmond, P, Pronk, M, Smith, DJ, Herfst, S, Fouchier, RAM, and Richard, M

Abstract

Avian A/H7 influenza viruses are a global threat to animal and human health. These viruses continue to cause outbreaks in poultry and have caused the highest number of reported zoonotic infections to date, highlighting their pandemic threat. Evidence for antigenic diversification of avian A/H7 influenza viruses exists; however, knowledge of the drivers and molecular basis of antigenic evolution of these viruses is limited. Here, antigenic cartography was used to analyze the global antigenic diversity of A/H7 influenza viruses and to determine the molecular basis of antigenic change in A/H7N9 viruses. A phylogenetic tree based on all available A/H7 HA sequences was generated, from which 52 representative, genetically diverse, antigens were selected for antigenic characterization using hemagglutination inhibition assays. The resulting data were used to compute an antigenic map using multidimensional scaling algorithms. High antigenic relatedness was observed between antigens and sera belonging to genetically divergent A/H7 (sub)lineages. The most striking antigenic change relative to the timespan of virus isolation was observed for the A/H7N9 viruses isolated between 2013 and 2019 in China. Amino acid changes at positions 116, 118, 125, 130, 151, and 217 in the hemagglutinin globular head were found to be the main determinants of antigenic evolution between A/H7N9 influenza virus prototypes. The A/H7 antigenic map and knowledge of the molecular determinants of their antigenic evolution will aid pandemic preparedness against A/H7 influenza viruses, specifically regarding the design of novel vaccines and vaccination strategies. IMPORTANCE A/H7 avian influenza viruses cause outbreaks in poultry globally, resulting in outbreaks with significant socio-economical impact and zoonotic risks. Occasionally, poultry vaccination programs have been implemented to reduce the burden of these viruses, which might result in an increased immune pressure accelerating antigenic evolut

Published
2023

14. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, Ruderfer, DM, Mullins, N, Kang, J, Campos, A, Coleman, JR, Edwards, AC, Galfalvy, H, Levey, DF, Lori, A, Shabalin, A, Starnawska, A, Su, M-H, Watson, HJ, Adams, M, Awasthi, S, Ganda, M, Hafferty, JD, Hishimoto, A, Kim, M, Okazaki, S, Otsuka, I, Ripke, S, Ware, EB, Bergen, AW, Berrettini, WH, Bohus, M, Brandt, H, Chang, X, Chen, WJ, Chen, H-C, Crawford, S, Crow, S, DiBlasi, E, Duriez, P, Fernandez-Aranda, F, Fichter, MM, Gallinger, S, Glatt, SJ, Gorwood, P, Guo, Y, Hakonarson, H, Halmi, KA, Hwu, H-G, Jain, S, Jamain, S, Jimenez-Murcia, S, Johnson, C, Kaplan, AS, Kaye, WH, Keel, PK, Kennedy, JL, Klump, KL, Li, D, Liao, S-C, Lieb, K, Lilenfeld, L, Liu, C-M, Magistretti, PJ, Marshall, CR, Mitchell, JE, Monson, ET, Myers, RM, Pinto, D, Powers, A, Ramoz, N, Roepke, S, Rozanov, V, Scherer, SW, Schmahl, C, Sokolowski, M, Strober, M, Thornton, LM, Treasure, J, Tsuang, MT, Witt, SH, Woodside, DB, Yilmaz, Z, Zillich, L, Adolfsson, R, Agartz, I, Air, TM, Alda, M, Alfredsson, L, Andreassen, OA, Anjorin, A, Appadurai, V, Artigas, MS, Van der Auwera, S, Azevedo, MH, Bass, N, Bau, CHD, Baune, BT, Bellivier, F, Berger, K, Biernacka, JM, Bigdeli, TB, Binder, EB, Boehnke, M, Boks, MP, Bosch, R, Braff, DL, Bryant, R, Budde, M, Byrne, EM, Cahn, W, Casas, M, Castelao, E, Cervilla, JA, Chaumette, B, Cichon, S, Corvin, A, Craddock, N, Craig, D, Degenhardt, F, Djurovic, S, Edenberg, HJ, Fanous, AH, Foo, JC, Forstner, AJ, Frye, M, Fullerton, JM, Gatt, JM, Gejman, P, Giegling, I, Grabe, HJ, Green, MJ, Grevet, EH, Grigoroiu-Serbanescu, M, Gutierrez, B, Guzman-Parra, J, Hamilton, SP, Hamshere, ML, Hartmann, A, Hauser, J, Heilmann-Heimbach, S, Hoffmann, P, Ising, M, Jones, I, Jones, LA, Jonsson, L, Kahn, RS, Kelsoe, JR, Kendler, KS, Kloiber, S, Koenen, KC, Kogevinas, M, Konte, B, Krebs, M-O, Lander, M, Lawrence, J, Leboyer, M, Lee, PH, Levinson, DF, Liao, C, Lissowska, J, Lucae, S, Mayoral, F, McElroy, SL, McGrath, P, McGuffin, P, McQuillin, A, Medland, SE, Mehta, D, Melle, I, Milaneschi, Y, Mitchell, PB, Molina, E, Morken, G, Mortensen, PB, Mueller-Myhsok, B, Nievergelt, C, Nimgaonkar, V, Noethen, MM, O'Donovan, MC, Ophoff, RA, Owen, MJ, Pato, C, Pato, MT, Penninx, BWJH, Pimm, J, Pistis, G, Potash, JB, Power, RA, Preisig, M, Quested, D, Ramos-Quiroga, JA, Reif, A, Ribases, M, Richarte, V, Rietschel, M, Rivera, M, Roberts, A, Roberts, G, Rouleau, GA, Rovaris, DL, Rujescu, D, Sanchez-Mora, C, Sanders, AR, Schofield, PR, Schulze, TG, Scott, LJ, Serretti, A, Shi, J, Shyn, S, Sirignano, L, Sklar, P, Smeland, OB, Smoller, JW, Sonuga-Barke, EJS, Spalletta, G, Strauss, JS, Swiatkowska, B, Trzaskowski, M, Turecki, G, Vilar-Ribo, L, Vincent, JB, Voelzke, H, Walters, JTR, Weickert, CS, Weickert, TW, Weissman, MM, Williams, LM, Wray, NR, Zai, CC, Ashley-Koch, AE, Beckham, JC, Hauser, ER, Hauser, MA, Kimbrel, NA, Lindquist, JH, McMahon, B, Oslin, DW, Qin, X, Agerbo, E, Borglum, AD, Breen, G, Erlangsen, A, Esko, T, Gelernter, J, Hougaard, DM, Kessler, RC, Kranzler, HR, Li, QS, Martin, NG, McIntosh, AM, Mors, O, Nordentoft, M, Olsen, CM, Porteous, D, Ursano, RJ, Wasserman, D, Werge, T, Whiteman, DC, Bulik, CM, Coon, H, Demontis, D, Docherty, AR, Kuo, P-H, Lewis, CM, Mann, JJ, Renteria, ME, Smith, DJ, Stahl, EA, Stein, MB, Streit, F, Willour, V, and Ruderfer, DM

Abstract

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

15. Development of a Biotechnology Platform for the Fast-Growing Cyanobacterium Synechococcus sp. PCC 11901

Author

Mills, LA, Moreno-Cabezuelo, JÁ, Włodarczyk, A, Victoria, AJ, Mejías, R, Nenninger, A, Moxon, S, Bombelli, P, Selão, TT, McCormick, AJ, Lea-Smith, DJ, Mills, LA, Moreno-Cabezuelo, JÁ, Włodarczyk, A, Victoria, AJ, Mejías, R, Nenninger, A, Moxon, S, Bombelli, P, Selão, TT, McCormick, AJ, and Lea-Smith, DJ

Abstract

Synechococcus sp. PCC 11901 reportedly demonstrates the highest, most sustained growth of any known cyanobacterium under optimized conditions. Due to its recent discovery, our knowledge of its biology, including the factors underlying sustained, fast growth, is limited. Furthermore, tools specific for genetic manipulation of PCC 11901 are not established. Here, we demonstrate that PCC 11901 shows faster growth than other model cyanobacteria, including the fast-growing species Synechococcuselongatus UTEX 2973, under optimal growth conditions for UTEX 2973. Comparative genomics between PCC 11901 and Synechocystis sp. PCC 6803 reveal conservation of most metabolic pathways but PCC 11901 has a simplified electron transport chain and reduced light harvesting complex. This may underlie its superior light use, reduced photoinhibition, and higher photosynthetic and respiratory rates. To aid biotechnology applications, we developed a vitamin B12 auxotrophic mutant but were unable to generate unmarked knockouts using two negative selectable markers, suggesting that recombinase- or CRISPR-based approaches may be required for repeated genetic manipulation. Overall, this study establishes PCC 11901 as one of the most promising species currently available for cyanobacterial biotechnology and provides a useful set of bioinformatics tools and strains for advancing this field, in addition to insights into the factors underlying its fast growth phenotype.

