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1. Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge

Author

Cousins, Oliver, Schubert, Julia J., Chandra, Avinash, Veronese, Mattia, Valkimadi, Polena, Creese, Byron, Khan, Zunera, Arathimos, Ryan, Hampshire, Adam, Rosenzweig, Ivana, Ballard, Clive, Corbett, Anne, Aasland, Dag, Velayudhan, Latha, O’Neill, Michael, Collier, David, Awais, Ramla, Sander, Kerstin, Årstad, Erik, Howes, Oliver, Turkheimer, Federico, and Hodges, Angela

Published
2023
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4. Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Author

Reese, Sarah E., Xu, Cheng-Jian, den Dekker, Herman T., Lee, Mi Kyeong, Sikdar, Sinjini, Ruiz-Arenas, Carlos, Merid, Simon K., Rezwan, Faisal I., Page, Christian M., Ullemar, Vilhelmina, Melton, Phillip E., Oh, Sam S., Yang, Ivana V., Burrows, Kimberley, Söderhäll, Cilla, Jima, Dereje D., Gao, Lu, Arathimos, Ryan, Küpers, Leanne K., Wielscher, Matthias, Rzehak, Peter, Lahti, Jari, Laprise, Catherine, Madore, Anne-Marie, Ward, James, Bennett, Brian D., Wang, Tianyuan, Bell, Douglas A., Vonk, Judith M., Håberg, Siri E., Zhao, Shanshan, Karlsson, Robert, Hollams, Elysia, Hu, Donglei, Richards, Adam J., Bergström, Anna, Sharp, Gemma C., Felix, Janine F., Bustamante, Mariona, Gruzieva, Olena, Maguire, Rachel L., Gilliland, Frank, Baïz, Nour, Nohr, Ellen A., Corpeleijn, Eva, Sebert, Sylvain, Karmaus, Wilfried, Grote, Veit, Kajantie, Eero, Magnus, Maria C., Örtqvist, Anne K., Eng, Celeste, Liu, Andrew H., Kull, Inger, Jaddoe, Vincent W.V., Sunyer, Jordi, Kere, Juha, Hoyo, Cathrine, Annesi-Maesano, Isabella, Arshad, Syed Hasan, Koletzko, Berthold, Brunekreef, Bert, Binder, Elisabeth B., Räikkönen, Katri, Reischl, Eva, Holloway, John W., Jarvelin, Marjo-Riitta, Snieder, Harold, Kazmi, Nabila, Breton, Carrie V., Murphy, Susan K., Pershagen, Göran, Anto, Josep Maria, Relton, Caroline L., Schwartz, David A., Burchard, Esteban G., Huang, Rae-Chi, Nystad, Wenche, Almqvist, Catarina, Henderson, A. John, Melén, Erik, Duijts, Liesbeth, Koppelman, Gerard H., and London, Stephanie J.

Published
2019
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8. Investigating the genetic relationship between depression symptoms and Alzheimer’s Disease in clinically diagnosed and proxy cases

Author

Gilchrist, Lachlan, primary, Spargo, Thomas P., additional, Green, Rebecca E., additional, Coleman, Jonathan R.I., additional, Howard, David M., additional, Thorp, Jackson G., additional, Adey, Brett, additional, Lord, Jodie, additional, Davies, Helena L., additional, Mundy, Jessica, additional, ter Kuile, Abigail, additional, Davies, Molly R., additional, Hübel, Christopher, additional, Bristow, Shannon, additional, Lee, Sang Hyuck, additional, Rogers, Henry, additional, Curtis, Charles, additional, Kalsi, Gursharan, additional, Arathimos, Ryan, additional, Corbett, Anne, additional, Ballard, Clive, additional, Brooker, Helen, additional, Creese, Byron, additional, Aarsland, Dag, additional, Hampshire, Adam, additional, Velayudhan, Latha, additional, Eley, Thalia C., additional, Breen, Gerome, additional, Iacoangeli, Alfredo, additional, Koks, Sulev, additional, Lewis, Cathryn M., additional, and Proitsi, Petroula, additional

Published
2023
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16. SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts

Author

Beckmeyer-Borowko, Anna, Imboden, Medea, Rezwan, Faisal I., Wielscher, Matthias, Amaral, Andre F. S., Jeong, Ayoung, Schaffner, Emmanuel, Auvinen, Juha, Sebert, Sylvain, Karhunen, Ville, Bettschart, Robert, Turk, Alexander, Pons, Marco, Stolz, Daiana, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma C., Relton, Caroline, Henderson, Alexander J., Jarvelin, Marjo-Riitta, Jarvis, Deborah, Holloway, John W., and Probst-Hensch, Nicole M.

