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8 results on '"Richardson, T. G. (Tom G.)"'

1. Genetic evidence for protective effects of angiotensin-converting enzyme against alzheimer disease but not other neurodegenerative diseases in European populations

Author

Ryan, D. K. (David K.), Karhunen, V. (Ville), Su, B. (Bowen), Traylor, M. (Matthew), Richardson, T. G. (Tom G.), Burgess, S. (Stephen), Tzoulaki, I. (Ioanna), Gill, D. (Dipender), Ryan, D. K. (David K.), Karhunen, V. (Ville), Su, B. (Bowen), Traylor, M. (Matthew), Richardson, T. G. (Tom G.), Burgess, S. (Stephen), Tzoulaki, I. (Ioanna), and Gill, D. (Dipender)

Abstract

Background and objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits. Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.

Published
2022

2. A phenome-wide bidirectional Mendelian randomization analysis of atrial fibrillation

Author

Wang, Q. (Qin), Richardson, T. G. (Tom G.), Sanderson, E. (Eleanor), Tudball, M. J. (Matthew J.), Ala-Korpela, M. (Mika), Smith, G. D. (George Davey), Holmes, M. V. (Michael V.), Wang, Q. (Qin), Richardson, T. G. (Tom G.), Sanderson, E. (Eleanor), Tudball, M. J. (Matthew J.), Ala-Korpela, M. (Mika), Smith, G. D. (George Davey), and Holmes, M. V. (Michael V.)

Abstract

Background: The prevalence of atrial fibrillation (AF) is increasing with an aging worldwide population, yet a comprehensive understanding of its causes and consequences remains limited. We aim to assess the causes and consequences of AF via a bidirectional Mendelian randomization (MR) analysis. Methods: We used publicly available genome-wide association study (GWAS) summary data, centralized and harmonized by an open GWAS database. We assessed the genetically predicted effects of 5048 exposures on risk of AF, and the genetically predicted effects of genetic liability to AF, on 10 308 outcomes via two-sample MR analysis. Multivariable MR analysis was further conducted to explore the comparative roles of identified risk factors. Results: MR analysis suggested that 55 out of 5048 exposure traits, including four proteins, play a causal role in AF (P <1e-5 allowing for multiple comparisons). Multivariable analysis suggested that higher body mass index, height and systolic blood pressure as well as genetic liability to coronary artery diseases independently cause AF. Three out of the four proteins (DUSP13, TNFSF12 and IL6R) had a drug prioritizing score for atrial fibrillation of 0.26, 0.38 and 0.88, respectively (values closer to 1 indicating stronger evidence of the protein as a potential drug target). Genetic liability to AF was linked to a higher risk of cardio-embolic ischaemic stroke. Conclusions: Our results suggest body mass index, height, systolic blood pressure and genetic liability to coronary artery disease are independent causal risk factors for AF. Several proteins, including DUSP13, IL-6R and TNFSF12, may have therapeutic potential for AF.

Published
2022

3. Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes:a mendelian randomisation analysis using outcomes in first-degree relatives

Author

Richardson, T. G. (Tom G.), Wang, Q. (Qin), Sanderson, E. (Eleanor), Mahajan, A. (Anubha), McCarthy, M. I. (Mark I.), Frayling, T. M. (Timothy M.), Ala-Korpela, M. (Mika), Sniderman, A. (Allan), Smith, G. D. (George Davey), and Holmes, M. V. (Michael V.)

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Background: Apolipoprotein B (apoB) is emerging as the crucial lipoprotein trait for the role of lipoprotein lipids in the aetiology of coronary heart disease. In this study, we evaluated the effects of genetically predicted apoB on outcomes in first-degree relatives. Methods: Data on lipoprotein lipids and disease outcomes in first-degree relatives were obtained from the UK Biobank study. We did a univariable mendelian randomisation analysis using a weighted genetic instrument for apoB. For outcomes with which apoB was associated at a false discovery rate (FDR) of less than 5%, multivariable mendelian randomisation analyses were done, including genetic instruments for LDL cholesterol and triglycerides. Associations between apoB and self-reported outcomes in first-degree relatives were characterised for 12 diseases (including heart disease, stroke, and hypertension) and parental vital status together with age at death. Estimates were inferred causal effects per 1 SD elevated lipoprotein trait (for apoB, 1 SD=0·24 g/L). Replication of estimates for lifespan and type 2 diabetes was done using conventional two-sample mendelian randomisation with summary estimates from genome-wide association study consortia. Findings: In univariable mendelian randomisation, genetically elevated apoB in participants was identified to lead to a shorter lifespan in parents (fathers: 0·89 years of life lost per 1 SD higher apoB in offspring, 95% CI 0·63–1·16, FDR-adjusted p=4·0 × 10⁻¹⁰; mothers: 0·48 years of life lost per 1 SD higher apoB in offspring, 0·25–0·71, FDR-adjusted p=1·7 × 10⁻⁴). The effects were strengthened to around 2 years of life lost in multivariable mendelian randomisation and were replicated in conventional two-sample mendelian randomisation (odds ratio [OR] of surviving to the 90th centile of lifespan: 0·38 per 1 SD higher apoB in offspring, 95% CI 0·22–0·65). Genetically elevated apoB caused higher risks of heart disease in all first-degree relatives and a higher risk of stroke in mothers. Findings in first-degree relatives were replicated in two-sample multivariable mendelian randomisation, which identified apoB to increase (OR 2·32 per 1 SD higher apoB, 95% CI 1·49–3·61) and LDL cholesterol to decrease (0·34 per 1 SD higher LDL cholesterol, 0·21–0·54) the risk of type 2 diabetes. Interpretation: Higher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes. Funding: British Heart Foundation, UK Medical Research Council, and UK Research and Innovation.