Published
2022

16. Knocking on the door: policy, agency and path creation in the post-industrial city

Author

Rossiter, W and Smith, DJ

Subjects
Political science, Geography, Planning and Development, Agency (sociology), Path creation, Context (language use), Industrial city, Public administration
Abstract

At the time of the Millennium, Nottingham, a former manufacturing city in the English Midlands, faced serious challenges as a consequence of de-industrialisation. This was the context from which a new development path based on life sciences emerged. This paper explores the role of policy interventions and the agency of local actors in this path creation process. Kingdon’s [1995. Agendas, Alternatives, and Public Policy. 2nd ed. New York: Longman] multiple streams framework (MSF) is used as an analytical framework through which to assess the interaction and local implementation of three related strands of national policy: regional policy, industrial policy (with an emphasis on clusters) and innovation policy and their role in the emergence of a life science cluster in the city. The case is explored with reference to the experience of other European cities that have faced similar structural challenges and sought to respond with development strategies based on life sciences.

Published
2020

17. Glucocorticoid maturation of mitochondrial respiratory capacity in skeletal muscle before birth

Author

Davies, KL, Camm, EJ, Smith, DJ, Vaughan, OR, Forhead, AJ, Murray, AJ, Fowden, AL, Forhead, Alison [0000-0003-2125-4811], Murray, Andrew [0000-0002-0929-9315], Fowden, Abigail [0000-0002-3384-4467], and Apollo - University of Cambridge Repository

Subjects
Organelle Biogenesis, Sheep, Hydrocortisone, Myosin Heavy Chains, maturation, Cell Respiration, cortisol, Oxidative Phosphorylation, Mitochondria, Muscle, mitochondria, fetus, Oxygen Consumption, Animals, Newborn, Pregnancy, Animals, Female, Muscle, Skeletal
Abstract

In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

Published
2021

18. The 'pod shaving' revival: how rural entrepreneurship is leading to a re-birth of craft production in cricket bat manufacturing in England

Author

Smith, DJ, Rossiter, W, and Matthews, R

Abstract

The resurgence of craft (Kroezen et al., 2021) observed in a number of industry sectors reflects the success of new entrants in challenging the prevailing industrial orthodoxy. This study finds that in the UK, part of the sports equipment industry, responsible for the manufacture of cricket bats, has seen a surprising increase in new entrants over the last two decades. This re-structuring reflects significant changes in the sports equipment sector, that have included the rise of global sports brands and the offshoring of production. The emergence of a number of small independent bat makers, virtually all of whom are located in rural areas, are the focus of this study. It was found that while the backgrounds and prior experience of these rural entrepreneurs varied widely, they all shared a strong commitment to producing an authentic handmade product using traditional craft-based artisanal methods. This, combined with their embeddedness within their local communities and the extent to which the internet offered a cost effective route to market, was found to explain the emergence of this new wave of rural entrepreneurship.

Published
2021

19. The broad clinical spectrum of bipolar disorder: implications for research and practice

Author

Smith, DJ, Ghaemi, SN, and Craddock, N.

Subjects
Bipolar disorder -- Diagnosis -- Drug therapy -- Genetic aspects, Antidepressants -- Dosage and administration, Depression, Mental -- Diagnosis -- Drug therapy -- Genetic aspects, Pharmaceuticals and cosmetics industries, Psychology and mental health, Diagnosis, Drug therapy, Genetic aspects, Dosage and administration
Abstract

Byline: DJ Smith (Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, UK, smithdj3@cardiff.ac.uk); SN Ghaemi (Bipolar Disorders Research Program, Emory University, Atlanta, GA, USA.); N. Craddock (Department of [...]

Published
2008
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21. Resolving conservation and development tensions in a small island state: A governance analysis of Curieuse Marine National Park, Seychelles

Author

Clifton, J, Osman, EO, Suggett, DJ, and Smith, DJ

Subjects
Fisheries, 0502 Environmental Science and Management, 1606 Political Science, 1801 Law
Abstract

© 2019 Elsevier Ltd The management and conservation of marine resources in Seychelles, a small island developing state (SIDS) in the western Indian Ocean, is fundamental to maintaining the flow of international visitors which forms the mainstay of the nation's economy. There is an increasing trend towards empowering non-governmental organisations and parastatal entities with protected area management responsibilities, which partly reflects the chronic underfunding of the state protected area management institution. This paper explores these and related issues through a governance analysis of Curieuse Marine National Park, which is the most popular state-owned marine national park in terms of recorded visitor numbers. This demonstrates that the inability to implement economic incentives through not fully capitalising on the use and non-use values of the park has deleterious consequences for managing the combined impacts of tourism and fisheries on the ecological assets of the park. Furthermore, the capacity of the state management institution is being eroded through a focus on the development of an extensive network of new marine protected areas under the direction of an international non-governmental organisation. Suggestions are made that could strengthen economic, participative and interpretative incentives to provide a more sustainable basis for marine national park management.

Published
2020

22. Coral bleaching patterns are the outcome of complex biological and environmental networking

Author

Suggett, DJ and Smith, DJ

Subjects
Ecology, Coral Reefs, Climate Change, Animals, Anthozoa
Abstract

© 2019 John Wiley & Sons Ltd Continued declines in coral reef health over the past three decades have been punctuated by severe mass coral bleaching-induced mortality events that have grown in intensity and frequency under climate change. Intensive global research efforts have therefore persistently focused on bleaching phenomena to understand where corals bleach, when and why—resulting in a large—yet still somewhat patchy—knowledge base. Particularly catastrophic bleaching-induced coral mortality events in the past 5 years have catalyzed calls for a more diverse set of reef management tools, extending far beyond climate mitigation and reef protection, to also include more aggressive interventions. However, the effectiveness of these various tools now rests on rapidly assimilating our knowledge base of coral bleaching into more integrated frameworks. Here, we consider how the past three decades of intensive coral bleaching research has established the basis for complex biological and environmental networks, which together regulate outcomes of bleaching severity. We discuss how we now have enough scaffold for conceptual biological and environmental frameworks underpinning bleaching susceptibility, but that new tools are urgently required to translate this to an operational system informing—and testing—bleaching outcomes. Specifically, adopting network models that can fully describe and predict metabolic functioning of coral holobionts, and how this functioning is regulated by complex doses and interactions among environmental factors. Identifying knowledge gaps limiting operation of such models is the logical step to immediately guide and prioritize future experiments and observations. We are at a time-critical point where we can implement new capacity to resolve how coral bleaching patterns emerge from complex biological–environmental networks, and so more effectively inform rapidly evolving ecological management and social adaptation frameworks aimed at securing the future of coral reefs.

Published
2020

23. International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic)

Author

Soda, T, McLoughlin, DM, Clark, SR, Oltedal, L, Kessler, U, Haavik, J, Bousman, C, Smith, DJ, Bioque, M, Clements, CC, Loo, C, Vila-Rodriguez, F, Minelli, A, Mickey, BJ, Milev, R, Docherty, AR, Langan Martin, J, Achtyes, ED, Arolt, V, Redlich, R, Dannlowski, U, Cardoner, N, Clare, E, Craddock, N, Di Florio, A, Dmitrzak-Weglarz, M, Forty, L, Gordon-Smith, K, Husain, M, Ingram, WM, Jones, L, Jones, I, Juruena, M, Kirov, G, Landén, M, Müller, DJ, Nordensköld, A, Pålsson, E, Paul, M, Permoda, A, Pliszka, B, Rea, J, Schubert, KO, Sonnen, JA, Soria, V, Stageman, W, Takamiya, A, Urretavizacaya, M, Watson, S, Zavorotny, M, Young, AH, Vieta, E, Rybakowski, JK, Gennarelli, M, Zandi, PP, Sullivan, PF, Baune, BT, Soda, T, McLoughlin, DM, Clark, SR, Oltedal, L, Kessler, U, Haavik, J, Bousman, C, Smith, DJ, Bioque, M, Clements, CC, Loo, C, Vila-Rodriguez, F, Minelli, A, Mickey, BJ, Milev, R, Docherty, AR, Langan Martin, J, Achtyes, ED, Arolt, V, Redlich, R, Dannlowski, U, Cardoner, N, Clare, E, Craddock, N, Di Florio, A, Dmitrzak-Weglarz, M, Forty, L, Gordon-Smith, K, Husain, M, Ingram, WM, Jones, L, Jones, I, Juruena, M, Kirov, G, Landén, M, Müller, DJ, Nordensköld, A, Pålsson, E, Paul, M, Permoda, A, Pliszka, B, Rea, J, Schubert, KO, Sonnen, JA, Soria, V, Stageman, W, Takamiya, A, Urretavizacaya, M, Watson, S, Zavorotny, M, Young, AH, Vieta, E, Rybakowski, JK, Gennarelli, M, Zandi, PP, Sullivan, PF, and Baune, BT

