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1. The association between long-term conditions and uptake of population-based screening for colorectal cancer: results from two English cohort studies

Author

Kearns B, Chilcott J, Relton C, Whyte S, Woods HB, Nickerson C, and Loban A

Subjects
Colorectal cancer, faecal occult blood test, population screening, uptake, depression, anxiety, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Benjamin Kearns,1 Jim Chilcott,1 Clare Relton,1 Sophie Whyte,1 Helen Buckley Woods,1 Claire Nickerson,2 Amanda Loban1 1School of Health and Related Research, University of Sheffield, Sheffield, UK; 2Cancer Screening Programmes, Public Health England, Sheffield, UK Introduction: Uptake of screening for colorectal cancer (CRC) can reduce mortality, and population-based screening is offered in England. To date, there is little evidence on the association between having a long-term condition (LTC) and CRC screening uptake. The objective of this study was to examine the association between having an LTC and uptake of CRC screening in England with the guaiac fecal occult blood test, with a particular focus on common mental disorders.Methods: The study was a preregistered secondary analysis of two cohorts: first, a linked data set between the regional Yorkshire Health Study (YHS) and the National Health Service National Bowel Cancer Screening Program (BCSP, years 2006–2014); second, the national English Longitudinal Study of Ageing (ELSA, years 2014–2015). Individuals eligible for BCSP screening who participated in either the YHS (7,142) or ELSA Wave 7 (4,099) were included. Study registration: ClinicalTrials.gov, number NCT02503969.Results: In both the cohorts, diabetes was associated with lower uptake (YHS odds ratio [OR] for non-uptake 1.35, 95% CI 1.03–1.78; ELSA 1.33, 1.03–1.72) and osteoarthritis was associated with increased uptake (YHS 0.75, 0.57–0.99; ELSA 0.76, 0.62–0.93). After controlling for broader determinants of health, there was no evidence of significantly different uptake for individuals with common mental disorders.Conclusion: Two large independent cohorts provided evidence that uptake of CRC screening is lower among individuals with diabetes and higher among individuals with osteoarthritis. Further work should compare barriers and facilitators to screening among individuals with either of these conditions. This study also demonstrates the benefits of data linkage for improving clinical decision-making. Keywords: colorectal cancer, fecal occult blood test, population screening, uptake, depression, anxiety

Published
2018

2. Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects

Author

Christiansen, C., Castillo-Fernandez, J. E., Domingo-Relloso, A., Zhao, W., El-Sayed Moustafa, J. S., Tsai, P.-C., Maddock, J., Haack, K., Cole, S. A., Kardia, S. L. R., Molokhia, M., Suderman, M., Power, C., Relton, C., Wong, A., Kuh, D., Goodman, A., Small, K. S., Smith, J. A., Tellez-Plaza, M., Navas-Acien, A., Ploubidis, G. B., Hardy, R., and Bell, J. T.

Published
2021
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4. Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3)

Author

Zuo, H., Ueland, P.M., Midttun, Ø, Tell, G.S., Fanidi, A., Zheng, W., Shu, X., Xiang, Y., Wu, J., Prentice, R., Pettinger, M., Thomson, C.A., Giles, G.G., Hodge, A., Cai, Q., Blot, W.J., Johansson, M., Hultdin, J., Grankvist, K., Stevens, V.L., McCullough, M.L., Weinstein, S.J., Albanes, D., Ziegler, R.G., Freedman, N.D., Caporaso, N.E., Langhammer, A., Hveem, K., Næss, M., Buring, J.E., Lee, I., Gaziano, J.M., Severi, G., Zhang, X., Stampfer, M.J., Han, J., Zeleniuch-Jacquotte, A., Marchand, L.L., Yuan, J., Wang, R., Koh, W., Gao, Y., Ericson, U., Visvanathan, K., Jones, M.R., Relton, C., Brennan, P., and Ulvik, A.

Published
2019
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7. Analysis of Systemic Epigenetic Alterations in Inflammatory Bowel Disease: Defining Geographical, Genetic and Immune-Inflammatory influences on the Circulating Methylome

Author

Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Nowak, J. K., Bergemalm, D., Vatn, S., Ventham, N. A., Kennedy, N. A., Ricanek, P., Lindstrom, J., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Richmond, R., Relton, C. L., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.

Abstract

Background Epigenetic alterations may provide valuable insights into gene-environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohns disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [p = 9.11 x 10(-15)] and RPS6KA2 [6.43 x 10(-13)], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [p = 1.53 x 10(-15)]. Age acceleration is seen in IBD [coefficient 0.94, p < 2.2 x 10(-16)]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = -0.32, p = 3.64 x 10(-7) vs non-IBD r = -0.14, p = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [TAP1, TESPA1, RPTOR] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14-12.56], logrank p = 9.70 x 10(-4)). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease., Funding Agencies|European Commission [2858546]; Wellcome Trust [WT097943MA]

Published
2023
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13. An epigenome-wide association study meta-analysis of educational attainment

Author

Linnér, R Karlsson, Marioni, R E, Rietveld, C A, Simpkin, A J, Davies, N M, Watanabe, K, Armstrong, N J, Auro, K, Baumbach, C, Bonder, M J, Buchwald, J, Fiorito, G, Ismail, K, Iurato, S, Joensuu, A, Karell, P, Kasela, S, Lahti, J, McRae, A F, Mandaviya, P R, Seppälä, I, Wang, Y, Baglietto, L, Binder, E B, Harris, S E, Hodge, A M, Horvath, S, Hurme, M, Johannesson, M, Latvala, A, Mather, K A, Medland, S E, Metspalu, A, Milani, L, Milne, R L, Pattie, A, Pedersen, N L, Peters, A, Polidoro, S, Räikkönen, K, Severi, G, Starr, J M, Stolk, L, Waldenberger, M, Consortium, B IOS, Eriksson, J G, Esko, T, Franke, L, Gieger, C, Giles, G G, Hägg, S, Jousilahti, P, Kaprio, J, Kähönen, M, Lehtimäki, T, Martin, N G, van Meurs, J BC, Ollikainen, M, Perola, M, Posthuma, D, Raitakari, O T, Sachdev, P S, Taskesen, E, Uitterlinden, A G, Vineis, P, Wijmenga, C, Wright, M J, Relton, C, Smith, G Davey, Deary, I J, Koellinger, P D, and Benjamin, D J

Published
2017
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16. Fresh street: the development and feasibility of a place-based, subsidy for fresh fruit and vegetables

Author

Relton, C., Crowder, M., Blake, M., and Strong, M.

Abstract

Background\ud \ud Many UK communities experience food insecurity, and consume diets high in energy-dense, nutrient poor, processed foods and low in fruit and vegetables (FV). We explored a novel area-based approach to promote FV consumption and healthy eating in one such community.\ud \ud \ud Methods\ud \ud We developed a weekly subsidy scheme for fresh FV with key local stakeholders in an area of socioeconomic deprivation in Northern England. The scheme (Fresh Street) offered five £1 vouchers to every household, regardless of income or household type. Vouchers were redeemable with local suppliers of fresh FV (not supermarkets). The feasibility of the scheme was assessed in four streets using rapid ethnographic assessment and voucher redemption information.\ud \ud \ud Results\ud \ud Local councillors and public health teams were supportive of the scheme. Most eligible households joined the scheme (n = 80/97, 83%), and 89.3% (17 849/19 982) of vouchers issued were redeemed. Householders reported that the scheme made them think about what they were eating, and prompted them to buy and eat more FV.\ud \ud \ud Conclusions\ud \ud This feasibility study reported high levels of acceptance for a place-based, household-level weekly FV subsidy scheme. Further research is required to evaluate the effectiveness of this approach to creating healthy diets, eating behaviours and food systems.