Published
2021

4. Evaluating the direct effects of childhood adiposity on adult systemic metabolism:a multivariable Mendelian randomization analysis

Author

Richardson, T. G. (Tom G), Mykkänen, J. (Juha), Pahkala, K. (Katja), Ala-Korpela, M. (Mika), Bell, J. A. (Joshua A), Taylor, K. (Kurt), Viikari, J. (Jorma), Lehtimäki, T. (Terho), Raitakari, O. (Olli), Smith, G. D. (George Davey), Richardson, T. G. (Tom G), Mykkänen, J. (Juha), Pahkala, K. (Katja), Ala-Korpela, M. (Mika), Bell, J. A. (Joshua A), Taylor, K. (Kurt), Viikari, J. (Jorma), Lehtimäki, T. (Terho), Raitakari, O. (Olli), and Smith, G. D. (George Davey)

Abstract

Background: Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways. Methods: Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls. Results: Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P < 4.07 × 10−4). However, the majority of these effects (35/42) substantially attenuated when accounting for adult body size using multivariable MR. We found little evidence that the biomarkers that were potentially influenced directly by childhood body size (leucine, isoleucine and tyrosine) mediate this effect onto adult disease risk. Very-low-density lipoprotein markers provided the strongest evidence of mediating the long-term effect of adiposity on CAD risk. Conclusions: Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.

Published
2021

5. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease:a multivariable Mendelian randomisation analysis

Author

Richardson, T. G. (Tom G.), Sanderson, E. (Eleanor), Palmer, T. M. (Tom M.), Ala-Korpela, M. (Mika), Ference, B. A. (Brian A.), Smith, G. D. (George Davey), and Holmes, M. V. (Michael V.)

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

Background: Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD. Methods and findings: We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39–73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10−8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%–93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10−8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation–higher trait; 95% CI: 1.49–1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25–1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56–1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31–2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57–1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02–1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation–higher HDL cholesterol (OR 0.80; 95% CI: 0.75–0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77–0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components. Conclusions: These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.