Abstract

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Published
2020

24. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author

Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, Borglum, AD, Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, and Borglum, AD

Abstract

BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

Published
2020

25. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

Author

Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, Sullivan, PF, Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, and Sullivan, PF

Abstract

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Published
2020

26. Accelerometry-assessed sleep duration and timing in late childhood and adolescence in Scottish schoolchildren: A feasibility study

Author

Hashimoto, K, Lyall, LM, Sangha, N, Wyse, C, Hindle, E, Haughton, D, Campbell, K, Brown, J, Moore, L, Simpson, SA, Inchley, JC, Smith, DJ, Hashimoto, K, Lyall, LM, Sangha, N, Wyse, C, Hindle, E, Haughton, D, Campbell, K, Brown, J, Moore, L, Simpson, SA, Inchley, JC, and Smith, DJ

Abstract

Children and adolescents commonly suffer from sleep and circadian rhythm disturbances, which may contribute to poorer mental health and wellbeing during this critical developmental phase. Many studies however rely on self-reported sleep measures. This study assessed whether accelerometry data collection was feasible within the school setting as a method for investigating the extent of sleep and circadian disruption, and associations with subjective wellbeing, in Scotland. Fourteen days of wrist-worn accelerometry data were collected from 69 pupils, aged 10-14 years. Objective measures of sleep timing, sleep duration and circadian rest-activity patterns were derived. Questionnaires assessed subjective sleep timing, depressive symptoms, and experiences of wearing the accelerometer. Pupils slept on average less than 8 hours per night, failing to meet standard age-specific recommendations. Sleep timing was later and duration longer on weekends compared to weekdays (B = 0.87, 95% confidence interval (CI) 0.70, 1.04; B = 0.49, 95% CI 0.29, 0.69), indicating social jetlag. Lower daytime activity was correlated with higher depressive symptoms (r = -0.84, p = 0.008). Compared to primary school pupils, secondary pupils had shorter sleep window duration and lower circadian relative amplitude. Over half of participants reported some discomfort/inconvenience wearing the accelerometer. These data highlight that inadequate sleep is prevalent in this sample of schoolchildren. Future, larger scale investigations will examine in more detail the associations between sleep, circadian function and physical activity with mental health and wellbeing.

Published
2020

27. Coral microbiome composition along the northern Red Sea suggests high plasticity of bacterial and specificity of endosymbiotic dinoflagellate communities

Author

Osman, EO, Suggett, DJ, Voolstra, CR, Pettay, DT, Clark, DR, Pogoreutz, C, Sampayo, EM, Warner, ME, Smith, DJ, Osman, EO, Suggett, DJ, Voolstra, CR, Pettay, DT, Clark, DR, Pogoreutz, C, Sampayo, EM, Warner, ME, and Smith, DJ

Abstract

© 2020 The Author(s). Background: The capacity of reef-building corals to tolerate (or adapt to) heat stress is a key factor determining their resilience to future climate change. Changes in coral microbiome composition (particularly for microalgal endosymbionts and bacteria) is a potential mechanism that may assist corals to thrive in warm waters. The northern Red Sea experiences extreme temperatures anomalies, yet corals in this area rarely bleach suggesting possible refugia to climate change. However, the coral microbiome composition, and how it relates to the capacity to thrive in warm waters in this region, is entirely unknown. Results: We investigated microbiomes for six coral species (Porites nodifera, Favia favus, Pocillopora damicornis, Seriatopora hystrix, Xenia umbellata, and Sarcophyton trocheliophorum) from five sites in the northern Red Sea spanning 4° of latitude and summer mean temperature ranges from 26.6 °C to 29.3 °C. A total of 19 distinct dinoflagellate endosymbionts were identified as belonging to three genera in the family Symbiodiniaceae (Symbiodinium, Cladocopium, and Durusdinium). Of these, 86% belonged to the genus Cladocopium, with notably five novel types (19%). The endosymbiont community showed a high degree of host-specificity despite the latitudinal gradient. In contrast, the diversity and composition of bacterial communities of the surface mucus layer (SML) - a compartment particularly sensitive to environmental change - varied significantly between sites, however for any given coral was species-specific. Conclusion: The conserved endosymbiotic community suggests high physiological plasticity to support holobiont productivity across the different latitudinal regimes. Further, the presence of five novel algal endosymbionts suggests selection of certain genotypes (or genetic adaptation) within the semi-isolated Red Sea. In contrast, the dynamic composition of bacteria associated with the SML across sites may contribute to holobiont fun

Published
2020

28. Application of an adapted PRECIS-2 instrument to assess efficacy- and effectiveness-study designs in a systematic review of intervention studies of the hepatitis C virus-care continuum among people who use drugs

Author

Jordan AE, Perlman DC, Smith DJ, and Hagan H

Subjects
Efficacy, evidence base, lcsh:Public aspects of medicine, effectiveness, lcsh:RA1-1270, HCV care continuum, systematic review and meta-analysis
Abstract

Ashly E Jordan,1,2 David C Perlman,2,3 Daniel J Smith,1 Holly Hagan1,2 1New York University, Rory Meyers College of Nursing, New York, NY, USA; 2Center for Drug Use and HIV Research, 3Icahn School of Medicine, Mount Sinai Beth Israel, New York, NY, USA Introduction: Systematic reviews and meta-analyses examining intervention studies may need to categorize studies by the degree to which they reflect efficacy or effectiveness study-design elements when reporting systematic reviews and meta-analysis results.Materials and methods: We identified reports presenting data from intervention studies eligible for evaluation with an adapted PRECIS-II instrument as part of a larger systematic review of the hepatitis C virus (HCV)-care continuum among people who used drugs. We applied the instrument to score reports examining any of the HCV-care-continuum steps of testing, linkage to care, and treatment on an efficacy–effectiveness spectrum. Composite scores are presented in tabular format and in stacked dot plots.Results: The adapted PRECIS-II instrument was applied to 37 unique reports that presented data on 51 HCV-care-continuum outcomes of testing (n=16), linkage to care (n=12), and treatment (n=23). Totals of 28, six, and three reports had been produced on one, two, or all three outcomes, respectively. Ten and eight studies described themselves as having efficacy or effectiveness designs, respectively; 33 did not specify. PRECIS-II composite scores for reports produced on testing, linkage to care, and treatment ranged widely: 1.22–5. Composite scores for reports examining HCV treatment indicated study designs that tended toward effectiveness (3.35), but those examining testing (3.85) or linkage (3.8) had more effectiveness-study designs (P=0.003, P=0.013, respectively).Conclusion: Reviewed reports varied widely in their use of efficacy/effectiveness-study designs, suggesting that systematic reviews and meta-analyses need to consider heterogeneity in efficacy/effectiveness study design in analyses. Most reports tended modestly toward having effectiveness designs, and treatment studies contained the most elements of efficacy-study designs. When assessing large numbers of reports with the PRECIS-II instrument, stacked dot plots may aid visually in depicting the range of scores. This review suggests that studies of the effectiveness of HCV treatment of people who use drugs at a population level is a research gap. Keywords: efficacy, effectiveness, HCV-care continuum, systematic review and meta-analysis, evidence base

Published
2018

29. Nottingham Express Transit

Author

Disney, J, Rossiter, W, and Smith, DJ

Subjects
050210 logistics & transportation, business.industry, 05 social sciences, 0211 other engineering and technologies, Green innovation, 021107 urban & regional planning, 02 engineering and technology, Environmental economics, Modal shift, Traffic congestion, Management of Technology and Innovation, Public transport, Greenhouse gas, 0502 economics and business, Sustainability, Transit (astronomy), Business and International Management, Project management, business
Abstract

Traffic congestion at peak times has long been a problem facing cities in the United Kingdom.1 Latterly concern about combating congestion has been hightened by worries over carbon emissions and poor air quality. In tackling these problems, green innovations incorporating new technologies appear to have much to offer, although progress in implementing these sorts of innovation appears to have been slow. This case study analyses the efforts of one city to tackle these problems by pioneering a number of green innovations including the introduction of a light rail system employing trams known as Nottingham Express Transit as well as electric and gas-powered buses. The nature of these innovations is explored together with a detailed examination of how they came to be implemented and the impact they have had.

Published
2018

32. Urinary Steroid Profiling as a High-Throughput Screening Tool for the Detection of Malignancy in Patients with Adrenal Tumors.