Published
2018
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17. The consequences of a year of the COVID-19 pandemic for the mental health of young adult twins in England and Wales

Author

Rimfeld, Kaili, primary, Malanchini, Margherita, additional, Arathimos, Ryan, additional, Gidziela, Agnieszka, additional, Pain, Oliver, additional, McMillan, Andrew, additional, Ogden, Rachel, additional, Webster, Louise, additional, Packer, Amy E., additional, Shakeshaft, Nicholas G., additional, Schofield, Kerry L., additional, Pingault, Jean-Baptiste, additional, Allegrini, Andrea G., additional, Stringaris, Argyris, additional, von Stumm, Sophie, additional, Lewis, Cathryn M., additional, and Plomin, Robert, additional

Published
2022
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18. Latent subtypes of manic and/or irritable episode symptoms in two population-based cohorts – ERRATUM

Author

Arathimos, Ryan, primary, Fabbri, Chiara, additional, Vassos, Evangelos, additional, Davis, Katrina A. S., additional, Pain, Oliver, additional, Gillett, Alexandra, additional, Coleman, Jonathan R. I., additional, Hanscombe, Ken, additional, Hagenaars, Saskia, additional, Jermy, Bradley, additional, Corbett, Anne, additional, Ballard, Clive, additional, Aarsland, Dag, additional, Creese, Byron, additional, and Lewis, Cathryn M., additional

Published
2022
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21. The consequences of a year of the COVID-19 pandemic for the mental health of young adult twins in England and Wales

Author

Rimfeld, Kaili, primary, Malanchini, Margherita, additional, Arathimos, Ryan, additional, Gidziela, Agnieszka, additional, Pain, Oliver, additional, McMillan, Andrew, additional, Ogden, Rachel, additional, Webster, Louise, additional, Packer, Amy E., additional, Shakeshaft, Nicholas G., additional, Schofield, Kerry L., additional, Pingault, Jean-Baptiste, additional, Allegrini, Andrea G., additional, Stringaris, Argyris, additional, von Stumm, Sophie, additional, Lewis, Cathryn M., additional, and Plomin, Robert, additional

Published
2021
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22. 38. LATENT SUBTYPES OF MANIC OR IRRITABLE EPISODE SYMPTOMS IN TWO POPULATION-BASED COHORTS

Author

Arathimos, Ryan, primary, Fabbri, Chiara, additional, Vassos, Evangelos, additional, Davis, Katrina, additional, Pain, Oliver, additional, Gillett, Alexandra, additional, Coleman, Jonathan, additional, Hanscombe, Ken Benjamin, additional, Hagenaars, Saskia, additional, Jermy, Bradley, additional, Corbett, Anne, additional, Ballard, Clive, additional, Aarsland, Dag, additional, Creese, Byron, additional, and Lewis, Cathryn, additional

Published
2021
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24. Methylome-wide association study of early life stressors and adult mental health

Author

Howard, David M, primary, Pain, Oliver, additional, Arathimos, Ryan, additional, Barbu, Miruna C, additional, Amador, Carmen, additional, Walker, Rosie M, additional, Jermy, Bradley, additional, Adams, Mark J, additional, Deary, Ian J, additional, Porteous, David, additional, Campbell, Archie, additional, Sullivan, Patrick F, additional, Evans, Kathryn L, additional, Arseneault, Louise, additional, Wray, Naomi R, additional, Meaney, Michael, additional, McIntosh, Andrew M, additional, and Lewis, Cathryn M, additional

Published
2021
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25. Latent subtypes of manic or irritable episode symptoms in two population-based cohorts

Author

Arathimos, Ryan, primary, Fabbri, Chiara, additional, Vassos, Evangelos, additional, Davis, Katrina A S, additional, Pain, Oliver, additional, Gillett, Alexandra, additional, Coleman, Jonathan R I, additional, Hanscombe, Ken, additional, Hagenaars, Saskia, additional, Jermy, Bradley, additional, Corbett, Anne, additional, Ballard, Clive, additional, Aarsland, Dag, additional, Creese, Byron, additional, and Lewis, Cathryn M, additional