Published
2020

6. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Author

Surendran, P. (Praveen), Feofanova, E. V. (Elena, V), Lahrouchi, N. (Najim), Ntalla, I. (Ioanna), Karthikeyan, S. (Savita), Cook, J. (James), Chen, L. (Lingyan), Mifsud, B. (Borbala), Yao, C. (Chen), Kraja, A. T. (Aldi T.), Cartwright, J. H. (James H.), Hellwege, J. N. (Jacklyn N.), Giri, A. (Ayush), Tragante, V. (Vinicius), Thorleifsson, G. (Gudmar), Liu, D. J. (Dajiang J.), Prins, B. P. (Bram P.), Stewart, I. D. (Isobel D.), Cabrera, C. P. (Claudia P.), Eales, J. M. (James M.), Akbarov, A. (Artur), Auer, P. L. (Paul L.), Bielak, L. F. (Lawrence F.), Bis, J. C. (Joshua C.), Braithwaite, V. S. (Vickie S.), Brody, J. A. (Jennifer A.), Daw, E. W. (E. Warwick), Warren, H. R. (Helen R.), Drenos, F. (Fotios), Nielsen, S. F. (Sune Fallgaard), Faul, J. D. (Jessica D.), Fauman, E. B. (Eric B.), Fava, C. (Cristiano), Ferreira, T. (Teresa), Foley, C. N. (Christopher N.), Franceschini, N. (Nora), Gao, H. (He), Giannakopoulou, O. (Olga), Giulianini, F. (Franco), Gudbjartsson, D. F. (Daniel F.), Guo, X. (Xiuqing), Harris, S. E. (Sarah E.), Havulinna, A. S. (Aki S.), Helgadottir, A. (Anna), Huffman, J. E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Kanoni, S. (Stavroula), Kontto, J. (Jukka), Larson, M. G. (Martin G.), Li-Gao, R. (Ruifang), Lindstrom, J. (Jaana), Lotta, L. A. (Luca A.), Lu, Y. (Yingchang), Luan, J. (Jian'an), Mahajan, A. (Anubha), Malerba, G. (Giovanni), Masca, N. G. (Nicholas G. D.), Mei, H. (Hao), Menni, C. (Cristina), Mook-Kanamori, D. O. (Dennis O.), Mosen-Ansorena, D. (David), Muller-Nurasyid, M. (Martina), Pare, G. (Guillaume), Paul, D. S. (Dirk S.), Perola, M. (Markus), Poveda, A. (Alaitz), Rauramaa, R. (Rainer), Richard, M. (Melissa), Richardson, T. G. (Tom G.), Sepulveda, N. (Nuno), Sim, X. (Xueling), Smith, A. V. (Albert, V), Smith, J. A. (Jennifer A.), Staley, J. R. (James R.), Stanakova, A. (Alena), Sulem, P. (Patrick), Theriault, S. (Sebastien), Thorsteinsdottir, U. (Unnur), Trompet, S. (Stella), Varga, T. V. (Tibor V.), Edwards, D. R. (Digna R. Velez), Veronesi, G. (Giovanni), Weiss, S. (Stefan), Willems, S. M. (Sara M.), Yao, J. (Jie), Young, R. (Robin), Yu, B. (Bing), Zhang, W. (Weihua), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Evangelou, E. (Evangelos), Aeschbacher, S. (Stefanie), Asllanaj, E. (Eralda), Blankenberg, S. (Stefan), Bonnycastle, L. L. (Lori L.), Bork-Jensen, J. (Jette), Brandslund, I. (Ivan), Braund, P. S. (Peter S.), Burgess, S. (Stephen), Cho, K. (Kelly), Christensen, C. (Cramer), Connell, J. (John), de Mutsert, R. (Renee), Dominiczak, A. F. (Anna F.), Dorr, M. (Marcus), Eiriksdottir, G. (Gudny), Farmaki, A.-E. (Aliki-Eleni), Gaziano, J. M. (J. Michael), Grarup, N. (Niels), Grove, M. L. (Megan L.), Hallmans, G. (Goran), Hansen, T. (Torben), Have, C. T. (Christian T.), Heiss, G. (Gerardo), Jorgensen, M. E. (Marit E.), Jousilahti, P. (Pekka), Kajantie, E. (Eero), Kamat, M. (Mihir), Karajamaki, A. (AnneMari), Karpe, F. (Fredrik), Koistinen, H. A. (Heikki A.), Kovesdy, C. P. (Csaba P.), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Lannfelt, L. (Lars), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Linneberg, A. (Allan), Martin, L. W. (Lisa W.), Moitry, M. (Marie), Nadkarni, G. (Girish), Neville, M. J. (Matt J.), Palmer, C. N. (Colin N. A.), Papanicolaou, G. J. (George J.), Pedersen, O. (Oluf), Peters, J. (James), Poulter, N. (Neil), Rasheed, A. (Asif), Rasmussen, K. L. (Katrine L.), Rayner, N. W. (N. William), Magi, R. (Reedik), Renstrom, F. (Frida), Rettig, R. (Rainer), Rossouw, J. (Jacques), Schreiner, P. J. (Pamela J.), Sever, P. S. (Peter S.), Sigurdsson, E. L. (Emil L.), Skaaby, T. (Tea), Sun, Y. V. (Yan, V), Sundstrom, J. (Johan), Thorgeirsson, G. (Gudmundur), Esko, T. (Tonu), Trabetti, E. (Elisabetta), Tsao, P. S. (Philip S.), Tuomi, T. (Tiinamaija), Turner, S. T. (Stephen T.), Tzoulaki, I. (Ioanna), Vaartjes, I. (Ilonca), Vergnaud, A.