Author

Taylor, AE, primary, Biehl, M, additional, Hahner, S, additional, Libe, R, additional, Hughes, BA, additional, Stiekema, H, additional, Schneider, P, additional, Smith, DJ, additional, Krone, N, additional, Porfiri, E, additional, Opocher, G, additional, Bertherat, J, additional, Mantero, F, additional, Allolio, B, additional, Terzolo, M, additional, Nightingale, PJ, additional, Shackleton, CHL, additional, Bertagna, X, additional, Fassnacht, M, additional, Stewart, PM, additional, and Arlt, W, additional

Published
2010
Full Text
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34. Coral microbiome diversity reflects mass coral bleaching susceptibility during the 2016 El Niño heat wave

Author

Gardner, SG, Camp, EF, Smith, DJ, Kahlke, T, Osman, EO, Gendron, G, Hume, BCC, Pogoreutz, C, Voolstra, CR, Suggett, DJ, Gardner, SG, Camp, EF, Smith, DJ, Kahlke, T, Osman, EO, Gendron, G, Hume, BCC, Pogoreutz, C, Voolstra, CR, and Suggett, DJ

Abstract

Repeat marine heat wave-induced mass coral bleaching has decimated reefs in Seychelles for 35 years, but how coral-associated microbial diversity (microalgal endosymbionts of the family Symbiodiniaceae and bacterial communities) potentially underpins broad-scale bleaching dynamics remains unknown. We assessed microbiome composition during the 2016 heat wave peak at two contrasting reef sites (clear vs. turbid) in Seychelles, for key coral species considered bleaching sensitive (Acropora muricata, Acropora gemmifera) or tolerant (Porites lutea, Coelastrea aspera). For all species and sites, we sampled bleached versus unbleached colonies to examine how microbiomes align with heat stress susceptibility. Over 30% of all corals bleached in 2016, half of which were from Acropora sp. and Pocillopora sp. mass bleaching that largely transitioned to mortality by 2017. Symbiodiniaceae ITS2-sequencing revealed that the two Acropora sp. and P. lutea generally associated with C3z/C3 and C15 types, respectively, whereas C. aspera exhibited a plastic association with multiple D types and two C3z types. 16S rRNA gene sequencing revealed that bacterial communities were coral host-specific, largely through differences in the most abundant families, Hahellaceae (comprising Endozoicomonas), Rhodospirillaceae, and Rhodobacteraceae. Both Acropora sp. exhibited lower bacterial diversity, species richness, and community evenness compared to more bleaching-resistant P. lutea and C. aspera. Different bleaching susceptibility among coral species was thus consistent with distinct microbiome community profiles. These profiles were conserved across bleached and unbleached colonies of all coral species. As this pattern could also reflect a parallel response of the microbiome to environmental changes, the detailed functional associations will need to be determined in future studies. Further understanding such microbiome-environmental interactions is likely critical to target more effective manageme

Published
2019

35. Treatment-resistant and Multi-therapy resistant criteria for bipolar depression: A consensus definition - CORRIGENDUM

Author

Hidalgo-Mazzei, D, Berk, Michael, Cipriani, A, Cleare, AJ, Di Florio, A, Dietch, D, Geddes, JR, Goodwin, GM, Grunze, H, Hayes, JF, Jones, I, Kasper, S, MacRitchie, K, Hamish McAllister-Williams, R, Morriss, R, Nayrouz, S, Pappa, S, Soares, JC, Smith, DJ, Suppes, T, Talbot, P, Vieta, E, Watson, S, Yatham, LN, Young, AH, Stokes, PRA, Hidalgo-Mazzei, D, Berk, Michael, Cipriani, A, Cleare, AJ, Di Florio, A, Dietch, D, Geddes, JR, Goodwin, GM, Grunze, H, Hayes, JF, Jones, I, Kasper, S, MacRitchie, K, Hamish McAllister-Williams, R, Morriss, R, Nayrouz, S, Pappa, S, Soares, JC, Smith, DJ, Suppes, T, Talbot, P, Vieta, E, Watson, S, Yatham, LN, Young, AH, and Stokes, PRA

Published
2019

36. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Author

Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF

Abstract

Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression; disorder severity and unfavorable treatment outcomes are shown to be influenced by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment and response/nonresponse are associated with an increased genetic burden for major depression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive episode underwent ECT. MD-PRS were calculated for these inpatients and a separate population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases: n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate that ECT cohorts show an increased genetic burden for MD and are consistent with the hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic risk for MD. Larger samples are needed to better substantiate these findings.

Published
2019

37. Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Author

Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, Sullivan, PF, Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, and Sullivan, PF

Abstract

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.

Published
2019

38. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Author

Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF

Abstract

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.

Published
2019

39. Resolving conservation and development tensions in a small island state: A governance analysis of Curieuse Marine National Park, Seychelles

Author

Clifton, J, Osman, EO, Suggett, DJ, Smith, DJ, Clifton, J, Osman, EO, Suggett, DJ, and Smith, DJ

Abstract

© 2019 Elsevier Ltd The management and conservation of marine resources in Seychelles, a small island developing state (SIDS) in the western Indian Ocean, is fundamental to maintaining the flow of international visitors which forms the mainstay of the nation's economy. There is an increasing trend towards empowering non-governmental organisations and parastatal entities with protected area management responsibilities, which partly reflects the chronic underfunding of the state protected area management institution. This paper explores these and related issues through a governance analysis of Curieuse Marine National Park, which is the most popular state-owned marine national park in terms of recorded visitor numbers. This demonstrates that the inability to implement economic incentives through not fully capitalising on the use and non-use values of the park has deleterious consequences for managing the combined impacts of tourism and fisheries on the ecological assets of the park. Furthermore, the capacity of the state management institution is being eroded through a focus on the development of an extensive network of new marine protected areas under the direction of an international non-governmental organisation. Suggestions are made that could strengthen economic, participative and interpretative incentives to provide a more sustainable basis for marine national park management.

Published
2019

41. The sustainable and green engine (SAGE) – Aircraft engine of the future?

Author

Smith, DJ

Subjects
Economic growth, Air transport, 05 social sciences, Green innovation, Climate change, 010501 environmental sciences, 01 natural sciences, Disruptive technology, Management of Technology and Innovation, 0502 economics and business, media_common.cataloged_instance, Business, Business and International Management, European union, Environmental planning, 050203 business & management, 0105 earth and related environmental sciences, media_common
Abstract

The case of the European Union’s (EU) Clean Sky initiative and its sustainable and green engine programme focuses on a sector where the implications of climate change are likely to be keenly felt in the coming decades, namely air transport. It is a sector where to date there have been few green or eco innovations. The case focuses on a current EU-funded initiative designed to limit the impact of air transport on climate change. The initiative aims to foster innovation through the introduction of open rotor technology to power the next generation of short-/medium-haul airliners. This technology could potentially cut carbon dioxide emissions from commercial aircraft by 100 million tonnes per year. However, it may also prove to be a disruptive technology rendering existing aircraft and possibly some of the firms that produce them, obsolete. As well as introducing some of the features of disruptive technologies, the case highlights both the drivers for and barriers to the successful adoption of green innovations. Another important aspect of the case is that it also highlights the value of appropriate business strategies, such as the use of technology demonstrator programmes, in supporting and facilitating the adoption and diffusion of green innovations.

Published
2016

42. MALFORMATION RISKS OF ANTIEPILEPTIC DRUG MONOTHERAPIES IN PREGNANCY: AN UPDATE FROM THE UK AND IRELAND EPILEPSY AND PREGNANCY REGISTERS

Author

Boyle, AJ, Digangi, A, Mottram, LJ, Hamid, U, McNamee, L, White, G, Cross, LJM, McNamee, J, O'Kane, C, McAuley, DM, Campbell, E, Kennedy, F, Russell, A, Smithson, WH, Parsons, L, Robertson, I, Irwin, B, Liggan, B, Delanty, N, Morrison, PJ, Hunt, SJ, Craig, J, Morrow, J, Major, EH, O'Connor, P, Mullan, B, Savage, EM, McCormick, D, McDonald, S, Moore, O, Stevenson, M, Cairns, AP, McKavanagh, P, Lusk, L, Ball, PA, Trinick, TR, Duly, E, Verghis, RM, Agus, AM, Walls, GW, McCusker, S, James, B, Orr, C, Hamilton, A, Smyth, A, Harbinson, MT, Donnelly, PM, Ling, P, MacPherson, J, McCrossan, L, Wethers, G, O'Neill, FA, Forty, L, Di Florio, A, Gordon-Smith, K, Fraser, C, Jones, L, Jones, I, Craddock, N, Smith, DJ, Murphy, L, McKenna, S, Shirley, D, Hodgins, N, Damkat-Thomas, L, Shamsian, N, Yew, P, Lewis, H, Khan, K, Cooke, I, Hunt, S, McCauley, M, Mark, D, Leonard, C, Breen, H, Graydon, R, O'Gorman, C, Kirk, S, Blayney, GV, Hardy, CL, Stratton, S, Bhat, S, Cash, J, Cadden, I, Kennedy, P, Ellis, P, Collins, A, Dargin, A, McDougall, N, McQuillan, LM, Graham, UM, Lindsay, JR, Warnock, M, Campbell, B, Macauley, G, Hegarty, S, Spence, RAJ, Gordon, E, Boyd, K, Weir, CD, Wallace, IR, McEvoy, CT, Hunter, SJ, Hamill, LL, Ennis, CN, Woodside, JV, Bell, PM, Young, IS, McKinley, MC, Spence, A, Finnegan, S, Flannery, T, Harty, J, Haughey, N, Booth, K, Jeganathan, R, Leeper, AD, Dixon, JM, and Harrison, D