Published
2021
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26. Methylome-wide association study of early life stressors and adult mental health reveals a relationship between birth date and cell type composition in blood

Author

Howard, David M., primary, Pain, Oliver, additional, Arathimos, Ryan, additional, Barbu, Miruna C., additional, Amador, Carmen, additional, Walker, Rosie M., additional, Jermy, Bradley, additional, Adams, Mark J., additional, Deary, Ian J., additional, Porteous, David, additional, Campbell, Archie, additional, Sullivan, Patrick F., additional, Evans, Kathryn L., additional, Arseneault, Louise, additional, Wray, Naomi R., additional, Meaney, Michael, additional, McIntosh, Andrew M., additional, and Lewis, Cathryn M., additional

Published
2021
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29. Sex‐specific associations of asthma acquisition with changes in DNA methylation during adolescence

Author

Patel, Rutu, primary, Solatikia, Farnaz, additional, Zhang, Hongmei, additional, Wolde, Alemayehu, additional, Kadalayil, Latha, additional, Karmaus, Wilfried, additional, Ewart, Susan, additional, Arathimos, Ryan, additional, Relton, Caroline, additional, Ring, Susan, additional, Henderson, Alexander John, additional, Arshad, Syed Hasan, additional, and Holloway, John W., additional

Published
2020
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30. DNA methylation at birth is associated with lung function development until age 26 years

Author

Mukherjee, Nandini, primary, Arathimos, Ryan, additional, Chen, Su, additional, Kheirkhah Rahimabad, Parnian, additional, Han, Luhang, additional, Zhang, Hongmei, additional, Holloway, John W., additional, Relton, Caroline, additional, Henderson, A. John, additional, Arshad, Syed Hasan, additional, Ewart, Susan, additional, and Karmaus, Wilfried, additional

Published
2020
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34. Epigenome-wide association study of lung function level and its change

Author

Imboden, Medea, Wielscher, Matthias, Rezwan, Faisal I, Amaral, André F S, Schaffner, Emmanuel, Jeong, Ayoung, Beckmeyer-Borowko, Anna, Harris, Sarah E, Starr, John M, Deary, Ian J, Flexeder, Claudia, Waldenberger, Melanie, Peters, Annette, Schulz, Holger, Chen, Su, Sunny, Shadia Khan, Karmaus, Wilfried J J, Jiang, Yu, Erhart, Gertraud, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma C, Henderson, Alexander John, Fu, Yu, Piirilä, Päivi, Pietiläinen, Kirsi H, Ollikainen, Miina, Johansson, Åsa, Gyllensten, Ulf B., de Vries, Maaike, van der Plaat, Diana A, de Jong, Kim, Boezen, H Marike, Hall, Ian P, Tobin, Martin D, Jarvelin, Marjo-Riitta, Holloway, John W, Jarvis, Deborah, Probst-Hensch, Nicole M, Imboden, Medea, Wielscher, Matthias, Rezwan, Faisal I, Amaral, André F S, Schaffner, Emmanuel, Jeong, Ayoung, Beckmeyer-Borowko, Anna, Harris, Sarah E, Starr, John M, Deary, Ian J, Flexeder, Claudia, Waldenberger, Melanie, Peters, Annette, Schulz, Holger, Chen, Su, Sunny, Shadia Khan, Karmaus, Wilfried J J, Jiang, Yu, Erhart, Gertraud, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma C, Henderson, Alexander John, Fu, Yu, Piirilä, Päivi, Pietiläinen, Kirsi H, Ollikainen, Miina, Johansson, Åsa, Gyllensten, Ulf B., de Vries, Maaike, van der Plaat, Diana A, de Jong, Kim, Boezen, H Marike, Hall, Ian P, Tobin, Martin D, Jarvelin, Marjo-Riitta, Holloway, John W, Jarvis, Deborah, and Probst-Hensch, Nicole M

Abstract

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and i

Published
2019
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35. Additional file 1: of SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts

Author

Beckmeyer-Borowko, Anna, Imboden, Medea, Rezwan, Faisal, Wielscher, Matthias, Amaral, Andre, Ayoung Jeong, Schaffner, Emmanuel, Auvinen, Juha, Sebert, Sylvain, Karhunen, Ville, Bettschart, Robert, Turk, Alexander, Pons, Marco, Stolz, Daiana, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma, Relton, Caroline, Henderson, Alexander, Marjo-Riitta Jarvelin, Jarvis, Deborah, Holloway, John, and Probst-Hensch, Nicole