-C. (Anne-Claire), Willer, C. J. (Cristen J.), Wilson, P. W. (Peter W. F.), Witte, D. R. (Daniel R.), Yonova-Doing, E. (Ekaterina), Zhang, H. (He), Aliya, N. (Naheed), Almgren, P. (Peter), Amouyel, P. (Philippe), Asselbergs, F. W. (Folkert W.), Barnes, M. R. (Michael R.), Blakemore, A. I. (Alexandra, I), Boehnke, M. (Michael), Bots, M. L. (Michiel L.), Bottinger, E. P. (Erwin P.), Buring, J. E. (Julie E.), Chambers, J. C. (John C.), Chen, Y. I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Conen, D. (David), Correa, A. (Adolfo), Smith, G. D. (George Davey), de Boer, R. A. (Rudolf A.), Deary, I. J. (Ian J.), Dedoussis, G. (George), Deloukas, P. (Panos), Di Angelantonio, E. (Emanuele), Elliott, P. (Paul), Felix, S. B. (Stephan B.), Ferrieres, J. (Jean), Ford, I. (Ian), Fornage, M. (Myriam), Franks, P. W. (Paul W.), Franks, S. (Stephen), Frossard, P. (Philippe), Gambaro, G. (Giovanni), Gaunt, T. R. (Tom R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Harris, T. B. (Tamara B.), Hayward, C. (Caroline), Hennig, B. J. (Branwen J.), Herzig, K.-H. (Karl-Heinz), Ingelsson, E. (Erik), Tuomilehto, J. (Jaakko), Järvelin, M.-R. (Marjo-Riitta), Jukema, J. W. (J. Wouter), Kardia, S. L. (Sharon L. R.), Kee, F. (Frank), Kooner, J. S. (Jaspal S.), Kooperberg, C. (Charles), Launer, L. J. (Lenore J.), Lind, L. (Lars), Loos, R. J. (Ruth J. F.), Majumder, A. A. (Abdulla Al Shafi), Laakso, M. (Markku), McCarthy, M. I. (Mark, I), Melander, O. (Olle), Mohlke, K. L. (Karen L.), Murray, A. D. (Alison D.), Nordestgaard, B. G. (Borge Gronne), Orho-Melander, M. (Marju), Packard, C. J. (Chris J.), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Polasek, O. (Ozren), Porteous, D. J. (David J.), Prentice, A. M. (Andrew M.), Province, M. A. (Michael A.), Relton, C. L. (Caroline L.), Rice, K. (Kenneth), Ridker, P. M. (Paul M.), Rolandsson, O. (Olov), Rosendaal, F. R. (Frits R.), Rotter, J. I. (Jerome, I), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N. J. (Nilesh J.), Sattar, N. (Naveed), Sheu, W. H. (Wayne H-H), Smith, B. H. (Blair H.), Soranzo, N. (Nicole), Spector, T. D. (Timothy D.), Starr, J. M. (John M.), Sebert, S. (Sylvain), Taylor, K. D. (Kent D.), Lakka, T. A. (Timo A.), Timpson, N. J. (Nicholas J.), Tobin, M. D. (Martin D.), van der Harst, P. (Pim), van der Meer, P. (Peter), Ramachandran, V. S. (Vasan S.), Verweij, N. (Niek), Virtamo, J. (Jarmo), Volker, U. (Uwe), Weir, D. R. (David R.), Zeggini, E. (Eleftheria), Charchar, F. J. (Fadi J.), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Tomaszewski, M. (Maciej), Butterworth, A. S. (Adam S.), Caulfield, M. J. (Mark J.), Danesh, J. (John), Edwards, T. L. (Todd L.), Holm, H. (Hilma), Hung, A. M. (Adriana M.), Lindgren, C. M. (Cecilia M.), Liu, C. (Chunyu), Manning, A. K. (Alisa K.), Morris, A. P. (Andrew P.), Morrison, A. C. (Alanna C.), O'Donnell, C. J. (Christopher J.), Psaty, B. M. (Bruce M.), Saleheen, D. (Danish), Stefansson, K. (Kari), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel, I), Levy, D. (Daniel), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), Howson, J. M. (Joanna