Subjects
Abstracts, respiratory system, Article, respiratory tract diseases
Abstract

Introduction Platelet activation has a role in the pathogenesis of acute lung injury (ALI). Observational data suggests aspirin treatment may prevent the development of ALI in critically ill patients. However, it is unknown if aspirin usage alters outcomes in patients with established ALI. Methods All patients with ALI were identified prospectively in a single large regional medical and surgical Intensive Care Unit (ICU) between December 2010 and July 2012. Demographic, clinical, and laboratory variables were recorded. Aspirin usage, both pre-hospital and during Intensive Care Unit (ICU) stay, was included. The primary outcome was ICU mortality. We used univariate and multivariate analyses to assess the impact of these variables on ICU mortality. Results Two hundred and two patients with ALI were included. 56 (28%) of these received aspirin either prehospital, in ICU, or both. Using multivariate logistic regression analysis, aspirin was found to be protective for ICU mortality. Conclusion Aspirin usage is associated with reduced mortality in patients with ALI. Whilst trials are ongoing to assess if aspirin can prevent ALI, these new data support the need for a clinical trial to investigate if aspirin improves outcomes in patients with established ALI., Aim To assess risk of major congenital malformations (MCMs) from exposure to anti-epileptic drugs (AEDs) during pregnancy. Methods Fifteen-year prospective observational study from 1996 until 2012. Outcomes are reported for valproate, carbamazepine, lamotrigine and levetiracetam monotherapy exposures. Main outcome measure is the MCM rate. Results Informative outcomes were available for 5510 cases. 1290 women were exposed to valproate monotherapy, 1718 to carbamazepine monotherapy, 2198 to lamotrigine monotherapy and 304 to levetiracetam monotherapy. The MCM risk with valproate monotherapy exposure in-utero is 6.7% (95% CI 5.5%-8.3%), compared to 2.6% with carbamazepine (95% CI 1.9%-3.5%), 2.3% with lamotrigine (95% CI 1.8%-3.1%) and 0.70% (95% CI 0.2%-2.5%) with levetiracetam. A significant dose effect is seen with valproate (p= 0.0006) and carbamazepine (p=0.03) exposed pregnancies, but not with exposure to lamotrigine (p=0.26) or levetiracetam (p=0.09). MCM rate for even the highest doses of lamotrigine (>400mg daily) were lower than the MCM rate observed in pregnancies exposed to less than 600mg daily of valproate (3.4% compared to 5.0%, p=0.35). Conclusions AED exposure during pregnancy increases the risk of MCM in the infants of women with epilepsy. In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001), levetiracetam (p=0.0001) or carbamazepine (p=0.0001) monotherapy. Our results are in contrast to previous suggestions that the MCM risk with exposure to low doses of valproate is preferable to that seen with exposure to high doses of lamotrigine. Together with recently published neurodevelopmental data, this data suggests that either lamotrigine or levetiracetam should be used as drugs of choice over valproate, even at low dose, in women of childbearing age with epilepsy., Background In recent years hypertonic saline has attracted increasing interest in the treatment of traumatic intracranial hypertension, and has a number of documented and theoretical advantages over other hyperosmolar agents. To date, no consensus has been achieved on the safest and most effective HTS concentration for administration. Aims The purpose of this paper was to evaluate the efficacy of intravenous bolus administration of highly concentrated (30%) hypertonic saline (HTS) in the treatment of refractory intracranial hypertension secondary to traumatic brain injury. Methods Patients were treated with an intravenous bolus of 10mls of 30% hypertonic saline. Multiple physiological parameters were measured throughout, including intracranial pressure, mean arterial pressure, cerebral perfusion pressure, pulse and inotrope/pressor requirements. Laboratory investigation pre and post HTS administration included: arterial pH, pCO2, HCO3, base excess; serum biochemistry measurements of sodium, potassium, chloride, urea and creatinine; and coagulation studies. Results TBI patients saw a rapid and significant reduction in ICP from a baseline value of 28 ± 5.31 mmHg to 18.44 ± 6.17 mmHg at 1-hour post HTS, a statistically significant reduction that was maintained for up to 7 hours. This response was maintained even with repeated HTS administration, which was also associated with an augmented cerebral perfusion pressure from a baseline of 58.0 ± 6.48 mmHg to 76.33 mmHg within 1 hour of HTS administration. Conclusions No associated harmful biochemical or haematological abnormalities were noted. In conclusion, highly concentrated 30% HTS appears to be both effective and safe in the management of refractory intracranial hypertension., Background Patients with rheumatoid Arthritis (RA) often report increasing joint pain and stiffness with colder, wet weather. Previous studies examining weather impact on pain severity have yielded contradictory results1-2. The relationship between disease activity in RA patients and weather variance has not been formally examined. Methods Patients attending Musgrave Park Hospital, Belfast; with a diagnosis of RA on anti-TNF were invited to participate. A longitudinal analysis of 133 patients was performed. Data collected at 5 time points included TJC, SJC, visual analogue score, ESR, CRP, and DAS-28. This was correlated with maximum/minimum temperature, hours of sunshine, rainfall, relative humidity, pressure and windspeed from a local weather station on day of attendance. A linear regression analysis was used to determine relationship between weather components, disease activity and pain. Results The weather-based components were extracted after a global factor analysis using data from all time-points revealed three components from the seven quantitative variables. Three components indicated by the factor analysis were as follows: temperature component, sunny/dry component, wet/windy component. All components were calculated from z-scores. A significant correlation was noted between low DAS-28 scores and sunny, dry conditions (p=0.001). Sunny and dry conditions ((hours of sunshine – relative humidity)/2) were associated with a DAS-28 reduction of 0.143 (95% CIs -0.230, -0.057) p=0.001. Higher temperatures (max temperature + min temperature/2) were associated with a DAS-28 reduction of 0.048 (95% CIs -0.129, 0.032), p=0.23. Wet and windy conditions (rainfall + wind-speed – pressure)/3 were associated with a higher DAS-28 (95% CIs -0.098, 0.123) p=0.82. Conclusions This study highlights statistically significant lower DAS-28 scores in sunny and dry conditions., Aim The Cardiac Computerised Tomography (CT) for the Assessment of Pain and Plaque (CAPP) study compared the economic and clinical outcomes of using cardiac CT compared to Exercise Stress Test (EST) in the patients with suspected stable chest pain. Method CAPP randomised 500 patients without known coronary artery disease to either EST or cardiac CT. All patients were followed up for clinical outcomes and for angina symptoms with the Seattle Angina Questionnaires (SAQ). Results Of the 500 patients 12 withdrew over the year, with 245 in the EST arm and 243 in CT arm receiving follow up. In the CT arm there were less chest pain Emergency Department attendances and unplanned admissions. Patients in the CT arm also had less secondary investigations and less time to diagnosis. The EST arm had 7 patients who underwent Coronary Artery Bypass Grafting (CABG) and 12 who had Percutaneous Coronary Intervention (PCI), compared to 8 CABG and 29 PCI in the CT arm. There was a significant improvement in domains of the SAQ scores at 1 year in the CT arm compared to EST (p =, Background There is currently a joint epilepsy and learning disability clinic for the South Eastern Health and Social Care Trust that began in October 2006. The clinic is for patients who would otherwise have to attend separate epilepsy and learning disability appointments. Aims Service evaluation and provide information for future comparison with similar services. Method There were forty-eight patients who attended the joint clinic during the period of October 2006, when the clinic first began and December 2011. Chart reviews for these patients were completed to evaluate the number of appointments attended and missed, reasons for referral, outcome from attendance at the clinic such as changes in seizure frequency and duration. Results The majority of patients attended one appointment (52 %) and missed no appointments (90%). The most common reason for referral was due to increase in seizure frequency (32%) and the most common intervention was change in medications (61%). The majority showed improvement in seizure frequency (68%) with a significant number having improvement in seizure duration (33%). Conclusion There was sixty-eight per cent that showed an improvement in seizure frequency. Thirty-three per cent showed an improvement in seizure duration while fourteen per cent had no further seizures. This would suggest that the clinic provides a useful tool to ensure good quality care to those people with learning disabilities and epilepsy., Random coagulation screening is a poor predictor of perioperative bleeding and has a poor yield in detecting haemostatic abnormalities. Current guidelines advocate selecting patients requiring coagulation screens using a structured bleeding history. Using a completed audit cycle as the vehicle for implementing change, ensuring guideline adherence, random ‘routine’ use of the £6.50 coagulation screen has decreased; avoiding patient anxiety, theatre delays, increased pressure on labs and a high cost to an already stretched NHS budget. One hundred surgical inpatients in the UHD were identified, and notes were reviewed to determine reasons for testing which were audited against current guidelines (NICE, GAIN-NI and BCSH) Initial audit found inappropriate testing was widespread; only 23% of samples were guideline adherent. Staff education sessions and poster distribution detailing the uses/limitations of coagulation screening, importance of bleeding history and current guidelines preceded the re-audit and closure of the loop which showed significant improvement; 61% of samples were now appropriate, a 265% increase in guideline compliance. It is clear that this completed audit-cycle has successfully implemented significant change in practice; improved cost efficiency, decreased theater delays, patient anxiety and unnecessary venepuncture; ultimately