Subjects
respiratory tract diseases
Abstract

Table ES1. Meta-Analysis of the association of methylation at CpGs in the SERPINA* Gene Cluster with FVC level and decline in adult ever smokers from SAPALDIA, ECRHS and NFBC (n = 1076) and with circulating AAT concentrations in SAPALDIA (n = 561). Table ES2. Meta-Analysis of the association of methylation at 119 CpGs in the SERPINA* cluster with FEV1 level and decline in adult ever smokers from SAPALDIA, ECRHS and NFBC (n = 1076) and with circulating AAT concentrations in SAPALDIA (n = 561). Table ES3. Meta-analysis of the association of methylation at 119 CpGs in the SERPINA* gene cluster with FVC level and decline in adult ever smokers from SAPALDIA, ECRHS and NFBC (n = 1076) and with circulating AAT concentrations in SAPALDIA (n = 561). Table ES4. Meta-analysis of the association of methylation at 119 CpGs in the SERPINA* gene cluster with FEV1/FVC level and decline in adult ever smokers from SAPALDIA, ECRHS and NFBC (n = 1076) and with circulating AAT concentrations in SAPALDIA (n = 561). Table ES5. Association of methylation at 119 CpGs in the SERPINA* gene cluster with FEV1 level and decline in ALSPAC children exposed to tobacco smoke (n = 259). Table ES6. Association of methylation at 119 CpGs in the SERPINA* gene cluster with FVC level and decline in in ALSPAC children exposed to tobacco smoke (n = 259). Table ES7. Association of methylation at 119 CpGs in the SERPINA* gene cluster with FEV1/FVC level and decline in ALSPAC children exposed to tobacco smoke (n = 259). Table ES8. Association of methylation at 119 CpGs in the SERPINA* gene cluster with FEV1 level and decline in adult smokers from SAPALDIA, basic adjustment and adjustment for PIS and PIZ genotypes. Table ES9. Association of methylation at 119 CpGs in the SERPINA* gene cluster with FEV1/FVC level and decline in adult smokers from SAPALDIA, basic adjustment and adjustment for PIS and PIZ genotypes. (DOCX 349 kb)

Published
2018
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36. Epigenome-wide association study of lung function level and its change

Author

Imboden, Medea, primary, Wielscher, Matthias, additional, Rezwan, Faisal I., additional, Amaral, André F.S., additional, Schaffner, Emmanuel, additional, Jeong, Ayoung, additional, Beckmeyer-Borowko, Anna, additional, Harris, Sarah E., additional, Starr, John M., additional, Deary, Ian J., additional, Flexeder, Claudia, additional, Waldenberger, Melanie, additional, Peters, Annette, additional, Schulz, Holger, additional, Chen, Su, additional, Sunny, Shadia Khan, additional, Karmaus, Wilfried J.J., additional, Jiang, Yu, additional, Erhart, Gertraud, additional, Kronenberg, Florian, additional, Arathimos, Ryan, additional, Sharp, Gemma C., additional, Henderson, Alexander John, additional, Fu, Yu, additional, Piirilä, Päivi, additional, Pietiläinen, Kirsi H., additional, Ollikainen, Miina, additional, Johansson, Asa, additional, Gyllensten, Ulf, additional, de Vries, Maaike, additional, van der Plaat, Diana A., additional, de Jong, Kim, additional, Boezen, H. Marike, additional, Hall, Ian P., additional, Tobin, Martin D., additional, Jarvelin, Marjo-Riitta, additional, Holloway, John W., additional, Jarvis, Deborah, additional, and Probst-Hensch, Nicole M., additional

Published
2019
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38. Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate

Author

Howe, Laurence J, primary, Richardson, Tom G, additional, Arathimos, Ryan, additional, Alvizi, Lucas, additional, Passos-Bueno, Maria R, additional, Stanier, Philip, additional, Nohr, Ellen, additional, Ludwig, Kerstin U, additional, Mangold, Elisabeth, additional, Knapp, Michael, additional, Stergiakouli, Evie, additional, Pourcain, Beate St, additional, Smith, George Davey, additional, Sandy, Jonathan, additional, Relton, Caroline L, additional, Lewis, Sarah J, additional, Hemani, Gibran, additional, and Sharp, Gemma C, additional

Published
2019
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40. Sex‐specific associations of asthma acquisition with changes in DNA methylation during adolescence.