M. M.), Surendran, P. (Praveen), Feofanova, E. V. (Elena, V), Lahrouchi, N. (Najim), Ntalla, I. (Ioanna), Karthikeyan, S. (Savita), Cook, J. (James), Chen, L. (Lingyan), Mifsud, B. (Borbala), Yao, C. (Chen), Kraja, A. T. (Aldi T.), Cartwright, J. H. (James H.), Hellwege, J. N. (Jacklyn N.), Giri, A. (Ayush), Tragante, V. (Vinicius), Thorleifsson, G. (Gudmar), Liu, D. J. (Dajiang J.), Prins, B. P. (Bram P.), Stewart, I. D. (Isobel D.), Cabrera, C. P. (Claudia P.), Eales, J. M. (James M.), Akbarov, A. (Artur), Auer, P. L. (Paul L.), Bielak, L. F. (Lawrence F.), Bis, J. C. (Joshua C.), Braithwaite, V. S. (Vickie S.), Brody, J. A. (Jennifer A.), Daw, E. W. (E. Warwick), Warren, H. R. (Helen R.), Drenos, F. (Fotios), Nielsen, S. F. (Sune Fallgaard), Faul, J. D. (Jessica D.), Fauman, E. B. (Eric B.), Fava, C. (Cristiano), Ferreira, T. (Teresa), Foley, C. N. (Christopher N.), Franceschini, N. (Nora), Gao, H. (He), Giannakopoulou, O. (Olga), Giulianini, F. (Franco), Gudbjartsson, D. F. (Daniel F.), Guo, X. (Xiuqing), Harris, S. E. (Sarah E.), Havulinna, A. S. (Aki S.), Helgadottir, A. (Anna), Huffman, J. E. (Jennifer E.), Hwang, S.-J. (Shih-Jen), Kanoni, S. (Stavroula), Kontto, J. (Jukka), Larson, M. G. (Martin G.), Li-Gao, R. (Ruifang), Lindstrom, J. (Jaana), Lotta, L. A. (Luca A.), Lu, Y. (Yingchang), Luan, J. (Jian'an), Mahajan, A. (Anubha), Malerba, G. (Giovanni), Masca, N. G. (Nicholas G. D.), Mei, H. (Hao), Menni, C. (Cristina), Mook-Kanamori, D. O. (Dennis O.), Mosen-Ansorena, D. (David), Muller-Nurasyid, M. (Martina), Pare, G. (Guillaume), Paul, D. S. (Dirk S.), Perola, M. (Markus), Poveda, A. (Alaitz), Rauramaa, R. (Rainer), Richard, M. (Melissa), Richardson, T. G. (Tom G.), Sepulveda, N. (Nuno), Sim, X. (Xueling), Smith, A. V. (Albert, V), Smith, J. A. (Jennifer A.), Staley, J. R. (James R.), Stanakova, A. (Alena), Sulem, P. (Patrick), Theriault, S. (Sebastien), Thorsteinsdottir, U. (Unnur), Trompet, S. (Stella), Varga, T. V. (Tibor V.), Edwards, D. R. (Digna R. Velez), Veronesi, G. (Giovanni), Weiss, S. (Stefan), Willems, S. M. (Sara M.), Yao, J. (Jie), Young, R. (Robin), Yu, B. (Bing), Zhang, W. (Weihua), Zhao, J.-H. (Jing-Hua), Zhao, W. (Wei), Evangelou, E. (Evangelos), Aeschbacher, S. (Stefanie), Asllanaj, E. (Eralda), Blankenberg, S. (Stefan), Bonnycastle, L. L. (Lori L.), Bork-Jensen, J. (Jette), Brandslund, I. (Ivan), Braund, P. S. (Peter S.), Burgess, S. (Stephen), Cho, K. (Kelly), Christensen, C. (Cramer), Connell, J. (John), de Mutsert, R. (Renee), Dominiczak, A. F. (Anna F.), Dorr, M. (Marcus), Eiriksdottir, G. (Gudny), Farmaki, A.-E. (Aliki-Eleni), Gaziano, J. M. (J. Michael), Grarup, N. (Niels), Grove, M. L. (Megan L.), Hallmans, G. (Goran), Hansen, T. (Torben), Have, C. T. (Christian T.), Heiss, G. (Gerardo), Jorgensen, M. E. (Marit E.), Jousilahti, P. (Pekka), Kajantie, E. (Eero), Kamat, M. (Mihir), Karajamaki, A. (AnneMari), Karpe, F. (Fredrik), Koistinen, H. A. (Heikki A.), Kovesdy, C. P. (Csaba P.), Kuulasmaa, K. (Kari), Laatikainen, T. (Tiina), Lannfelt, L. (Lars), Lee, I.-T. (I-Te), Lee, W.