improving patient care., Objectives Bipolar I disorder (BPI) is known to have high rates of comorbid alcohol-use disorders (AUD) but the impact of this comorbidity on long-term outcomes such as episode recurrence and suicidal behaviour is unclear. Methods We compared lifetime demographic and clinical characteristics of illness for individuals with BPI and comorbid AUD (n= 436) to those with BPI without AUD (n=1020) using data from the Bipolar Disorder Research Network (BDRN). A logistic regression approach was used to test for associations. Results Comorbid BPI and AUD patients had a worse course of illness with significantly more suicidal ideation and a greater number of depressive and manic episodes compared to patients with BPI alone. Being male, unemployed, a current smoker, current cannabis use and the presence of rapid cycling were also significantly associated with comorbid BPI+AUD. Despite this, our data suggest that those with comorbid BPI+AUD were admitted less frequently to hospital than those with BPI alone. Conclusions Clinical services need to provide an integrated treatment approach for AUD which is comorbid with BPI. Stigma, interventional nihilism or self-medication may explain why patients with BPI+AUD appear to have been admitted less often to hospital. Early intervention and suicide prevention initiatives should be targeted at young men with BPI plus comorbid AUD., Current hip fractures guidelines recommend surgery within 36 hours of admission. The 2011 National Hip Fracture Database (NHFD) report shows our institute has the fewest patients meeting this target (9%). Northern Irelands’ exclusion from the “Best Practice Tariff” means no incentive-led treatment or prioritisation of hip fracture patients. We performed a systematic review of post-operative results to highlight deficiencies in delivery of patient care. We reviewed 702 patients admitted between September 2009 and April 2012. Patients were prospectively identified and added to our fracture outcome and research database (FORD). Results were compared to national average values from the NHFD. 16.7% of patients met the 36-hour target to theatre compared to the UK average of 66%. 81.7% underwent a pre-operative orthogeriatric review. The main reasons for surgical delay were inadequate theatre space (58%) and medically unfit patients (29%). After exclusion of medically unfit patients, medically fit patients were divided into delayed surgery and not delayed categories. Medically fit patients who had delayed surgery had inferior outcomes- longer hospital stay and higher mortality as an inpatient and at 30 days. Without a change in funding, Northern Ireland will struggle to compete with the UK mainland and decrease mortality in this patient group., Necrotising Fasciitis is a destructive infection of the skin and soft tissues, associated with significant mortality and morbidity. Survival from the condition necessitates patient referral to plastic surgery units for reconstructive procedures. We selected all cases referred to the regional plastic surgery service in Belfast over the last 6 years. We identified 46 referred patients (25 male: 21 female) and performed a retrospective case note review. The mean patient age was 59.4 years. Risk factors identified were diabetes, smoking, obesity, and immunocompromise. The most frequently affected anatomical site was the lower limb in 16 cases (35%). Infections contributed to 1555 hospital bed days with a median hospital stay per patient of 33.8 days. Necrotising fasciitis cases in Northern Ireland have been steadily increasing over the last 6 years reaching a peak in 2012. The majority are type 1 polymicrobial cases (50%). However, we observed a significant increase in type 2 Group A streptococcal infections over the timescale studied. The overall mortality rate was 28%. This is the first study from Northern Ireland, and one of the largest from the UK in the last 10 years, investigating the epidemiological features of necrotising fasciitis. It has identified a causative microbiology pool, along with changing bacterial trends that validate our current antibiotic policy. Mortality rates are consistent with those published from the rest of the UK., Background Preconceptual counselling (PC) to optimise seizure control and antiepileptic drug (AED) regimen is recommended as routine practice for women with epilepsy who are considering pregnancy. PC often takes place during routine outpatient clinic appointments, and previous studies have shown that information given in this context is often not retained. Methods Retrospective study of the outcome of PC in women attending our PC clinic over a ten-year period from 2003 to 2013. Comparison made to a cohort of pregnant women with epilepsy attending our Joint Epilepsy Obstetric Clinic from 2011-2012. Results A total of 122 women attended for preconceptual counselling. Overall, 74% of women attending for PC decided to continue to pregnancy without any change to their previous AED regimen. More women taking valproate, either in monotherapy or as part of a polytherapy regimen, made changes to their AED regimen following counselling than those on other drugs (42.8% compared to 4.9% for monotherapy exposures, p=0.0001 and 70% compared to 28.6% for polytherapy, p=0.03). Of those attempting to change from valproate regimens, women taking valproate as part of a polytherapy regimen were more likely achieve a sustained change than those on valproate monotherapy (85.7% compared to 50% on monotherapy). Pregnancy was subsequently recorded in 84 women. Rates of preconceptual folic acid consumption varied between the groups who had attended PC clinic and those who had not. More pregnant women who had attended PC clinic took high dose folic acid preconceptually (82.1%) compared to those attending neurology clinics (38.7%, p, Aim To assess the incidence and to circumstances associated with maternal mortality. Method Labour ward registration book was used to obtained details of patients who had died over the past 20 months. Medical records were then reviewed retrospectively. Results A total 48 patients were identified. Mean age was 25, and mean parity P1. 36% of patients self referred, 25% were referred from a health centre and 25% were referred from another hospital. Only 10% received antenatal care. The causes of death were severe eclampsia 32%; uterine rupture 28%; haemorrhage 24%; sepsis 10% and anaesthetic complications 6%. 75% of neonates were stillborn. 21% were comatose on arrival to hospital and died shortly afterwards. 11% died post operatively after surgery for ruptured uterus. On review only 14% of deaths may have been preventable with better inpatient management. Only 32% of patients had a discharge or death summary documented. Discussion The incidence of maternal mortality in Yirgalem was 1 in 67. This small study demonstrates that mothers in Ethiopia are still dying needlessly. There is an ongoing urgent effort required to reduce this unacceptably high incidence., Mobile phones have become increasingly integrated into the practice of doctors and allied medical professions. Recent studies suggest they represent reservoirs for pathogens with potential to cause nosocomial infections. We aimed to investigate the level of contamination on phones used on surgical wards and identify strategies for their safe use. The phones of 50 members of the surgical multidisciplinary team were swabbed using a standardized technique by two trained investigators. The samples streaked out using an automated specimen inoculator onto two types of culture media (Columbia blood agar and MacConkey agar). Colonies were identified and counted by a single trained investigator in a blinded fashion. Simultaneously a questionnaire investigating usage levels of phones was given to 150 healthcare workers. 60% of individuals sampled had some form of contaminant isolated from their phone. 31 (62%) of phones had only 3 colonies or less isolated on medium. No nosocomial bacterial contamination or drug resistant isolates were identified. Touch screen smart phones may be used safely in a clinical environment in the setting of effective adherence to hand hygiene policies., Background Lichen sclerosus (LS) is an autoimmune, inflammatory dermatosis with incidence quoted as 1:300-1:1000 and carrying a 2-4% lifetime risk of developing invasive vulval cancer. Appropriate management may reduce this risk. We audited the management of patients with biopsyconfirmed LS, against RCOG Green Top Guideline No 58. Methods A list of patients with biopsy-confirmed LS during 2012 was obtained from our Trust histopathology database. A proforma was devised and case notes reviewed. Results 23 dermatological and gynaecological patients were identified. In 3 cases, the notes were unobtainable. All were post-menopausal and aged 53-84 years. In over 60% of cases, there was no attempt to explore a wider relevant history including enquiry into incontinence or personal or family history of autoimmune or atopic conditions. Examination appeared limited and was poorly documented with only dermatologists achieving best practice through considering systemic examination. The decision to biopsy was usually taken at presentation (55%), the main indication being uncertain diagnosis (60%). Whilst recognised as safe and appropriate, only 35% had an outpatient biopsy. Following diagnosis, 10% were investigated for other autoimmune disorders and 25% were advised regarding general vulval skin care. Only 45% were prescribed ultra-potent steroids, 44% of whom were treated with the recommended regimen and appropriately instructed regarding use. In 25%, there was no communication of diagnosis, appropriate treatment or review to the patient or GP. Only 25% of patients were given an information leaflet and 20%, specifically informed regarding the risk of malignancy and the importance of selfsurveillance. Conclusion This audit highlights that the management of LS, a pre-malignant condition, is consistently falling below recommended practice. Continued education and the use of a proforma to guide management may significantly improve practice and potentially minimise disease progression., Background Transarterial chemoembolisation (TACE) is used to palliate patients with inoperable hepatocellular cancer (HCC) and as a holding procedure prior to transplantation. All TACE therapy in Northern Ireland is delivered by a single centre. Aims To determine outcomes for patients treated with TACE for HCC since 2006. Methods Patients with HCC diagnosed between 1 Jan 2006 and 31 Dec 2011 who underwent TACE therapy were identified. Relevant premorbid clinical