Published
2022

17. Reporting transparency and completeness in trials: Paper 3 - Trials conducted using administrative databases do not adequately report elements related to use of databases

Author

Imran, M., McCord, K.A., McCall, S.J., Kwakkenbos, L., Sampson, M., Fröbert, O., Gale, C., Hemkens, L.G., Langan, S.M., Moher, D., Relton, C., Zwarenstein, M., Juszczak, E., Thombs, B.D., Imran, M., McCord, K.A., McCall, S.J., Kwakkenbos, L., Sampson, M., Fröbert, O., Gale, C., Hemkens, L.G., Langan, S.M., Moher, D., Relton, C., Zwarenstein, M., Juszczak, E., and Thombs, B.D.

Abstract

Item does not contain fulltext, Objective: We evaluated reporting completeness and transparency in randomised controlled trials (RCTs) conducted using administrative data based on 2021 CONSORT Extension for Trials Conducted Using Cohorts and Routinely Collected Data (CONSORT-ROUTINE) criteria. Study Design and Setting: MEDLINE and the Cochrane Methodology Register were searched (2011 and 2018). Eligible RCTs used administrative databases for identifying eligible participants or collecting outcomes. We evaluated reporting based on CONSORT-ROUTINE, which modified eight items from CONSORT 2010 and added five new items. Results: Of 33 included trials (76% used administrative databases for outcomes, 3% for identifying participants, 21% both), most were conducted in the United States (55%), Canada (18%), or the United Kingdom (12%). Of eight items modified in the extension; six were adequately reported in a majority (>50%) of trials. For the CONSORT-ROUTINE modification portion of those items, three items were reported adequately in >50% of trials, two in <50%, two only applied to some trials, and one only had wording modifications and was not evaluated. For five new items, four that address use of routine data in trials were reported inadequately in most trials. Conclusion: How administrative data are used in trials is often sub-optimally reported. CONSORT-ROUTINE uptake may improve reporting.

Published
2022

18. Reporting transparency and completeness in trials: Paper 2 - Reporting of randomised trials using registries was often inadequate and hindered the interpretation of results

Author

McCord, K.A., Imran, M., Rice, D.B., McCall, S.J., Kwakkenbos, L., Sampson, M., Fröbert, O., Gale, C., Langan, S.M., Moher, D., Relton, C., Zwarenstein, M., Juszczak, E., Thombs, B.D., McCord, K.A., Imran, M., Rice, D.B., McCall, S.J., Kwakkenbos, L., Sampson, M., Fröbert, O., Gale, C., Langan, S.M., Moher, D., Relton, C., Zwarenstein, M., Juszczak, E., and Thombs, B.D.

Abstract

Item does not contain fulltext, Objective: Registries are important data sources for randomised controlled trials (RCTs), but reporting of how they are used may be inadequate. The objective was to describe the current adequacy of reporting of RCTs using registries. Study Design and Setting: We used a database of trials using registries from a scoping review supporting the development of the 2021 CONSORT extension for Trials Conducted Using Cohorts and Routinely Collected Data (CONSORT-ROUTINE). Reporting completeness of 13 CONSORT-ROUTINE items was assessed. Results: We assessed reports of 47 RCTs that used a registry, published between 2011 and 2018. Of the 13 CONSORT-ROUTINE items, 6 were adequately reported in at least half of reports (2 in at least 80%). The 7 other items were related to routinely collected data source eligibility (32% adequate), data linkage (8% adequate), validation and completeness of data used for outcome assessment (8% adequate), validation and completeness of data used for participant recruitment (0% adequate), participant flow (9% adequate), registry funding (6% adequate) and interpretation of results in consideration of registry use (25% adequate). Conclusion: Reporting of trials using registries was often poor, particularly details on data linkage and quality. Better reporting is needed for appropriate interpretation of the results of these trials.

Published
2022

19. Reporting transparency and completeness in trials: Paper 4 - Reporting of randomised controlled trials conducted using routinely collected electronic records - room for improvement

Author

McCall, S.J., Imran, M., Hemkens, L.G., McCord, K.A., Kwakkenbos, L., Sampson, M., Jawad, S., Zwarenstein, M., Relton, C., Langan, S.M., Moher, D., Fröbert, O., Thombs, B.D., Gale, C., Juszczak, E., McCall, S.J., Imran, M., Hemkens, L.G., McCord, K.A., Kwakkenbos, L., Sampson, M., Jawad, S., Zwarenstein, M., Relton, C., Langan, S.M., Moher, D., Fröbert, O., Thombs, B.D., Gale, C., and Juszczak, E.

Abstract

Item does not contain fulltext, Objective: To describe characteristics of randomised controlled trials (RCTs) conducted using electronic health records (EHRs), including completeness and transparency of reporting assessed against the 2021 CONSORT Extension for RCTs Conducted Using Cohorts and Routinely Collected Data (CONSORT-ROUTINE) criteria. Study design: MEDLINE and Cochrane Methodology Register were searched for a sample of RCTs published from 2011–2018. Completeness of reporting was assessed in a random sample using a pre-defined coding form. Results 183 RCT publications were identified; 122 (67%) used EHRs to identify eligible participants, 139 (76%) used the EHR as part of the intervention and 137 (75%) to ascertain outcomes. When 60 publications were evaluated against the CONSORT 2010 item and the corresponding extension for the 8 modified items, four items were 'adequately reported' for the majority of trials. Five new reporting items were identified for the CONSORT-ROUTINE extension; when evaluated, one was 'adequately reported', three were reported 'inadequately or not at all', the other 'partially'. There were, however, some encouraging signs with adequate and partial reporting of many important items, including descriptions of trial design, the consent process, outcome ascertainment and interpretation. Conclusion: Aspects of RCTs using EHRs are sub-optimally reported. Uptake of the CONSORT-ROUTINE Extension may improve reporting.

Published
2022

20. Epigenetic Regulation of F2RL3 Associates With Myocardial Infarction and Platelet Function

Author

Corbin, LJ, White, SJ, Taylor, AE, Williams, CM, Taylor, K, van den Bosch, MT, Teasdale, JE, Jones, M, Bond, M, Harper, MT, Falk, L, Groom, A, Hazell, GGJ, Paternoster, L, Munafò, MR, Nordestgaard, BG, Tybjærg-Hansen, A, Bojesen, SE, Relton, C, Min, JL, Davey Smith, G, Mumford, AD, Poole, AW, Timpson, NJ, Corbin, LJ, White, SJ, Taylor, AE, Williams, CM, Taylor, K, van den Bosch, MT, Teasdale, JE, Jones, M, Bond, M, Harper, MT, Falk, L, Groom, A, Hazell, GGJ, Paternoster, L, Munafò, MR, Nordestgaard, BG, Tybjærg-Hansen, A, Bojesen, SE, Relton, C, Min, JL, Davey Smith, G, Mumford, AD, Poole, AW, and Timpson, NJ

Abstract

BACKGROUND: DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. METHODS: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. RESULTS: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2-2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. CONCLUSIONS: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evi

Published
2022

21. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

Author

Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, Holland, N, Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, and Holland, N