Author

Patel, Rutu, Solatikia, Farnaz, Zhang, Hongmei, Wolde, Alemayehu, Kadalayil, Latha, Karmaus, Wilfried, Ewart, Susan, Arathimos, Ryan, Relton, Caroline, Ring, Susan, Henderson, Alexander John, Arshad, Syed Hasan, and Holloway, John W.

Subjects
DNA methylation, ASTHMA, ADOLESCENCE, LOGISTIC regression analysis, GENE expression
Abstract

Summary: Background: Underlying biological mechanisms involved in sex differences in asthma status changes from pre‐ to post‐adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma. Objective: We hypothesized that asthma acquisition from pre‐ to post‐adolescence was associated with changes in DNAm during this period at asthma‐associated cytosine‐phosphate‐guanine (CpG) sites and such an association was sex‐specific. Methods: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training‐testing approach, epigenome‐wide CpGs associated with asthma were identified. Logistic regression was used to examine sex‐specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma‐associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed. Results: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P‐values <1.0 × 10−3). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex‐specific effects on asthma transition (P‐values <.01 in both cohorts). Conclusion and clinical relevance: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre‐ to post‐adolescence at asthma‐associated CpGs. These CpGs are potential biomarkers of sex‐specific asthma acquisition in adolescence. [ABSTRACT FROM AUTHOR]

Published
2021
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42. DNA methylation mediates genetic liability to non-syndromic cleft lip/palate

Author

Howe, Laurence J, primary, Richardson, Tom G, additional, Arathimos, Ryan, additional, Alvizi, Lucas, additional, Passos-Bueno, Maria-Rita, additional, Stanier, Philip, additional, Nohr, Ellen, additional, Ludwig, Kerstin U, additional, Mangold, Elisabeth, additional, Knapp, Michael, additional, Stergiakouli, Evie, additional, St Pourcain, Beate, additional, Davey Smith, George, additional, Sandy, Jonathan, additional, Relton, Caroline L, additional, Lewis, Sarah J, additional, Hemani, Gibran, additional, and Sharp, Gemma C, additional

Published
2018
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45. Maternal alcohol consumption and offspring DNA methylation: findings from six general population-based birth cohorts.

Author

Sharp, Gemma C, Arathimos, Ryan, Reese, Sarah E, Page, Christian M, Felix, Janine, Küpers, Leanne K, Rifas-Shiman, Sheryl L, Liu, Chunyu, Burrows, Kimberley, Zhao, Shanshan, Magnus, Maria C, Duijts, Liesbeth, Corpeleijn, Eva, DeMeo, Dawn L, Litonjua, Augusto, Baccarelli, Andrea, Hivert, Marie-France, Oken, Emily, Snieder, Harold, and Jaddoe, Vincent

Published
2018
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46. Epigenome-wide association study of lung function level and its change

Author

Imboden, Medea, Wielscher, Matthias, Rezwan, Faisal I., Amaral, André F. S., Schaffner, Emmanuel, Jeong, Ayoung, Beckmeyer-Borowko, Anna, Harris, Sarah E., Starr, John M., Deary, Ian J., Flexeder, Claudia, Waldenberger, Melanie, Peters, Annette, Schulz, Holger, Chen, Su, Sunny, Shadia Khan, Karmaus, Wilfried J. J., Jiang, Yu, Erhart, Gertraud, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma C., Henderson, Alexander John, Fu, Yu, Piirilä, Päivi, Pietiläinen, Kirsi H., Ollikainen, Miina, Johansson, Asa, Gyllensten, Ulf, de Vries, Maaike, van der Plaat, Diana A., de Jong, Kim, Boezen, H. Marike, Hall, Ian P., Tobin, Martin D., Jarvelin, Marjo-Riitta, Holloway, John W., Jarvis, Deborah, and Probst-Hensch, Nicole M.

Subjects
3. Good health

48. SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults : a meta-analysis of ALEC population-based cohorts

Author

Beckmeyer-Borowko, Anna, Imboden, Medea, Rezwan, Faisal I., Wielscher, Matthias, Amaral, Andre F. S., Jeong, Ayoung, Schaffner, Emmanuel, Auvinen, Juha, Sebert, Sylvain, Karhunen, Ville, Bettschart, Robert, Turk, Alexander, Pons, Marco, Stolz, Daiana, Kronenberg, Florian, Arathimos, Ryan, Sharp, Gemma C., Relton, Caroline, Henderson, Alexander J., Jarvelin, Marjo-Riitta, Jarvis, Deborah, Holloway, John W., and Probst-Hensch, Nicole M.