information (UKELD, MELD, Childs-Pugh (CP) stage) was calculated. NI cancer registry database was used for mortality data. Results 75 patients (83% male, mean age 67yrs) with HCC had their first TACE during study period, rising from 5 in 2006 to 18 in 2011. Confirmed causes of cirrhosis included alcoholic liver disease, hepatitis B and C, haemochromatosis, primary biliary cirrhosis, and NASH. 49 patients were CP stage A, 24 were CP B and 1 CP C. Mean MELD score was 9.5 (range 6-20) and UKELD 48.5 (range 42-55). Mortality was 4% at 30 days, 39% at 1yr and 68.5% at 2yrs. Nine patients had TACE as a holding measure pretransplantation. Survival was influenced by age and gender. Conclusions The number of new patients receiving TACE for HCC in NI is rising. One year survival rate is 61%., A 58 year old non-diabetic caucasian man was admitted with a capillary glucose of 1.9mmol/l following an episode of confusion and disorientation. During his admission he had frequent episodes of nocturnal and early morning hypoglycaemia with capillary glucose 1000mU/l and C-peptide 19.6ug/l. Sulphonylurea screen was negative. Given the magnitude of serum insulin, insulin antibodies were measured and were positive. Serum insulin was corrected for the presence of antibodies using PEG precipitation yet remained elevated. CT imaging of pancreas was normal. Endoscopic ultrasound demonstrated a hyper-echoic abnormality in the tail of the pancreas measuring 13x11mm. He subsequently attended for calcium stimulated venous sampling which demonstrated high insulin production throughout the gland with no localisation. The patient started carbohydrate supplementation and 5mg daily prednisolone with resolution of hypoglycaemia over 8 weeks. Insulin autoimmune hypoglycaemia is a rare condition characterised by extremely high levels of insulin in the presence of anti-insulin antibodies. It is the third leading cause of hypoglycemia in Japan, but has rarely been described in the non-Asian population. Making the correct diagnosis is important to avoid an unnecessary pancreatic surgical procedure on a hypoglycemic patient., A previously well 27-year-old female presented with threemonth history of fatigue and weight loss. She did not report any other symptoms and there was no significant recent travel history. Clinically, there were no objective signs and basic investigations revealed a microcytic anaemia with raised inflammatory markers. HIV, hepatitis virology and liver specific antibodies were all negative. An OGD plus biopsies were normal. A CT abdomen revealed a 5cm soft tissue mass in the left side of the abdomen, separate from the pancreas and adjacent to the left kidney. At this point differential diagnoses included gastrointestinal stromal tumour, lymphoma, desmoid tumour and schwannoma. She proceeded to a laparotomy were a smooth walled lesion was resected from the proximal small bowel mesentery. Her postoperative recovery was unremarkable. The histology was returned as fitting a diagnosis of Castleman disease (CD). CD is a rare non-clonal lymphoproliferative disorder of unknown aetiology. There have been less than 2000 cases reported in the literature. Mesenteric CD is very rare event with only 43 cases reported in the English literature. Awareness of CD is important because the disease is potentially life threatening, is exceptionally rare and is incompletely understood., Aim Coagulation screens in surgical patients are routinely requested, often inappropriately. A coagulation screen costs £4.81, and often does not alter management. We performed four prospective audits (with audit cycle closed twice) of surgical inpatients in a district general hospital, comparing to Trust and NICE guidelines, to establish if coagulation screen requests were appropriate and identify cost implications. Methods All coagulation screen requests in surgical inpatients over two to five week periods were analysed and compared to Trust and NICE Guidelines. Medical notes and laboratory results were reviewed. This was repeated four times over a 3-year period (14 weeks in total). Results 313 coagulation screen requests were made over the four audit periods. Only 38% (119/313) requests were indicated as per guidelines. Inappropriate screens were typically requested for no apparent reason (29%), or unnecessary pre-operative, pre-procedure requests (28%), of the total 194 inappropriate requests. Only 3 unexpected coagulopathies were found. Over the four audit periods, total cost of inappropriate screens was £933.14 Conclusions Despite guidelines, there were a large number of unnecessary coagulation screens performed. Extrapolating our data over the 3-year period, £10,405.20 is spent on inappropriate screens., Whole diet observational studies suggest a beneficial effect on insulin resistance of diets rich in fruit and vegetables (FV). We examined the dose-response effect of FV consumption on insulin resistance in 105 overweight, non-diabetic individuals with no history of cardiovascular disease. After a 4 week wash-out diet of 1-2 portions FV per day, subjects were randomised to consume 1-2, 4 or 7 or more portions FV daily for 12 weeks. Insulin resistance was assessed pre and post intervention using a 2 step hyperinsulinemic euglycemic clamp. Between group comparisons of change were made with one-way ANOVA. Eighty-nine subjects completed the protocol; 28 (1-2FV), 29 (4FV) and 32 (7FV) attained a selfreported intake of 1.8, 3.8 and 7.0 portions per day (p, Observational studies suggest reduced vitamin D levels are associated with an increased incidence of type 2 diabetes mellitus (DM). We examined the relationship with insulin resistance (assessed using a two-step euglycaemic hyperinsulinaemic clamp) in 92 overweight, non-diabetic individuals with no history of cardiovascular disease - mean age 56 years (range 40 -77 years), 64% males, 36% females, body mass index 30.9 kg/m2 (range 26.4 – 36.9 kg/m2), fasting plasma glucose 5.8 mmol/L (range 4.9 – 7.0 mmol/L). Vitamin D was measured using an ultra performance liquid chromatography technique (UPLC) with tandem mass spectrometry. Statistical analysis was performed using Pearson's correlation coefficients and partial correlation. Mean total vitamin D concentration was 32.2 nmol/L. Pearson's correlation coefficients for vitamin D and GIR step 1 were -0.003 (p=0.98), GIR step 2 -0.036 (p=0.73) and HOMA-IR -0.163 (p=0.13). Partial correlation analysis did not elicit any significant correlations after correction for potential anthropometric, seasonal or gender confounders. We demonstrate no association between vitamin D and measures of insulin resistance in healthy overweight individuals at high risk of cardiovascular disease. We suggest that if vitamin D is associated with a reduced risk of DM, this may be due to effects on the beta-cell rather than on insulin resistance., Introduction Management of TBI in the DGH is based on national guidelines. There is little in the literature on the outcome of such patients. Methods Case notes, imaging and follow-up of 216 TBI patients admitted during one year were reviewed. Results The majority of patients admitted (median age: 50 years) were male (81%) and were assessed by trainee physicians; with 79% admitted between 5pm and 9am. 86 patients (41%) had evidence of alcohol consumption, 60 (29%) had decreased consciousness, 15 had dangerous mechanism of injury. 33 patients (22%) demonstrated an abnormality on initial CT brain including cerebral contusions (n=21), skull fractures (n=20), subdural (n=15), intraparenchymal (n=13), subarachnoid (n=6) and extradural haemorrhages (n=3). Four patients died shortly after initial presentation to the DGH due to a non-survivable TBI. Neurosurgical advice was sought on 19 patients - 13 were transferred of whom six required surgery; three eventually died. Glasgow Outcome Score (GOS) of the majority of available cases at last review was 5; a small number requiring minimal assistance (GOS=4, n=3); two patients had permanent disability (GOS=3, n=2). Conclusions Head injuries are common in a DGH and, while poor outcomes are rare, adherence to guidelines is essential to ensure optimal patient management., Introduction Locally, Cardiac Surgery consumes 2000 units of blood each year.1 Using Intraoperative cardiopulmonary bypass results in haemodilution and relative anaemia. Blood transfusion rate for the most commonly performed procedure, CABG is 59%. Resternotomy for bleeding occurs at a rate of 4.9% so we can assume that transfusion is occurring outside of post-operative blood loss. Red cell transfusion has adverse post-operative outcomes with a doubling of_5 year mortality (16% vs 7%).2 We established national trends in blood conservation and reviewed Retrograde Autologous Prime (RAP) of the bypass circuit as a method of blood conservation. Methodology An online survey was carried out across all UK and Ireland units. This was correlated with a local audit of patients receiving RAP versus no RAP. Forty-six patients undergoing cardiac surgery were prospectively studied. Results A response rate was seen of 88.6% to the questionnaire. The most common rate of blood transfusion reported was 25-50% with RAP used as a blood conservation method. In our cohort, the addition of RAP led to a 50% reduction in the blood transfusion rate (60.9% to 30.4%). Conclusions The method of RAP effectively reduces blood transfusion in this small study and we suggest it as part of patient blood management., Breast cancer is the most common cancer in the UK. Associated mortality is almost exclusively as a result of its ability to metastasise to and disrupt distant viscera. In order to improve survival rates in breast cancer, a better understanding of the mechanisms by which cancer disseminates is required. Here we describe a 3D assay which supports proliferation and invasion of primary breast cancer biopsies. Using real time video microscopy and histopathological techniques we identify a role for HER1 in the transformation of ER+ cancer cells into an ER- phenotype. Furthermore, activation of the HER1 receptor may result in epithelial cells developing mesenchymal characteristics along with increasingly invasive behaviour. Correlation with resected breast cancer specimens identified higher levels of HER1 expression alongside a reduction in ER expression over time in patients with recurrent breast cancer. Whilst further investigation is required in both the laboratory and clinical setting, these experiments indicate there may be a role for HER1 antagonists in the setting of ER+ breast cancer to reduce the rate of conversion to a more invasive basal phenotype and systemic dissemination.