Abstract

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Published
2022

22. DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

Author

Wielscher, M. (Matthias), Mandaviya, P. R. (Pooja R.), Kuehnel, B. (Brigitte), Joehanes, R. (Roby), Mustafa, R. (Rima), Robinson, O. (Oliver), Zhang, Y. (Yan), Bodinier, B. (Barbara), Walton, E. (Esther), Mishra, P. P. (Pashupati P.), Schlosser, P. (Pascal), Wilson, R. (Rory), Tsai, P.-C. (Pei-Chien), Palaniswamy, S. (Saranya), Marioni, R. E. (Riccardo E.), Fiorito, G. (Giovanni), Cugliari, G. (Giovanni), Karhunen, V. (Ville), Ghanbari, M. (Mohsen), Psaty, B. M. (Bruce M.), Loh, M. (Marie), Bis, J. C. (Joshua C.), Lehne, B. (Benjamin), Sotoodehnia, N. (Nona), Deary, I. J. (Ian J.), Chadeau-Hyam, M. (Marc), Brody, J. A. (Jennifer A.), Cardona, A. (Alexia), Selvin, E. (Elizabeth), Smith, A. K. (Alicia K.), Miller, A. H. (Andrew H.), Torres, M. A. (Mylin A.), Marouli, E. (Eirini), Gao, X. (Xin), van Meurs, J. B. (Joyce B. J.), Graf-Schindler, J. (Johanna), Rathmann, W. (Wolfgang), Koenig, W. (Wolfgang), Peters, A. (Annette), Weninger, W. (Wolfgang), Farlik, M. (Matthias), Zhang, T. (Tao), Chen, W. (Wei), Xia, Y. (Yujing), Teumer, A. (Alexander), Nauck, M. (Matthias), Grabe, H. J. (Hans J.), Doerr, M. (Macus), Lehtimaki, T. (Terho), Guan, W. (Weihua), Milani, L. (Lili), Tanaka, T. (Toshiko), Fisher, K. (Krista), Waite, L. L. (Lindsay L.), Kasela, S. (Silva), Vineis, P. (Paolo), Verweij, N. (Niek), van der Harst, P. (Pim), Iacoviello, L. (Licia), Sacerdote, C. (Carlotta), Panico, S. (Salvatore), Krogh, V. (Vittorio), Tumino, R. (Rosario), Tzala, E. (Evangelia), Matullo, G. (Giuseppe), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Kahonen, M. (Mika), Herzig, K.-H. (Karl-Heinz), Li, S. (Shengxu), BIOS consortium, Conneely, K. N. (Karen N.), Kooner, J. S. (Jaspal S.), Kottgen, A. (Anna), Heijmans, B. T. (Bastiaan T.), Deloukas, P. (Panos), Relton, C. (Caroline), Ong, K. K. (Ken K.), Bell, J. T. (Jordana T.), Boerwinkle, E. (Eric), Elliott, P. (Paul), Brenner, H. (Hermann), Beekman, M. (Marian), Levy, D. (Daniel), Waldenberger, M. (Melanie), Chambers, J. C. (John C.), Dehghan, A. (Abbas), Järvelin, M.-R. (Marjo-Riitta), Wielscher, M. (Matthias), Mandaviya, P. R. (Pooja R.), Kuehnel, B. (Brigitte), Joehanes, R. (Roby), Mustafa, R. (Rima), Robinson, O. (Oliver), Zhang, Y. (Yan), Bodinier, B. (Barbara), Walton, E. (Esther), Mishra, P. P. (Pashupati P.), Schlosser, P. (Pascal), Wilson, R. (Rory), Tsai, P.-C. (Pei-Chien), Palaniswamy, S. (Saranya), Marioni, R. E. (Riccardo E.), Fiorito, G. (Giovanni), Cugliari, G. (Giovanni), Karhunen, V. (Ville), Ghanbari, M. (Mohsen), Psaty, B. M. (Bruce M.), Loh, M. (Marie), Bis, J. C. (Joshua C.), Lehne, B. (Benjamin), Sotoodehnia, N. (Nona), Deary, I. J. (Ian J.), Chadeau-Hyam, M. (Marc), Brody, J. A. (Jennifer A.), Cardona, A. (Alexia), Selvin, E. (Elizabeth), Smith, A. K. (Alicia K.), Miller, A. H. (Andrew H.), Torres, M. A. (Mylin A.), Marouli, E. (Eirini), Gao, X. (Xin), van Meurs, J. B. (Joyce B. J.), Graf-Schindler, J. (Johanna), Rathmann, W. (Wolfgang), Koenig, W. (Wolfgang), Peters, A. (Annette), Weninger, W. (Wolfgang), Farlik, M. (Matthias), Zhang, T. (Tao), Chen, W. (Wei), Xia, Y. (Yujing), Teumer, A. (Alexander), Nauck, M. (Matthias), Grabe, H. J. (Hans J.), Doerr, M. (Macus), Lehtimaki, T. (Terho), Guan, W. (Weihua), Milani, L. (Lili), Tanaka, T. (Toshiko), Fisher, K. (Krista), Waite, L. L. (Lindsay L.), Kasela, S. (Silva), Vineis, P. (Paolo), Verweij, N. (Niek), van der Harst, P. (Pim), Iacoviello, L. (Licia), Sacerdote, C. (Carlotta), Panico, S. (Salvatore), Krogh, V. (Vittorio), Tumino, R. (Rosario), Tzala, E. (Evangelia), Matullo, G. (Giuseppe), Hurme, M. A. (Mikko A.), Raitakari, O. T. (Olli T.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Kahonen, M. (Mika), Herzig, K.-H. (Karl-Heinz), Li, S. (Shengxu), BIOS consortium, Conneely, K. N. (Karen N.), Kooner, J. S. (Jaspal S.), Kottgen, A. (Anna), Heijmans, B. T. (Bastiaan T.), Deloukas, P. (Panos), Relton, C. (Caroline), Ong, K. K. (Ken K.), Bell, J. T. (Jordana T.), Boerwinkle, E. (Eric), Elliott, P. (Paul), Brenner, H. (Hermann), Beekman, M. (Marian), Levy, D. (Daniel), Waldenberger, M. (Melanie), Chambers, J. C. (John C.), Dehghan, A. (Abbas), and Järvelin, M.-R. (Marjo-Riitta)

Abstract

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Published
2022

23. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Author

Universitat Rovira i Virgili, Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N, Universitat Rovira i Virgili, and Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N

Abstract

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Published
2022

25. AN EPIGENOME-WIDE VIEW OF OSTEOARTHRITIS IN PRIMARY TISSUES

Author

Kreitmaier, P., primary, Suderman, M., additional, Southam, L., additional, Coutinho de Almeida, R., additional, Hatzikotoulas, K., additional, Meulenbelt, I., additional, Steinberg, J., additional, Relton, C., additional, Wilkinson, J.M., additional, and Zeggini, E., additional

Published
2022
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29. Neonatal DNA methylation and childhood low prosocial behavior

Author

Luo, M.N., Meehan, A.J., Walton, E., Roder, S., Herberth, G., Zenclussen, A.C., Cosin-Tomas, M., Sunyer, J., Mulder, R.H., Hidalgo, A.P.C., Bakermans-Kranenburg, M.J., Felix, J.F., Relton, C., Suderman, M., Pappa, I., Kok, R., Tiemeier, H., Ijzendoorn, M.H. van, Barker, E.D., and Cecil, C.A.M.

Subjects
meta-analysis, DNA methylation, prosocial behavior, cord blood, epigenome-wide association study
Abstract

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

Published
2021

32. CONSORT extension for the reporting of randomised controlled trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE): Checklist with explanation and elaboration

Author

Kwakkenbos, L., Imran, M., McCall, S.J., McCord, K.A., Fröbert, O., Hemkens, L.G., Zwarenstein, M., Relton, C., Rice, D.B., Langan, S.M., Benchimol, E.I., Thabane, L., Campbell, M.K., Sampson, M., Erlinge, D., Verkooijen, H.M., Moher, D., Boutron, I., Ravaud, P., Nicholl, J., Uher, R., Sauvé, M., Fletcher, J., Torgerson, D., Gale, C., Juszczak, E., Thombs, B.D., Kwakkenbos, L., Imran, M., McCall, S.J., McCord, K.A., Fröbert, O., Hemkens, L.G., Zwarenstein, M., Relton, C., Rice, D.B., Langan, S.M., Benchimol, E.I., Thabane, L., Campbell, M.K., Sampson, M., Erlinge, D., Verkooijen, H.M., Moher, D., Boutron, I., Ravaud, P., Nicholl, J., Uher, R., Sauvé, M., Fletcher, J., Torgerson, D., Gale, C., Juszczak, E., and Thombs, B.D.

