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201. A Mendelian Randomization dictionary:Useful definitions and descriptions for undertaking, understanding and interpreting Mendelian Randomization studies

Author: Lawlor, Debbie A, Wade, K H, Borges, Maria Carolina, Palmer, Thomas Michael, Hartwig, Fernando Pires, Hemani, Gibran, Bowden, Jack, Lawlor, Debbie A, Wade, K H, Borges, Maria Carolina, Palmer, Thomas Michael, Hartwig, Fernando Pires, Hemani, Gibran, and Bowden, Jack
Abstract: Mendelian randomization (MR) has been increasingly used to interrogate the causal effects of modifiable risk factors on human health and disease over the last 15 years. As MR becomes more commonplace in clinical guidelines and drug development, there is a need for researchers and practitioners from multiple disciplines to understand the existing and rapidly evolving ‘language’ of MR. The MR Dictionary provides useful definitions and descriptions for undertaking, understanding and interpreting MR studies to a wide, inter-disciplinary audience – both those new to MR and those who are experienced in its use but who want to remain up to date. The full searchable (with terms cross-referenced throughout) version of the MR Dictionary is provided on the journal website. In the first instance, we aim to update the MR Dictionary annually and encourage users of the Dictionary to help us in this endeavour. By the first update (August 2020), we aim to have moved to an open, collaborative and interactive online tool on the journal website that will support more rapid and extensive linked searches and more immediate updates and online discussion.
Published: 2019

202. Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Author: Planningssecretariaat HCK, Onderzoek Precision medicine, Cardiovasculaire Epi Team 3, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Brain, Cancer, Cardiovasculaire Epidemiologie, Epi Methoden Team 6, Aios en Stafsecr. Cardiologie, Cardiovasculaire Epi Team 5, Cardiovasculaire Epi Team 9, Team Medisch, Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'An, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., De Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M., Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-Van Der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., Hingorani, Aroon D., Planningssecretariaat HCK, Onderzoek Precision medicine, Cardiovasculaire Epi Team 3, Circulatory Health, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, JC onderzoeksprogramma Kanker, Brain, Cancer, Cardiovasculaire Epidemiologie, Epi Methoden Team 6, Aios en Stafsecr. Cardiologie, Cardiovasculaire Epi Team 5, Cardiovasculaire Epi Team 9, Team Medisch, Schmidt, Amand F., Holmes, Michael V., Preiss, David, Swerdlow, Daniel I., Denaxas, Spiros, Fatemifar, Ghazaleh, Faraway, Rupert, Finan, Chris, Valentine, Dennis, Fairhurst-Hunter, Zammy, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, Van Iperen, Erik, Hovingh, Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Lill, Christina M., Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew, Panayiotou, Andrie G., Onland-Moret, N. Charlotte, Van Der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., Langenberg, Claudia, Scott, Robert A., Luan, Jian'An, Bobak, Martin, Malyutina, Sofia, Pajak, Andrzej, Kubinova, Ruzena, Tamosiunas, Abdonas, Pikhart, Hynek, Grarup, Niels, Pedersen, Oluf, Hansen, Torben, Linneberg, Allan, Jess, Tine, Cooper, Jackie, Humphries, Steve E., Brilliant, Murray, Kitchner, Terrie, Hakonarson, Hakon, Carrell, David S., McCarty, Catherine A., Lester, Kirchner H., Larson, Eric B., Crosslin, David R., De Andrade, Mariza, Roden, Dan M., Denny, Joshua C., Carty, Cara, Hancock, Stephen, Attia, John, Holliday, Elizabeth, Scott, Rodney, Schofield, Peter, O'Donnell, Martin, Yusuf, Salim, Chong, Michael, Pare, Guillaume, Van Der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Christen, Tim, Mook-Kanamori, D. O., Gustafsson, Stefan, Lind, Lars, Ingelsson, Erik, Pazoki, Raha, Franco, Oscar, Hofman, Albert, Uitterlinden, Andre, Dehghan, Abbas, Teumer, Alexander, Baumeister, Sebastian, Dörr, Marcus, Lerch, Markus M., Völker, Uwe, Völzke, Henry, Ward, Joey, Pell, Jill P., Meade, Tom, Christophersen, Ingrid E., Maitland-Van Der Zee, Anke H., Baranova, Ekaterina V., Young, Robin, Ford, Ian, Campbell, Archie, Padmanabhan, Sandosh, Bots, Michiel L., Grobbee, Diederick E., Froguel, Philippe, Thuillier, Dorothée, Roussel, Ronan, Bonnefond, Amélie, Cariou, Bertrand, Smart, Melissa, Bao, Yanchun, Kumari, Meena, Mahajan, Anubha, Hopewell, Jemma C., Seshadri, Sudha, Dale, Caroline, Costa, Rui Providencia E., Ridker, Paul M., Chasman, Daniel I., Reiner, Alex P., Ritchie, Marylyn D., Lange, Leslie A., Cornish, Alex J., Dobbins, Sara E., Hemminki, Kari, Kinnersley, Ben, Sanson, Marc, Labreche, Karim, Simon, Matthias, Bondy, Melissa, Law, Philip, Speedy, Helen, Allan, James, Li, Ni, Went, Molly, Weinhold, Niels, Morgan, Gareth, Sonneveld, Pieter, Nilsson, Björn, Goldschmidt, Hartmut, Sud, Amit, Engert, Andreas, Hansson, Markus, Hemingway, Harry, Asselbergs, Folkert W., Patel, Riyaz S., Keating, Brendan J., Sattar, Naveed, Houlston, Richard, Casas, Juan P., and Hingorani, Aroon D.
Published: 2019