-J. (Wen-Jane), Linneberg, A. (Allan), Martin, L. W. (Lisa W.), Moitry, M. (Marie), Nadkarni, G. (Girish), Neville, M. J. (Matt J.), Palmer, C. N. (Colin N. A.), Papanicolaou, G. J. (George J.), Pedersen, O. (Oluf), Peters, J. (James), Poulter, N. (Neil), Rasheed, A. (Asif), Rasmussen, K. L. (Katrine L.), Rayner, N. W. (N. William), Magi, R. (Reedik), Renstrom, F. (Frida), Rettig, R. (Rainer), Rossouw, J. (Jacques), Schreiner, P. J. (Pamela J.), Sever, P. S. (Peter S.), Sigurdsson, E. L. (Emil L.), Skaaby, T. (Tea), Sun, Y. V. (Yan, V), Sundstrom, J. (Johan), Thorgeirsson, G. (Gudmundur), Esko, T. (Tonu), Trabetti, E. (Elisabetta), Tsao, P. S. (Philip S.), Tuomi, T. (Tiinamaija), Turner, S. T. (Stephen T.), Tzoulaki, I. (Ioanna), Vaartjes, I. (Ilonca), Vergnaud, A.-C. (Anne-Claire), Willer, C. J. (Cristen J.), Wilson, P. W. (Peter W. F.), Witte, D. R. (Daniel R.), Yonova-Doing, E. (Ekaterina), Zhang, H. (He), Aliya, N. (Naheed), Almgren, P. (Peter), Amouyel, P. (Philippe), Asselbergs, F. W. (Folkert W.), Barnes, M. R. (Michael R.), Blakemore, A. I. (Alexandra, I), Boehnke, M. (Michael), Bots, M. L. (Michiel L.), Bottinger, E. P. (Erwin P.), Buring, J. E. (Julie E.), Chambers, J. C. (John C.), Chen, Y. I. (Yii-Der Ida), Chowdhury, R. (Rajiv), Conen, D. (David), Correa, A. (Adolfo), Smith, G. D. (George Davey), de Boer, R. A. (Rudolf A.), Deary, I. J. (Ian J.), Dedoussis, G. (George), Deloukas, P. (Panos), Di Angelantonio, E. (Emanuele), Elliott, P. (Paul), Felix, S. B. (Stephan B.), Ferrieres, J. (Jean), Ford, I. (Ian), Fornage, M. (Myriam), Franks, P. W. (Paul W.), Franks, S. (Stephen), Frossard, P. (Philippe), Gambaro, G. (Giovanni), Gaunt, T. R. (Tom R.), Groop, L. (Leif), Gudnason, V. (Vilmundur), Harris, T. B. (Tamara B.), Hayward, C. (Caroline), Hennig, B. J. (Branwen J.), Herzig, K.-H. (Karl-Heinz), Ingelsson, E. (Erik), Tuomilehto, J. (Jaakko), Järvelin, M.-R. (Marjo-Riitta), Jukema, J. W. (J. Wouter), Kardia, S. L. (Sharon L. R.), Kee, F. (Frank), Kooner, J. S. (Jaspal S.), Kooperberg, C. (Charles), Launer, L. J. (Lenore J.), Lind, L. (Lars), Loos, R. J. (Ruth J. F.), Majumder, A. A. (Abdulla Al Shafi), Laakso, M. (Markku), McCarthy, M. I. (Mark, I), Melander, O. (Olle), Mohlke, K. L. (Karen L.), Murray, A. D. (Alison D.), Nordestgaard, B. G. (Borge Gronne), Orho-Melander, M. (Marju), Packard, C. J. (Chris J.), Padmanabhan, S. (Sandosh), Palmas, W. (Walter), Polasek, O. (Ozren), Porteous, D. J. (David J.), Prentice, A. M. (Andrew M.), Province, M. A. (Michael A.), Relton, C. L. (Caroline L.), Rice, K. (Kenneth), Ridker, P. M. (Paul M.), Rolandsson, O. (Olov), Rosendaal, F. R. (Frits R.), Rotter, J. I. (Jerome, I), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N. J. (Nilesh J.), Sattar, N. (Naveed), Sheu, W. H. (Wayne H-H), Smith, B. H. (Blair H.), Soranzo, N. (Nicole), Spector, T. D. (Timothy D.), Starr, J. M. (John M.), Sebert, S. (Sylvain), Taylor, K. D. (Kent D.), Lakka, T. A. (Timo A.), Timpson, N. J. (Nicholas J.), Tobin, M. D. (Martin D.), van der Harst, P. (Pim), van der Meer, P. (Peter), Ramachandran, V. S. (Vasan S.), Verweij, N. (Niek), Virtamo, J. (Jarmo), Volker, U. (Uwe), Weir, D. R. (David R.), Zeggini, E. (Eleftheria), Charchar, F. J. (Fadi J.), Wareham, N. J. (Nicholas J.), Langenberg, C. (Claudia), Tomaszewski, M. (Maciej), Butterworth, A. S. (Adam S.), Caulfield, M. J. (Mark J.), Danesh, J. (John), Edwards, T. L. (Todd L.), Holm, H. (Hilma), Hung, A. M. (Adriana M.), Lindgren, C. M. (Cecilia M.), Liu, C. (Chunyu), Manning, A. K. (Alisa K.), Morris, A. P. (Andrew P.), Morrison, A. C. (Alanna C.), O'Donnell, C. J. (Christopher J.), Psaty, B. M. (Bruce M.), Saleheen, D. (Danish), Stefansson, K. (Kari), Boerwinkle, E. (Eric), Chasman, D. I. (Daniel, I), Levy, D. (Daniel), Newton-Cheh, C. (Christopher), Munroe, P. B. (Patricia B.), and Howson, J. M. (Joanna M. M.)

Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 x 10(⁻⁸)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets., Correction A Publisher Correction to this article was published on 16 March 2021.

Published
2020

7. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Author

Kupers, L. K. (Leanne K.), Monnereau, C. (Claire), Sharp, G. C. (Gemma C.), Yousefi, P. (Paul), Salas, L. A. (Lucas A.), Ghantous, A. (Akram), Page, C. M. (Christian M.), Reese, S. E. (Sarah E.), Wilcox, A. J. (Allen J.), Czamara, D. (Darina), Starling, A. P. (Anne P.), Novoloaca, A. (Alexei), Lent, S. (Samantha), Roy, R. (Ritu), Hoyo, C. (Cathrine), Breton, C. V. (Carrie, V), Allard, C. (Catherine), Just, A. C. (Allan C.), Bakulski, K. M. (Kelly M.), Holloway, J. W. (John W.), Everson, T. M. (Todd M.), Xu, C.-J. (Cheng-Jian), Huang, R.-C. (Rae-Chi), van der Plaat, D. A. (Diana A.), Wielscher, M. (Matthias), Merid, S. K. (Simon Kebede), Ullemar, V. (Vilhelmina), Rezwan, F. I. (Faisal, I), Lahti, J. (Jari), van Dongen, J. (Jenny), Langie, S. A. (Sabine A. S.), Richardson, T. G. (Tom G.), Magnus, M. C. (Maria C.), Nohr, E. A. (Ellen A.), Xu, Z. (Zongli), Duijts, L. (Liesbeth), Zhao, S. (Shanshan), Zhang, W. (Weiming), Plusquin, M. (Michelle), DeMeo, D. L. (Dawn L.), Solomon, O. (Olivia), Heimovaara, J. H. (Joosje H.), Jima, D. D. (Dereje D.), Gao, L. (Lu), Bustamante, M. (Mariona), Perron, P. (Patrice), Wright, R. O. (Robert O.), Hertz-Picciotto, I. (Irva), Zhang, H. (Hongmei), Karagas, M. R. (Margaret R.), Gehring, U. (Ulrike), Marsit, C. J. (Carmen J.), Beilin, L. J. (Lawrence J.), Vonk, J. M. (Judith M.), Jarvelin, M.-R. (Marjo-Riitta), Bergstrom, A. (Anna), Ortqvist, A. K. (Anne K.), Ewart, S. (Susan), Villa, P. M. (Pia M.), Moore, S. E. (Sophie E.), Willemsen, G. (Gonneke), Standaert, A. R. (Arnout R. L.), Haberg, S. E. (Siri E.), Sorensen, T. I. (Thorkild I. A.), Taylor, J. A. (Jack A.), Raikkonen, K. (Katri), Yang, I. V. (Ivana, V), Kechris, K. (Katerina), Nawrot, T. S. (Tim S.), Silver, M. J. (Matt J.), Gong, Y. Y. (Yun Yun), Richiardi, L. (Lorenzo), Kogevinas, M. (Manolis), Litonjua, A. A. (Augusto A.), Eskenazi, B. (Brenda), Huen, K. (Karen), Mbarek, H. (Hamdi), Maguire, R. L. (Rachel L.), Dwyer, T. (Terence), Vrijheid, M. (Martine), Bouchard, L. (Luigi), Baccarelli, A. A. (Andrea A.), Croen, L. A. (Lisa A.), Karmaus, W. (Wilfried), Anderson, D. (Denise), de Vries, M. (Maaike), Sebert, S. (Sylvain), Kere, J. (Juha), Karlsson, R. (Robert), Arshad, S. H. (Syed Hasan), Hamalainen, E. (Esa), Routledge, M. N. (Michael N.), Boomsma, D. I. (Dorret, I), Feinberg, A. P. (Andrew P.), Newschaffer, C. J. (Craig J.), Govarts, E. (Eva), Moisse, M. (Matthieu), Fallin, M. D. (M. Daniele), Melen, E. (Erik), Prentice, A. M. (Andrew M.), Kajantie, E. (Eero), Almqvist, C. (Catarina), Oken, E. (Emily), Dabelea, D. (Dana), Boezen, H. M. (H. Marike), Melton, P. E. (Phillip E.), Wright, R. J. (Rosalind J.), Koppelman, G. H. (Gerard H.), Trevisi, L. (Letizia), Hivert, M.-F. (Marie-France), Sunyer, J. (Jordi), Munthe-Kaas, M. C. (Monica C.), Murphy, S. K. (Susan K.), Corpeleijn, E. (Eva), Wiemels, J. (Joseph), Holland, N. (Nina), Herceg, Z. (Zdenko), Binder, E. B. (Elisabeth B.), Smith, G. D. (George Davey), Jaddoe, V. W. (Vincent W. V.), Lie, R. T. (Rolv T.), Nystad, W. (Wenche), London, S. J. (Stephanie J.), Lawlor, D. A. (Debbie A.), Relton, C. L. (Caroline L.), Snieder, H. (Harold), Felix, J. F. (Janine F.), Kupers, L. K. (Leanne K.), Monnereau, C. (Claire), Sharp, G. C. (Gemma C.), Yousefi, P. (Paul), Salas, L. A. (Lucas A.), Ghantous, A. (Akram), Page, C. M. (Christian M.), Reese, S. E. (Sarah E.), Wilcox, A. J. (Allen J.), Czamara, D. (Darina), Starling, A. P. (Anne P.), Novoloaca, A. (Alexei), Lent, S. (Samantha), Roy, R. (Ritu), Hoyo, C. (Cathrine), Breton, C. V. (Carrie, V), Allard, C. (Catherine), Just, A. C. (Allan C.), Bakulski, K. M. (Kelly M.), Holloway, J. W. (John W.), Everson, T. M. (Todd M.), Xu, C.