Abstract

Contains fulltext : 234331.pdf (Publisher’s version ) (Open Access)

Published
2021

33. Methods and results used in the development of a consensus-driven extension to the Consolidated Standards of Reporting Trials (CONSORT) statement for trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE)

Author

Imran, M., Kwakkenbos, L., McCall, S.J., McCord, K.A., Fröbert, O., Hemkens, L.G., Zwarenstein, M., Relton, C., Rice, D.B., Langan, S.M., Benchimol, E.I., Thabane, L., Campbell, M.K., Sampson, M., Erlinge, D., Verkooijen, H.M., Moher, D., Boutron, I., Ravaud, P., Nicholl, J., Uher, R., Sauvé, M., Fletcher, J., Torgerson, D., Gale, C., Juszczak, E., Thombs, B.D., Imran, M., Kwakkenbos, L., McCall, S.J., McCord, K.A., Fröbert, O., Hemkens, L.G., Zwarenstein, M., Relton, C., Rice, D.B., Langan, S.M., Benchimol, E.I., Thabane, L., Campbell, M.K., Sampson, M., Erlinge, D., Verkooijen, H.M., Moher, D., Boutron, I., Ravaud, P., Nicholl, J., Uher, R., Sauvé, M., Fletcher, J., Torgerson, D., Gale, C., Juszczak, E., and Thombs, B.D.

Abstract

Contains fulltext : 234358.pdf (Publisher’s version ) (Open Access), Objectives: Randomised controlled trials conducted using cohorts and routinely collected data, including registries, electronic health records and administrative databases, are increasingly used in healthcare intervention research. A Consolidated Standards of Reporting Trials (CONSORT) statement extension for trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE) has been developed with the goal of improving reporting quality. This article describes the processes and methods used to develop the extension and decisions made to arrive at the final checklist. Methods: The development process involved five stages: (1) identification of the need for a reporting guideline and project launch; (2) conduct of a scoping review to identify possible modifications to CONSORT 2010 checklist items and possible new extension items; (3) a three-round modified Delphi study involving key stakeholders to gather feedback on the checklist; (4) a consensus meeting to finalise items to be included in the extension, followed by stakeholder piloting of the checklist; and (5) publication, dissemination and implementation of the final checklist. Results: 27 items were initially developed and rated in Delphi round 1, 13 items were rated in round 2 and 11 items were rated in round 3. Response rates for the Delphi study were 92 of 125 (74%) invited participants in round 1, 77 of 92 (84%) round 1 completers in round 2 and 62 of 77 (81%) round 2 completers in round 3. Twenty-seven members of the project team representing a variety of stakeholder groups attended the in-person consensus meeting. The final checklist includes five new items and eight modified items. The extension Explanation & Elaboration document further clarifies aspects that are important to report. Conclusion: Uptake of CONSORT-ROUTINE and accompanying Explanation & Elaboration document will improve conduct of trials, as well as the transparency and completeness of reporting of trials conducted using

Published
2021

34. DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Author

Dongen, J. Van, Hagenbeek, F.A., Suderman, M., Roetman, P.J., Sugden, K., Chiocchetti, A.G., Ismail, K., Mulder, R.H., Hafferty, J.D., Adams, M.J., Walker, R.M., Morris, S.W., Lahti, J., Küpers, L.K., Escaramis, G., Alemany, S., Bonder, M. Jan, Meijer, M., Ip, H.F., Jansen, R., Baselmans, B.M.L., Parmar, P., Lowry, E., Streit, F., Sirignano, L., Send, T.S., Frank, J., Jylhävä, J., Wang, Y., Mishra, P.P., Colins, O.F., Corcoran, D.L., Poulton, R., Mill, J., Hannon, E., Arseneault, L., Korhonen, T., Vuoksimaa, E., Felix, J.F., Bakermans-Kranenburg, M.J., Campbell, A., Czamara, D., Binder, E., Corpeleijn, E., Gonzalez, J.R., Grazuleviciene, R., Gutzkow, K.B., Evandt, J., Vafeiadi, M., Klein, M., Meer, D. van der, Ligthart, L., Kluft, C., Davies, G.E., Hakulinen, C., Keltikangas-Järvinen, L., Franke, B., Freitag, C.M., Konrad, K., Hervas, A., Fernández-Rivas, A., Vetro, A., Raitakari, O., Lehtimäki, T., Vermeiren, R., Strandberg, T., Räikkönen, K., Snieder, H., Witt, S.H., Deuschle, M., Pedersen, N.L., Hägg, S., Sunyer, J., Franke, L., Kaprio, J., Ollikainen, M., Moffitt, T.E., Tiemeier, H., van, I.M.H., Relton, C., Vrijheid, M., Sebert, S., Jarvelin, M.R., Caspi, A., Evans, K.L., McIntosh, A.M., Bartels, M., Boomsma, D.I., Dongen, J. Van, Hagenbeek, F.A., Suderman, M., Roetman, P.J., Sugden, K., Chiocchetti, A.G., Ismail, K., Mulder, R.H., Hafferty, J.D., Adams, M.J., Walker, R.M., Morris, S.W., Lahti, J., Küpers, L.K., Escaramis, G., Alemany, S., Bonder, M. Jan, Meijer, M., Ip, H.F., Jansen, R., Baselmans, B.M.L., Parmar, P., Lowry, E., Streit, F., Sirignano, L., Send, T.S., Frank, J., Jylhävä, J., Wang, Y., Mishra, P.P., Colins, O.F., Corcoran, D.L., Poulton, R., Mill, J., Hannon, E., Arseneault, L., Korhonen, T., Vuoksimaa, E., Felix, J.F., Bakermans-Kranenburg, M.J., Campbell, A., Czamara, D., Binder, E., Corpeleijn, E., Gonzalez, J.R., Grazuleviciene, R., Gutzkow, K.B., Evandt, J., Vafeiadi, M., Klein, M., Meer, D. van der, Ligthart, L., Kluft, C., Davies, G.E., Hakulinen, C., Keltikangas-Järvinen, L., Franke, B., Freitag, C.M., Konrad, K., Hervas, A., Fernández-Rivas, A., Vetro, A., Raitakari, O., Lehtimäki, T., Vermeiren, R., Strandberg, T., Räikkönen, K., Snieder, H., Witt, S.H., Deuschle, M., Pedersen, N.L., Hägg, S., Sunyer, J., Franke, L., Kaprio, J., Ollikainen, M., Moffitt, T.E., Tiemeier, H., van, I.M.H., Relton, C., Vrijheid, M., Sebert, S., Jarvelin, M.R., Caspi, A., Evans, K.L., McIntosh, A.M., Bartels, M., and Boomsma, D.I.

Abstract

Item does not contain fulltext, DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Published
2021

35. DNA methylation signatures of aggression and closely related constructs:a meta-analysis of epigenome-wide studies across the lifespan