Published
2016

48. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author

de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, Shi, J, de Jong, S, Abdalla Diniz, MJ, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Curtis, C, Newhouse, SJ, Patel, H, Hall, LS, O'Reilly, PF, Belangero, S, Bressan, RA, Breen, G, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, Mcgrath, P, Mcguffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Borglum, AD, Sullivan, PF, Meier, S, Strauss, J, Xu, W, Vincent, JB, Matthews, K, Ferreira, M, O'Dushlaine, C, Purcell, S, Raychaudhuri, S, Ruderfer, DM, Sklar, P, Scott, LJ, Flickinger, M, Burmeister, M, Li, J, Guan, W, Absher, D, Thompson, RC, Meng, FG, Schatzberg, AF, Bunney, WE, Barchas, JD, Watson, SJ, Myers, RM, Akil, H, Boehnke, M, Chambert, K, Moran, J, Scolnick, E, Djurovic, S, Melle, I, Morken, G, Corvin, A, Anjorin, A, Kandaswamy, R, Lawrence, J, McLean, AW, Pickard, BS, Bergen, SE, Nimgaonkar, V, Landen, M, Schalling, M, Osby, U, Backlund, L, Frisen, L, Langstrom, N, Stahl, E, Dobbyn, A, Jamain, S, Etain, B, Bellivier, F, Leber, M, Maaser, A, Fischer, SB, Reinbold, CS, Kittel-Schneider, S, Fullerton, JM, Oruc, L, Para, JG, Mayoral, F, Rivas, F, Czerski, PM, Kammerer-Ciernioch, J, Vedder, H, Borrmann-Hassenbach, M, Pfennig, A, Brennan, P, McKay, JD, Kogevinas, M, Schwarz, M, Schofield, PR, Muehleisen, TW, Schumacher, J, Bauer, M, Wright, A, Mitchell, PB, Hautzinger, M, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, Shilling, PD, Smith, EN, Bloss, CS, Edenberg, HJ, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Lohoff, FW, Zandi, PP, Mahon, PB, McInnis, MG, Zollner, S, Zhang, P, Szelinger, S, St Clair, D, Caesar, S, Gordon-Smith, K, Fraser, C, Green, EK, Grozeva, D, Hamshere, ML, Kirov, G, Nikolov, I, Collier, DA, Elkin, A, Williamson, R, Young, AH, Ferrier, IN, Milanova, V, Alda, M, Cervantes, P, Cruceanu, C, Rouleau, GA, Turecki, G, Paciga, S, Winslow, AR, Grigoroiu-Serbanescu, M, Ophoff, R, Adolfsson, R, Adolfsson, AN, Del-Favero, J, Pato, C, Biernacka, JM, Frye, MA, Morris, D, Schork, NJ, Reif, A, Lissowska, J, Hauser, J, Szeszenia-Dabrowska, N, McGhee, K, Quinn, E, Moskvina, V, Holmans, PA, Farmer, A, Kennedy, JL, Andreassen, OA, Mattingsdal, M, Bass, NJ, Gurling, H, McQuillin, A, Breuer, R, Hultman, C, Lichtenstein, P, Huckins, LM, Leboyer, M, Lathrop, M, Nurnberger, J, Steffens, M, Foroud, TM, Berrettini, WH, Craig, DW, and Shi, J

Abstract

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

Published
2018

49. Thermal refugia against coral bleaching throughout the northern Red Sea

Author

Osman, EO, Smith, DJ, Ziegler, M, Kürten, B, Conrad, C, El-Haddad, KM, Voolstra, CR, Suggett, DJ, Osman, EO, Smith, DJ, Ziegler, M, Kürten, B, Conrad, C, El-Haddad, KM, Voolstra, CR, and Suggett, DJ

Abstract

© 2017 John Wiley & Sons Ltd Tropical reefs have been impacted by thermal anomalies caused by global warming that induced coral bleaching and mortality events globally. However, there have only been very few recordings of bleaching within the Red Sea despite covering a latitudinal range of 15° and consequently it has been considered a region that is less sensitive to thermal anomalies. We therefore examined historical patterns of sea surface temperature (SST) and associated anomalies (1982–2012) and compared warming trends with a unique compilation of corresponding coral bleaching records from throughout the region. These data indicated that the northern Red Sea has not experienced mass bleaching despite intensive Degree Heating Weeks (DHW) of >15°C-weeks. Severe bleaching was restricted to the central and southern Red Sea where DHWs have been more frequent, but far less intense (DHWs <4°C-weeks). A similar pattern was observed during the 2015–2016 El Niño event during which time corals in the northern Red Sea did not bleach despite high thermal stress (i.e. DHWs >8°C-weeks), and bleaching was restricted to the central and southern Red Sea despite the lower thermal stress (DHWs < 8°C-weeks). Heat stress assays carried out in the northern (Hurghada) and central (Thuwal) Red Sea on four key reef-building species confirmed different regional thermal susceptibility, and that central Red Sea corals are more sensitive to thermal anomalies as compared to those from the north. Together, our data demonstrate that corals in the northern Red Sea have a much higher heat tolerance than their prevailing temperature regime would suggest. In contrast, corals from the central Red Sea are close to their thermal limits, which closely match the maximum annual water temperatures. The northern Red Sea harbours reef-building corals that live well below their bleaching thresholds and thus we propose that the region represents a thermal refuge of global importance.

Published
2018

50. The future of coral reefs subject to rapid climate change: Lessons from natural extreme environments

Author

Camp, EF, Schoepf, V, Mumby, PJ, Hardtke, LA, Rodolfo-Metalpa, R, Smith, DJ, Suggett, DJ, Camp, EF, Schoepf, V, Mumby, PJ, Hardtke, LA, Rodolfo-Metalpa, R, Smith, DJ, and Suggett, DJ

Abstract

© 2018 Camp, Schoepf, Mumby, Hardtke, Rodolfo-Metalpa, Smith and Suggett. Global climate change and localized anthropogenic stressors are driving rapid declines in coral reef health. In vitro experiments have been fundamental in providing insight into how reef organisms will potentially respond to future climates. However, such experiments are inevitably limited in their ability to reproduce the complex interactions that govern reef systems. Studies examining coral communities that already persist under naturally-occurring extreme and marginal physicochemical conditions have therefore become increasingly popular to advance ecosystem scale predictions of future reef form and function, although no single site provides a perfect analog to future reefs. Here we review the current state of knowledge that exists on the distribution of corals in marginal and extreme environments, and geographic sites at the latitudinal extremes of reef growth, as well as a variety of shallow reef systems and reef-neighboring environments (including upwelling and CO2 vent sites). We also conduct a synthesis of the abiotic data that have been collected at these systems, to provide the first collective assessment on the range of extreme conditions under which corals currently persist. We use the review and data synthesis to increase our understanding of the biological and ecological mechanisms that facilitate survival and success under sub-optimal physicochemical conditions. This comprehensive assessment can begin to: (i) highlight the extent of extreme abiotic scenarios under which corals can persist, (ii) explore whether there are commonalities in coral taxa able to persist in such extremes, (iii) provide evidence for key mechanisms required to support survival and/or persistence under sub-optimal environmental conditions, and (iv) evaluate the potential of current sub-optimal coral environments to act as potential refugia under changing environmental conditions. Such a collective approach

Published
2018

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