-J. (Cheng-Jian), Huang, R.-C. (Rae-Chi), van der Plaat, D. A. (Diana A.), Wielscher, M. (Matthias), Merid, S. K. (Simon Kebede), Ullemar, V. (Vilhelmina), Rezwan, F. I. (Faisal, I), Lahti, J. (Jari), van Dongen, J. (Jenny), Langie, S. A. (Sabine A. S.), Richardson, T. G. (Tom G.), Magnus, M. C. (Maria C.), Nohr, E. A. (Ellen A.), Xu, Z. (Zongli), Duijts, L. (Liesbeth), Zhao, S. (Shanshan), Zhang, W. (Weiming), Plusquin, M. (Michelle), DeMeo, D. L. (Dawn L.), Solomon, O. (Olivia), Heimovaara, J. H. (Joosje H.), Jima, D. D. (Dereje D.), Gao, L. (Lu), Bustamante, M. (Mariona), Perron, P. (Patrice), Wright, R. O. (Robert O.), Hertz-Picciotto, I. (Irva), Zhang, H. (Hongmei), Karagas, M. R. (Margaret R.), Gehring, U. (Ulrike), Marsit, C. J. (Carmen J.), Beilin, L. J. (Lawrence J.), Vonk, J. M. (Judith M.), Jarvelin, M.-R. (Marjo-Riitta), Bergstrom, A. (Anna), Ortqvist, A. K. (Anne K.), Ewart, S. (Susan), Villa, P. M. (Pia M.), Moore, S. E. (Sophie E.), Willemsen, G. (Gonneke), Standaert, A. R. (Arnout R. L.), Haberg, S. E. (Siri E.), Sorensen, T. I. (Thorkild I. A.), Taylor, J. A. (Jack A.), Raikkonen, K. (Katri), Yang, I. V. (Ivana, V), Kechris, K. (Katerina), Nawrot, T. S. (Tim S.), Silver, M. J. (Matt J.), Gong, Y. Y. (Yun Yun), Richiardi, L. (Lorenzo), Kogevinas, M. (Manolis), Litonjua, A. A. (Augusto A.), Eskenazi, B. (Brenda), Huen, K. (Karen), Mbarek, H. (Hamdi), Maguire, R. L. (Rachel L.), Dwyer, T. (Terence), Vrijheid, M. (Martine), Bouchard, L. (Luigi), Baccarelli, A. A. (Andrea A.), Croen, L. A. (Lisa A.), Karmaus, W. (Wilfried), Anderson, D. (Denise), de Vries, M. (Maaike), Sebert, S. (Sylvain), Kere, J. (Juha), Karlsson, R. (Robert), Arshad, S. H. (Syed Hasan), Hamalainen, E. (Esa), Routledge, M. N. (Michael N.), Boomsma, D. I. (Dorret, I), Feinberg, A. P. (Andrew P.), Newschaffer, C. J. (Craig J.), Govarts, E. (Eva), Moisse, M. (Matthieu), Fallin, M. D. (M. Daniele), Melen, E. (Erik), Prentice, A. M. (Andrew M.), Kajantie, E. (Eero), Almqvist, C. (Catarina), Oken, E. (Emily), Dabelea, D. (Dana), Boezen, H. M. (H. Marike), Melton, P. E. (Phillip E.), Wright, R. J. (Rosalind J.), Koppelman, G. H. (Gerard H.), Trevisi, L. (Letizia), Hivert, M.-F. (Marie-France), Sunyer, J. (Jordi), Munthe-Kaas, M. C. (Monica C.), Murphy, S. K. (Susan K.), Corpeleijn, E. (Eva), Wiemels, J. (Joseph), Holland, N. (Nina), Herceg, Z. (Zdenko), Binder, E. B. (Elisabeth B.), Smith, G. D. (George Davey), Jaddoe, V. W. (Vincent W. V.), Lie, R. T. (Rolv T.), Nystad, W. (Wenche), London, S. J. (Stephanie J.), Lawlor, D. A. (Debbie A.), Relton, C. L. (Caroline L.), Snieder, H. (Harold), and Felix, J. F. (Janine F.)

Abstract

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

Published
2019

8. DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

Author

Wiklund, P. (Petri), Karhunen, V. (Ville), Richmond, R. C. (Rebecca C.), Parmar, P. (Priyanka), Rodriguez, A. (Alina), De Silva, M. (Maneka), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Richardson, T. G. (Tom G.), Veijola, J. (Juha), Herzig, K.-H. (Karl-Heinz), Holloway, J. W. (John W.), Relton, C. L. (Caroline L.), Sebert, S. (Sylvain), Järvelin, M.-R. (Marjo-Riitta), Wiklund, P. (Petri), Karhunen, V. (Ville), Richmond, R. C. (Rebecca C.), Parmar, P. (Priyanka), Rodriguez, A. (Alina), De Silva, M. (Maneka), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Richardson, T. G. (Tom G.), Veijola, J. (Juha), Herzig, K.-H. (Karl-Heinz), Holloway, J. W. (John W.), Relton, C. L. (Caroline L.), Sebert, S. (Sylvain), and Järvelin, M.-R. (Marjo-Riitta)

Abstract

Background: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. Methods: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. Results: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10⁻⁷) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. Conclusions: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

Published
2019

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