Author

van Dongen, J. (Jenny), Hagenbeek, F. A. (Fiona A.), Suderman, M. (Matthew), Roetman, P. J. (Peter J.), Sugden, K. (Karen), Chiocchetti, A. G. (Andreas G.), Ismail, K. (Khadeeja), Mulder, R. H. (Rosa H.), Hafferty, J. D. (Jonathan D.), Adams, M. J. (Mark J.), Walker, R. M. (Rosie M.), Morris, S. W. (Stewart W.), Lahti, J. (Jari), Kupers, L. K. (Leanne K.), Escaramis, G. (Georgia), Alemany, S. (Silvia), Bonder, M. J. (Marc Jan), Meijer, M. (Mandy), Ip, H. F. (Hill F.), Jansen, R. (Rick), Baselmans, B. M. (Bart M. L.), Parmar, P. (Priyanka), Lowry, E. (Estelle), Streit, F. (Fabian), Sirignano, L. (Lea), Send, T. S. (Tabea S.), Frank, J. (Josef), Jylhava, J. (Juulia), Wang, Y. (Yunzhang), Mishra, P. P. (Pashupati Prasad), Colins, O. F. (Olivier F.), Corcoran, D. L. (David L.), Poulton, R. (Richie), Mill, J. (Jonathan), Hannon, E. (Eilis), Arseneault, L. (Louise), Korhonen, T. (Tellervo), Vuoksimaa, E. (Eero), Felix, J. F. (Janine F.), Bakermans-Kranenburg, M. J. (Marian J.), Campbell, A. (Archie), Czamara, D. (Darina), Binder, E. (Elisabeth), Corpeleijn, E. (Eva), Gonzalez, J. R. (Juan R.), Grazuleviciene, R. (Regina), Gutzkow, K. B. (Kristine B.), Evandt, J. (Jorunn), Vafeiadi, M. (Marina), Klein, M. (Marieke), van der Meer, D. (Dennis), Ligthart, L. (Lannie), Kluft, C. (Cornelis), Davies, G. E. (Gareth E.), Hakulinen, C. (Christian), Keltikangas-Jarvinen, L. (Liisa), Franke, B. (Barbara), Freitag, C. M. (Christine M.), Konrad, K. (Kerstin), Hervas, A. (Amaia), Fernandez-Rivas, A. (Aranzazu), Vetro, A. (Agnes), Raitakari, O. (Olli), Lehtimaki, T. (Terho), Vermeiren, R. (Robert), Strandberg, T. (Timo), Raikkonen, K. (Katri), Snieder, H. (Harold), Witt, S. H. (Stephanie H.), Deuschle, M. (Michael), Pedersen, N. L. (Nancy L.), Hagg, S. (Sara), Sunyer, J. (Jordi), Franke, L. (Lude), Kaprio, J. (Jaakko), Ollikainen, M. (Miina), Moffitt, T. E. (Terrie E.), Tiemeier, H. (Henning), van IJzendoorn, M. H. (Marinus H.), Relton, C. (Caroline), Vrijheid, M. (Martine), Sebert, S. (Sylvain), Järvelin, M.-R. (Marjo-Riitta), Caspi, A. (Avshalom), Evans, K. L. (Kathryn L.), McIntosh, A. M. (Andrew M.), Bartels, M. (Meike), Boomsma, D. I. (Dorret, I), van Dongen, J. (Jenny), Hagenbeek, F. A. (Fiona A.), Suderman, M. (Matthew), Roetman, P. J. (Peter J.), Sugden, K. (Karen), Chiocchetti, A. G. (Andreas G.), Ismail, K. (Khadeeja), Mulder, R. H. (Rosa H.), Hafferty, J. D. (Jonathan D.), Adams, M. J. (Mark J.), Walker, R. M. (Rosie M.), Morris, S. W. (Stewart W.), Lahti, J. (Jari), Kupers, L. K. (Leanne K.), Escaramis, G. (Georgia), Alemany, S. (Silvia), Bonder, M. J. (Marc Jan), Meijer, M. (Mandy), Ip, H. F. (Hill F.), Jansen, R. (Rick), Baselmans, B. M. (Bart M. L.), Parmar, P. (Priyanka), Lowry, E. (Estelle), Streit, F. (Fabian), Sirignano, L. (Lea), Send, T. S. (Tabea S.), Frank, J. (Josef), Jylhava, J. (Juulia), Wang, Y. (Yunzhang), Mishra, P. P. (Pashupati Prasad), Colins, O. F. (Olivier F.), Corcoran, D. L. (David L.), Poulton, R. (Richie), Mill, J. (Jonathan), Hannon, E. (Eilis), Arseneault, L. (Louise), Korhonen, T. (Tellervo), Vuoksimaa, E. (Eero), Felix, J. F. (Janine F.), Bakermans-Kranenburg, M. J. (Marian J.), Campbell, A. (Archie), Czamara, D. (Darina), Binder, E. (Elisabeth), Corpeleijn, E. (Eva), Gonzalez, J. R. (Juan R.), Grazuleviciene, R. (Regina), Gutzkow, K. B. (Kristine B.), Evandt, J. (Jorunn), Vafeiadi, M. (Marina), Klein, M. (Marieke), van der Meer, D. (Dennis), Ligthart, L. (Lannie), Kluft, C. (Cornelis), Davies, G. E. (Gareth E.), Hakulinen, C. (Christian), Keltikangas-Jarvinen, L. (Liisa), Franke, B. (Barbara), Freitag, C. M. (Christine M.), Konrad, K. (Kerstin), Hervas, A. (Amaia), Fernandez-Rivas, A. (Aranzazu), Vetro, A. (Agnes), Raitakari, O. (Olli), Lehtimaki, T. (Terho), Vermeiren, R. (Robert), Strandberg, T. (Timo), Raikkonen, K. (Katri), Snieder, H. (Harold), Witt, S. H. (Stephanie H.), Deuschle, M. (Michael), Pedersen, N. L. (Nancy L.), Hagg, S. (Sara), Sunyer, J. (Jordi), Franke, L. (Lude), Kaprio, J. (Jaakko), Ollikainen, M. (Miina), Moffitt, T. E. (Terrie E.), Tiemeier, H. (Henning), van IJzendoorn, M. H. (Marinus H.), Relton, C. (Caroline), Vrijheid, M. (Martine), Sebert, S. (Sylvain), Järvelin, M.-R. (Marjo-Riitta), Caspi, A. (Avshalom), Evans, K. L. (Kathryn L.), McIntosh, A. M. (Andrew M.), Bartels, M. (Meike), and Boomsma, D. I. (Dorret, I)

Abstract

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Published
2021

36. Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation

Author

Sammallahti, S. (Sara), Cortes Hidalgo, A. P. (Andrea P.), Tuominen, S. (Samuli), Malmberg, A. (Anni), Mulder, R. H. (Rosa H.), Brunst, K. J. (Kelly J.), Alemany, S. (Silvia), McBride, N. S. (Nancy S.), Yousefi, P. (Paul), Heiss, J. A. (Jonathan A.), McRae, N. (Nia), Page, C. M. (Christian M.), Jin, J. (Jianping), Pesce, G. (Giancarlo), Caramaschi, D. (Doretta), Rifas-Shiman, S. L. (Sheryl L.), Koen, N. (Nastassja), Adams, C. D. (Charleen D.), Magnus, M. C. (Maria C.), Baiz, N. (Nour), Ratanatharathorn, A. (Andrew), Czamara, D. (Darina), Haberg, S. E. (Siri E.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Cardenas, A. (Andres), DeMeo, D. L. (Dawn L.), Lawlor, D. A. (Deborah A.), Relton, C. L. (Caroline L.), Felix, J. F. (Janine F.), van IJzendoorn, M. H. (Marinus H.), Bakermans-Kranenburg, M. J. (Marian J.), Kajantie, E. (Eero), Raikkonen, K. (Katri), Sunyer, J. (Jordi), Sharp, G. C. (Gemma C.), Houtepen, L. C. (Lotte C.), Nohr, E. A. (Ellen A.), Sorensen, T. I. (Thorkild I. A.), Tellez-Rojo, M. M. (Martha M.), Wright, R. O. (Robert O.), Annesi-Maesano, I. (Isabella), Wright, J. (John), Hivert, M.-F. (Marie-France), Wright, R. J. (Rosalind J.), Zar, H. J. (Heather J.), Stein, D. J. (Dan J.), London, S. J. (Stephanie J.), Cecil, C. A. (Charlotte A. M.), Tiemeier, H. (Henning), Lahti, J. (Jari), Sammallahti, S. (Sara), Cortes Hidalgo, A. P. (Andrea P.), Tuominen, S. (Samuli), Malmberg, A. (Anni), Mulder, R. H. (Rosa H.), Brunst, K. J. (Kelly J.), Alemany, S. (Silvia), McBride, N. S. (Nancy S.), Yousefi, P. (Paul), Heiss, J. A. (Jonathan A.), McRae, N. (Nia), Page, C. M. (Christian M.), Jin, J. (Jianping), Pesce, G. (Giancarlo), Caramaschi, D. (Doretta), Rifas-Shiman, S. L. (Sheryl L.), Koen, N. (Nastassja), Adams, C. D. (Charleen D.), Magnus, M. C. (Maria C.), Baiz, N. (Nour), Ratanatharathorn, A. (Andrew), Czamara, D. (Darina), Haberg, S. E. (Siri E.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Cardenas, A. (Andres), DeMeo, D. L. (Dawn L.), Lawlor, D. A. (Deborah A.), Relton, C. L. (Caroline L.), Felix, J. F. (Janine F.), van IJzendoorn, M. H. (Marinus H.), Bakermans-Kranenburg, M. J. (Marian J.), Kajantie, E. (Eero), Raikkonen, K. (Katri), Sunyer, J. (Jordi), Sharp, G. C. (Gemma C.), Houtepen, L. C. (Lotte C.), Nohr, E. A. (Ellen A.), Sorensen, T. I. (Thorkild I. A.), Tellez-Rojo, M. M. (Martha M.), Wright, R. O. (Robert O.), Annesi-Maesano, I. (Isabella), Wright, J. (John), Hivert, M.-F. (Marie-France), Wright, R. J. (Rosalind J.), Zar, H. J. (Heather J.), Stein, D. J. (Dan J.), London, S. J. (Stephanie J.), Cecil, C. A. (Charlotte A. M.), Tiemeier, H. (Henning), and Lahti, J. (Jari)