Subjects
3. Good health

49. Stratified genome-wide association analysis of type 2 diabetes reveals subgroups with genetic and environmental heterogeneity

Author

Christiansen, Colette E., Arathimos, Ryan, Pain, Oliver, Molokhia, Mariam, Bell, Jordana T., Lewis, Cathryn M., Christiansen, Colette E., Arathimos, Ryan, Pain, Oliver, Molokhia, Mariam, Bell, Jordana T., and Lewis, Cathryn M.

Abstract

Type 2 diabetes (T2D) is a heterogeneous illness caused by genetic and environmental factors. Previous genome wide association studies (GWAS) have identified many genetic variants associated with T2D and found evidence of differing genetic profiles by age-at-onset. This study seeks to explore further the genetic and environmental drivers of T2D by analysing subgroups based on age-at-onset of diabetes and body mass index (BMI). In UK Biobank, 36 494 T2D cases were stratified into 3 subgroups and GWAS performed for all T2D cases and for each subgroup relative to 421 021 controls. Altogether, 18 SNPs significantly associated genome-wide with T2D in one or more subgroups also showed evidence of heterogeneity between the subgroups, (Cochrane’s Q p < 0.01) with 2 remaining significant after multiple testing (in CDKN2B and CYTIP). Combined risk scores, based on genetic profile, BMI and age, resulted in excellent diabetes prediction (AUC = 0.92). A modest improvement in prediction (AUC = 0.93) was seen when the contribution of genetic and environmental factors was evaluated separately for each subgroup. Increasing sample sizes of genetic studies enables us to stratify disease cases into subgroups which have sufficient power to highlight areas of genetic heterogeneity. Despite some evidence that optimising combined risk scores by subgroup improves prediction, larger sample sizes are likely needed for prediction when using a stratification approach.

50. Late-life onset psychotic symptoms and incident cognitive impairment in people without dementia: Modification by genetic risk for Alzheimer's disease.

Author

Creese B, Arathimos R, Aarsland D, Ballard C, Brooker H, Hampshire A, Corbett A, and Ismail Z

Abstract

Introduction: Late-life onset psychosis is associated with faster progression to dementia in cognitively normal people, but little is known about its relationship with cognitive impairment in advance of dementia., Methods: Clinical and genetic data from 2750 people ≥50 years of age without dementia were analyzed. Incident cognitive impairment was operationalized using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and psychosis was rated using the Mild Behavioral Impairment Checklist (henceforth MBI-psychosis). The whole sample was analyzed before stratification on apolipoprotein E ( APOE ) ε4 status., Results: In Cox proportional hazards models, MBI-psychosis had a higher hazard for cognitive impairment relative to the No Psychosis group (hazard ratio [HR]: 3.6, 95% confidence interval [CI]: 2.2-6, p < 0.0001). The hazard for MBI-psychosis was higher in APOE ε4 carriers and there was an interaction between the two (HR for interaction: 3.4, 95% CI: 1.2-9.8, p = 0.02)., Discussion: Psychosis assessment in the MBI framework is associated with incident cognitive impairment in advance of dementia. These symptoms may be particularly important in the context of APOE genotype., Competing Interests: Clive Ballard has received contract grant funding from ACADIA, Lundbeck, Takeda, and Axovant pharmaceutical companies; and honoraria from Lundbeck, Lilly, Otsuka, and Orion pharmaceutical companies. Dag Aarsland has received research support and/or honoraria from Astra‐Zeneca, H. Lundbeck, Novartis Pharmaceuticals, and GE Health; and serves as a paid consultant for H. Lundbeck and Axovant. Zahinoor Ismail has received honoraria/consulting fees from Lundbeck and Otsuka, although not related to this work. Adam Hampshire is owner and director of Future Cognition Ltd., a software company that produces bespoke cognitive assessment technology and that was paid to produce cognitive tasks for PROTECT. Helen Brooker was employed by Wesnes Cognition 2011 to 2018, who provided some of the cognitive tests for PROTECT and is the director of Ecog Pro Ltd. who provide cognitive tests to PROTECT. All other authors have nothing to declare. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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