Abstract

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Published
2021

37. Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis

Author

Luo, M., Meehan, A.J., Walton, E., Röder, Stefan, Herberth, Gunda, Zenclussen, Ana Claudia, Cosín-Tomás, M., Sunyer, J., Mulder, R.H., Cortes Hidalgo, A.P., Bakermans-Kranenburg, M.J., Felix, J.F., Relton, C., Suderman, M., Pappa, I., Kok, R., Tiemeier, H., van IJzendoorn, M.H., Barker, E.D., Cecil, C.A.M., Luo, M., Meehan, A.J., Walton, E., Röder, Stefan, Herberth, Gunda, Zenclussen, Ana Claudia, Cosín-Tomás, M., Sunyer, J., Mulder, R.H., Cortes Hidalgo, A.P., Bakermans-Kranenburg, M.J., Felix, J.F., Relton, C., Suderman, M., Pappa, I., Kok, R., Tiemeier, H., van IJzendoorn, M.H., Barker, E.D., and Cecil, C.A.M.

Abstract

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of “chronic-low” versus “typical” prosocial behavior across childhood in a case–control design (N = 2,095), and (b) continuous “low prosocial” scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

Published
2021

38. Dietary Quality and Dietary Inflammatory Potential During Pregnancy and Offspring Emotional and Behavioral Symptoms in Childhood: An Individual Participant Data Meta-analysis of Four European Cohorts

Author

Polanska, K, Kaluzny, P, Aubert, AM, Bernard, M, Duijts, Liesbeth, El Marroun, Hanan, Hanke, W, Hébert, JR, Heude, B, Jankowska, A, Mancano, G, Mensink - Bout, Rosalie, Relton, C, Shivappa, N, Suderman, M, Trafalska, E, Wesolowska, E, Garcia-Esteban, R, Guxens Junyent, Monica, Casas, M, Philips, CM, Polanska, K, Kaluzny, P, Aubert, AM, Bernard, M, Duijts, Liesbeth, El Marroun, Hanan, Hanke, W, Hébert, JR, Heude, B, Jankowska, A, Mancano, G, Mensink - Bout, Rosalie, Relton, C, Shivappa, N, Suderman, M, Trafalska, E, Wesolowska, E, Garcia-Esteban, R, Guxens Junyent, Monica, Casas, M, and Philips, CM

Abstract

Background: The impact of maternal diet during pregnancy on child neurodevelopment is of public health and clinical relevance. We evaluated the associations of dietary quality based on the Dietary Approaches to Stop Hypertension (DASH) score and dietary inflammatory potential based on the energy-adjusted Dietary Inflammatory Index (E-DII) score during pregnancy with emotional and behavioral symptoms of offspring at 7 to 10 years of age. Methods: Individual participant data for 11,870 mother–child pairs from four European cohorts participating in the ALPHABET project were analyzed. Maternal antenatal DASH and E-DII scores were generated from self-completed food frequency questionnaires. Symptoms of depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder in children were assessed using mother-reported tests and classified within the normal or borderline/clinical ranges using validated cutoffs. Adjusted odds ratios were determined by multivariable logistic regression models and aggregated by the two-level individual participant data meta-analysis method. Results: Higher maternal DASH scores (indicating better dietary quality) were associated with lower risk of depressive and anxiety symptoms, aggressive behavior symptoms, and attention-deficit/hyperactivity disorder symptoms within the borderline/clinical ranges: odds ratio [OR] 0.97, 95% confidence interval [CI], 0.95–0.99; OR 0.97, 95% CI, 0.94–0.99; OR 0.97, 95% CI, 0.95–0.98, per one-unit DASH score increase, respectively. For depression and anxiety, aggressive behavior, and attention-deficit/hyperactivity disorder symptoms, a one-unit increase in E-DII scores (a more proinflammatory diet) was associated with a 7% increased risk of all three analyzed emotional and behavioral symptoms: OR 1.07, 95% CI, 1.03–1.11; OR 1.07, 95% CI, 1.02–1.13; OR 1.07, 95% CI, 1.01–1.13, respectively. Conclusions: Our findings suggest that a maternal low-quality and proinflammatory diet may increase

Published
2021

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

Author

Surendran, P., Feofanova, E. V., Lahrouchi, N., Ntalla, I., Karthikeyan, S., Cook, J., Chen, L., Mifsud, B., Yao, C., Kraja, A. T., Cartwright, J. H., Hellwege, J. N., Giri, A., Tragante, V., Thorleifsson, G., Liu, D. J., Prins, B. P., Stewart, I. D., Cabrera, C. P., Eales, J. M., Akbarov, A., Auer, P. L., Bielak, L. F., Bis, J. C., Braithwaite, V. S., Brody, J. A., Daw, E. W., Warren, H. R., Drenos, F., Nielsen, S. F., Faul, J. D., Fauman, E. B., Fava, C., Ferreira, T., Foley, C. N., Franceschini, N., Gao, H., Giannakopoulou, O., Giulianini, F., Gudbjartsson, D. F., Guo, X., Harris, S. E., Havulinna, A. S., Helgadottir, A., Huffman, J. E., Hwang, S. -J., Kanoni, S., Kontto, J., Larson, M. G., Li-Gao, R., Lindstrom, J., Lotta, L. A., Lu, Y., Luan, J., Mahajan, A., Malerba, G., Masca, N. G. D., Mei, H., Menni, C., Mook-Kanamori, D. O., Mosen-Ansorena, D., Muller-Nurasyid, M., Pare, G., Paul, D. S., Perola, M., Poveda, A., Rauramaa, R., Richard, M., Richardson, T. G., Sepulveda, N., Sim, X., Smith, A. V., Smith, J. A., Staley, J. R., Stanakova, A., Sulem, P., Theriault, S., Thorsteinsdottir, U., Trompet, S., Varga, T. V., Velez Edwards, D. R., Veronesi, G., Weiss, S., Willems, S. M., Yao, J., Young, R., Yu, B., Zhang, W., Zhao, J. -H., Zhao, W., Evangelou, E., Aeschbacher, S., Asllanaj, E., Blankenberg, S., Bonnycastle, L. L., Bork-Jensen, J., Brandslund, I., Braund, P. S., Burgess, S., Cho, K., Christensen, C., Connell, J., Mutsert, R., Dominiczak, A. F., Dorr, M., Eiriksdottir, G., Farmaki, A. -E., Gaziano, J. M., Grarup, N., Grove, M. L., Hallmans, G., Hansen, T., Have, C. T., Heiss, G., Jorgensen, M. E., Jousilahti, P., Kajantie, E., Kamat, M., Karajamaki, A. M., Karpe, F., Koistinen, H. A., Kovesdy, C. P., Kuulasmaa, K., Laatikainen, T., Lannfelt, L., Lee, I. -T., Lee, W. -J., de Boer, R. A., van der Harst, P., van der Meer, P., Verweij, N., Linneberg, A., Martin, L. W., Moitry, M., Nadkarni, G., Neville, M. J., Palmer, C. N. A., Papanicolaou, G. J., Pedersen, O., Peters, J., Poulter, N., Rasheed, A., Rasmussen, K. L., Rayner, N. W., Magi, R., Renstrom, F., Rettig, R., Rossouw, J., Schreiner, P. J., Sever, P. S., Sigurdsson, E. L., Skaaby, T., Sun, Y. V., Sundstrom, J., Thorgeirsson, G., Esko, T., Trabetti, E., Tsao, P. S., Tuomi, T., Turner, S. T., Tzoulaki, I., Vaartjes, I., Vergnaud, A. -C., Willer, C. J., Wilson, P. W. F., Witte, D. R., Yonova-Doing, E., Zhang, H., Aliya, N., Almgren, P., Amouyel, P., Asselbergs, F. W., Barnes, M. R., Blakemore, A. I., Boehnke, M., Bots, M. L., Bottinger, E. P., Buring, J. E., Chambers, J. C., Chen, Y. -D. I., Chowdhury, R., Conen, D., Correa, A., Davey Smith, G., Boer, R. A., Deary, I. J., Dedoussis, G., Deloukas, P., Di Angelantonio, E., Elliott, P., Butterworth, A. S., Danesh, J., Langenberg, C., Mccarthy, M. I., Franks, P. W., Rolandsson, O., Wareham, N. J., Felix, S. B., Ferrieres, J., Ford, I., Fornage, M., Franks, S., Frossard, P., Gambaro, G., Gaunt, T. R., Groop, L., Gudnason, V., Harris, T. B., Hayward, C., Hennig, B. J., Herzig, K. -H., Ingelsson, E., Tuomilehto, J., Jarvelin, M. -R., Jukema, J. W., Kardia, S. L. R., Kee, F., Kooner, J. S., Kooperberg, C., Launer, L. J., Lind, L., Loos, R. J. F., Majumder, A. S., Laakso, M., Melander, O., Mohlke, K. L., Murray, A. D., Nordestgaard, B. G., Orho-Melander, M., Packard, C. J., Padmanabhan, S., Palmas, W., Polasek, O., Porteous, D. J., Prentice, A. M., Province, M. A., Relton, C. L., Rice, K., Ridker, P. M., Rosendaal, F. R., Rotter, J. I., Rudan, I., Salomaa, V., Samani, N. J., Sattar, N., Sheu, W. H. -H., Smith, B. H., Soranzo, N., Spector, T. D., Starr, J. M., Sebert, S., Taylor, K. D., Lakka, T. A., Timpson, N. J., Tobin, M. D., Zeggini, E., Ramachandran, V. S., Virtamo, J., Volker, U., Weir, D. R., Charchar, F. J., Edwards, D. R. V., Edwards, T. L., Hung, A. M., O'Donnell, C. J., Tomaszewski, M., Caulfield, M. J., Holm, H., Lindgren, C. M., Liu, C., Manning, A. K., Morris, A. P., Morrison, A. C., Psaty, B. M., Saleheen, D., Stefansson, K., Boerwinkle, E., Chasman, D. I., Levy, D., Newton-Cheh, C., Munroe, P. B., Howson, J. M. M., Home Office, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), UNIVERSITY OF OULU, Epidemiology, Complex Disease Genetics, Research Programs Unit, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, HUS Children and Adolescents, Lastentautien yksikkö, Clinicum, Children's Hospital, Helsinki University Hospital Area, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Endokrinologian yksikkö, Department of Public Health, Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Feofanova, Elena V [0000-0003-1428-7199], Chasman, Daniel I [0000-0003-3357-0862], Munroe, Patricia B [0000-0002-4176-2947], Howson, Joanna MM [0000-0001-7618-0050], Apollo - University of Cambridge Repository, Cardiology, and ACS - Heart failure & arrhythmias

Subjects
Candidate gene, Blood Pressure, GATA5 Transcription Factor, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Hypertension, Mutation, Phospholipase C beta, Polymorphism, Single Nucleotide, LOCI, Genome-wide association study, 0302 clinical medicine, Polymorphism (computer science), genetics, GENOME-WIDE ASSOCIATION, MENDELIAN RANDOMIZATION, COMMON VARIANTS, IDENTIFIES COMMON, RISK, FREQUENCY, TRAITS, HYPERTENSION, GENETICS, EPIC-CVD, 11 Medical and Health Sciences, health care economics and organizations, Genetics & Heredity, Genetics, 0303 health sciences, Million Veteran Program, 1184 Genetics, developmental biology, physiology, Single Nucleotide, humanities, 3. Good health, genetic association study, EPIC-InterAct, epidemiology, Life Sciences & Biomedicine, Understanding Society Scientific Group, hypertension, education, Biology, Article, 03 medical and health sciences, Mendelian randomization, Polymorphism, Allele frequency, Gene, 030304 developmental biology, Science & Technology, 06 Biological Sciences, meta-analysis, Minor allele frequency, genome-wide association studies, 3111 Biomedicine, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology
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 ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P

Published
2020
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43. Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)

Author

Huang, JY, Larose, TL, Luu, HN, Wang, R, Fanidi, A, Alcala, K, Stevens, VL, Weinstein, SJ, Albanes, D, Caporaso, NE, Purdue, MP, Ziegler, RG, Freedman, ND, Lan, Q, Prentice, RL, Pettinger, M, Thomson, CA, Cai, Q, Wu, J, Blot, WJ, Shu, X-O, Zheng, W, Arslan, AA, Zeleniuch-Jacquotte, A, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Hveem, K, Xiang, Y-B, Li, H-L, Gao, Y-T, Visvanathan, K, Ueland, PM, Midttun, O, Ulvi, A, Buring, JE, Lee, I-M, SeSS, HD, Gaziano, JM, Manjer, J, Relton, C, Koh, W-P, Brennan, P, Yuan, J-M, Han, J, Huang, JY, Larose, TL, Luu, HN, Wang, R, Fanidi, A, Alcala, K, Stevens, VL, Weinstein, SJ, Albanes, D, Caporaso, NE, Purdue, MP, Ziegler, RG, Freedman, ND, Lan, Q, Prentice, RL, Pettinger, M, Thomson, CA, Cai, Q, Wu, J, Blot, WJ, Shu, X-O, Zheng, W, Arslan, AA, Zeleniuch-Jacquotte, A, Le Marchand, L, Wilkens, LR, Haiman, CA, Zhang, X, Stampfer, MJ, Giles, GG, Hodge, AM, Severi, G, Johansson, M, Grankvist, K, Langhammer, A, Hveem, K, Xiang, Y-B, Li, H-L, Gao, Y-T, Visvanathan, K, Ueland, PM, Midttun, O, Ulvi, A, Buring, JE, Lee, I-M, SeSS, HD, Gaziano, JM, Manjer, J, Relton, C, Koh, W-P, Brennan, P, Yuan, J-M, and Han, J

Abstract

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Published
2020

44. 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

45. DNA methylation and body mass index from birth to adolescence:meta-analyses of epigenome-wide association studies

Author

Vehmeijer, F. O. (Florianne O. L.), Kuepers, L. K. (Leanne K.), Sharp, G. C. (Gemma C.), Salas, L. A. (Lucas A.), Lent, S. (Samantha), Jima, D. D. (Dereje D.), Tindula, G. (Gwen), Reese, S. (Sarah), Qi, C. (Cancan), Gruzieva, O. (Olena), Page, C. (Christian), Rezwan, F. I. (Faisal, I), Melton, P. E. (Philip E.), Nohr, E. (Ellen), Escaramis, G. (Georgia), Rzehak, P. (Peter), Heiskala, A. (Anni), Gong, T. (Tong), Tuominen, S. T. (Samuli T.), Gao, L. (Lu), Ross, J. P. (Jason P.), Starling, A. P. (Anne P.), Holloway, J. W. (John W.), Yousefi, P. (Paul), Aasvang, G. M. (Gunn Marit), Beilin, L. J. (Lawrence J.), Bergstrom, A. (Anna), Binder, E. (Elisabeth), Chatzi, L. (Leda), Corpeleijn, E. (Eva), Czamara, D. (Darina), Eskenazi, B. (Brenda), Ewart, S. (Susan), Ferre, N. (Natalia), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Haberg, S. E. (Siri E.), Hoyo, C. (Cathrine), Huen, K. (Karen), Karlsson, R. (Robert), Kull, I. (Inger), Langhendries, J.-P. (Jean-Paul), Lepeule, J. (Johanna), Magnus, M. C. (Maria C.), Maguire, R. L. (Rachel L.), Molloy, P. L. (Peter L.), Monnereau, C. (Claire), Mori, T. A. (Trevor A.), Oken, E. (Emily), Raikkonen, K. (Katri), Rifas-Shiman, S. (Sheryl), Ruiz-Arenas, C. (Carlos), Sebert, S. (Sylvain), Ullemar, V. (Vilhelmina), Verduci, E. (Elvira), Vonk, J. M. (Judith M.), Xu, C.-j. (Cheng-jian), Yang, I. V. (Ivana, V), Zhang, H. (Hongmei), Zhang, W. (Weiming), Karmaus, W. (Wilfried), Dabelea, D. (Dana), Muhlhausler, B. S. (Beverly S.), Breton, C. V. (Carrie, V), Lahti, J. (Jari), Almqvist, C. (Catarina), Jarvelin, M.-R. (Marjo-Riitta), Koletzko, B. (Berthold), Vrijheid, M. (Martine), Sorensen, T. I. (Thorkild I. A.), Huang, R.-C. (Rae-Chi), Arshad, S. H. (Syed Hasan), Nystad, W. (Wenche), Melen, E. (Erik), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), Holland, N. (Nina), Bustamante, M. (Mariona), Murphy, S. K. (Susan K.), Hivert, M.-F. (Marie-France), Baccarelli, A. (Andrea), Relton, C. L. (Caroline L.), Snieder, H. (Harold), Jaddoe, V. W. (Vincent W. V.), Felix, J. F. (Janine F.), Vehmeijer, F. O. (Florianne O. L.), Kuepers, L. K. (Leanne K.), Sharp, G. C. (Gemma C.), Salas, L. A. (Lucas A.), Lent, S. (Samantha), Jima, D. D. (Dereje D.), Tindula, G. (Gwen), Reese, S. (Sarah), Qi, C. (Cancan), Gruzieva, O. (Olena), Page, C. (Christian), Rezwan, F. I. (Faisal, I), Melton, P. E. (Philip E.), Nohr, E. (Ellen), Escaramis, G. (Georgia), Rzehak, P. (Peter), Heiskala, A. (Anni), Gong, T. (Tong), Tuominen, S. T. (Samuli T.), Gao, L. (Lu), Ross, J. P. (Jason P.), Starling, A. P. (Anne P.), Holloway, J. W. (John W.), Yousefi, P. (Paul), Aasvang, G. M. (Gunn Marit), Beilin, L. J. (Lawrence J.), Bergstrom, A. (Anna), Binder, E. (Elisabeth), Chatzi, L. (Leda), Corpeleijn, E. (Eva), Czamara, D. (Darina), Eskenazi, B. (Brenda), Ewart, S. (Susan), Ferre, N. (Natalia), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Haberg, S. E. (Siri E.), Hoyo, C. (Cathrine), Huen, K. (Karen), Karlsson, R. (Robert), Kull, I. (Inger), Langhendries, J.-P. (Jean-Paul), Lepeule, J. (Johanna), Magnus, M. C. (Maria C.), Maguire, R. L. (Rachel L.), Molloy, P. L. (Peter L.), Monnereau, C. (Claire), Mori, T. A. (Trevor A.), Oken, E. (Emily), Raikkonen, K. (Katri), Rifas-Shiman, S. (Sheryl), Ruiz-Arenas, C. (Carlos), Sebert, S. (Sylvain), Ullemar, V. (Vilhelmina), Verduci, E. (Elvira), Vonk, J. M. (Judith M.), Xu, C.-j. (Cheng-jian), Yang, I. V. (Ivana, V), Zhang, H. (Hongmei), Zhang, W. (Weiming), Karmaus, W. (Wilfried), Dabelea, D. (Dana), Muhlhausler, B. S. (Beverly S.), Breton, C. V. (Carrie, V), Lahti, J. (Jari), Almqvist, C. (Catarina), Jarvelin, M.-R. (Marjo-Riitta), Koletzko, B. (Berthold), Vrijheid, M. (Martine), Sorensen, T. I. (Thorkild I. A.), Huang, R.-C. (Rae-Chi), Arshad, S. H. (Syed Hasan), Nystad, W. (Wenche), Melen, E. (Erik), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), Holland, N. (Nina), Bustamante, M. (Mariona), Murphy, S. K. (Susan K.), Hivert, M.-F. (Marie-France), Baccarelli, A. (Andrea), Relton, C. L. (Caroline L.), Snieder, H. (Harold), Jaddoe, V. W. (Vincent W. V.), and Felix, J. F. (Janine F.)

Abstract

Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10⁻⁷, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10⁻⁴; adolescence Penrichment = 2.10 × 10⁻⁷). Conclusions: There were only minimal associations of DNA methylation with childhood and adol

Published
2020

46. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author

Merid, S. K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G. C. (Gemma C.), Kupers, L. K. (Leanne K.), Kho, A. T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F. O. (Florianne O.), Kazmi, N. (Nabila), Salas, L. A. (Lucas A.), Rezwan, F. I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S. L. (Sheryl L.), Melton, P. E. (Phillip E.), Lawlor, D. A. (Debbie A.), Pershagen, G. (Goran), Breton, C. V. (Carrie V.), Huen, K. (Karen), Baiz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T. S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, E. A. (Ellen Aagaard), Bustamante, M. (Mariona), Ewart, S. L. (Susan L.), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C. M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A. A. (Andrea A.), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C. L. (Caroline L.), Bergstrom, A. (Anna), Eskenazi, B. (Brenda), Soomro, M. H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V. W. (Vincent W.), Sorensen, T. I. (Thorkild I. A.), Vrijheid, M. (Martine), Arshad, S. H. (S. Hasan), Holloway, J. W. (John W.), Haberg, S. E. (Siri E.), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E. B. (Elisabeth B.), DeMeo, D. L. (Dawn L.), Vonk, J. M. (Judith M.), Newnham, J. (John), Tantisira, K. G. (Kelan G.), Kull, I. (Inger), Wiemels, J. L. (Joseph L.), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M. C. (Monica C.), Raikkonen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S. T. (Scott T.), Anto, J. M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Soderhall, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S. E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J. F. (Janine F.), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), Melen, E. (Erik), Merid, S. K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G. C. (Gemma C.), Kupers, L. K. (Leanne K.), Kho, A. T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F. O. (Florianne O.), Kazmi, N. (Nabila), Salas, L. A. (Lucas A.), Rezwan, F. I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S. L. (Sheryl L.), Melton, P. E. (Phillip E.), Lawlor, D. A. (Debbie A.), Pershagen, G. (Goran), Breton, C. V. (Carrie V.), Huen, K. (Karen), Baiz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T. S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, E. A. (Ellen Aagaard), Bustamante, M. (Mariona), Ewart, S. L. (Susan L.), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C. M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A. A. (Andrea A.), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C. L. (Caroline L.), Bergstrom, A. (Anna), Eskenazi, B. (Brenda), Soomro, M. H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V. W. (Vincent W.), Sorensen, T. I. (Thorkild I. A.), Vrijheid, M. (Martine), Arshad, S. H. (S. Hasan), Holloway, J. W. (John W.), Haberg, S. E. (Siri E.), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E. B. (Elisabeth B.), DeMeo, D. L. (Dawn L.), Vonk, J. M. (Judith M.), Newnham, J. (John), Tantisira, K. G. (Kelan G.), Kull, I. (Inger), Wiemels, J. L. (Joseph L.), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M. C. (Monica C.), Raikkonen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S. T. (Scott T.), Anto, J. M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Soderhall, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S. E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J. F. (Janine F.), Koppelman, G. H. (Gerard H.), London, S. J. (Stephanie J.), and Melen, E. (Erik)

Abstract

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10⁻⁷, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2020

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