203. Effect modification of FADS2 polymorphisms on the association between breastfeeding and intelligence:results from a collaborative meta-analysis

Author: Hartwig, Fernando Pires, Davies, Neil Martin, Horta, Bernardo Lessa, Ahluwalia, Tarunveer S, Bisgaard, Hans, Bønnelykke, Klaus, Caspi, Avshalom, Moffitt, Terrie E, Poulton, Richie, Sajjad, Ayesha, Tiemeier, Henning W, Dalmau-Bueno, Albert, Guxens, Mònica, Bustamante, Mariona, Santa-Marina, Loreto, Parker, Nadine, Paus, Tomáš, Pausova, Zdenka, Lauritzen, Lotte, Schnurr, Theresia Maria, Michaelsen, Kim F., Hansen, Torben, Oddy, Wendy, Pennell, Craig E, Warrington, Nicole M, Davey Smith, George, Victora, Cesar Gomes, Hartwig, Fernando Pires, Davies, Neil Martin, Horta, Bernardo Lessa, Ahluwalia, Tarunveer S, Bisgaard, Hans, Bønnelykke, Klaus, Caspi, Avshalom, Moffitt, Terrie E, Poulton, Richie, Sajjad, Ayesha, Tiemeier, Henning W, Dalmau-Bueno, Albert, Guxens, Mònica, Bustamante, Mariona, Santa-Marina, Loreto, Parker, Nadine, Paus, Tomáš, Pausova, Zdenka, Lauritzen, Lotte, Schnurr, Theresia Maria, Michaelsen, Kim F., Hansen, Torben, Oddy, Wendy, Pennell, Craig E, Warrington, Nicole M, Davey Smith, George, and Victora, Cesar Gomes
Abstract: Background: Accumulating evidence suggests that breastfeeding benefits children's intelligence, possibly due to long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk. Under a nutritional adequacy hypothesis, an interaction between breastfeeding and genetic variants associated with endogenous LC-PUFAs synthesis might be expected. However, the literature on this topic is controversial.Methods: We investigated this gene × environment interaction through a collaborative effort. The primary analysis involved >12 000 individuals and used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores.Results: There was no strong evidence of interaction, with pooled covariate-adjusted interaction coefficients (i.e. difference between genetic groups of the difference in IQ Z scores comparing ever with never breastfed individuals) of 0.12[(95% confidence interval (CI): -0.19; 0.43] and 0.06 (95% CI: -0.16; 0.27) for the rs174575 and rs1535 variants, respectively. Secondary analyses corroborated these results. In studies with ≥5.85 and <5.85 months of breastfeeding duration, pooled estimates for the rs174575 variant were 0.50 (95% CI: -0.06; 1.06) and 0.14 (95% CI: -0.10; 0.38), respectively, and 0.27 (95% CI: -0.28; 0.82) and -0.01 (95% CI: -0.19; 0.16) for the rs1535 variant.Conclusions: Our findings did not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, subgroup analysis suggested that breastfeeding may supply LC-PUFAs requirements for cognitive development if breastfeeding lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and further improve our understanding on the breastfeeding × FADS2 interaction.
Published: 2019

204. Association between Breastfeeding and DNA Methylation over the Life Course: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Author: Doretta Caramaschi, Cesar G. Victora, Andrew J Simpkin, G Davey Smith, Fernando Pires Hartwig, and Caroline L Relton
Subjects: Epigenomics, Male, 0301 basic medicine, Longitudinal study, Adolescent, breastfeeding, life-course, Concordance, Longevity, Breastfeeding, lcsh:TX341-641, Article, Epigenesis, Genetic, Eating, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Longitudinal Studies, 030212 general & internal medicine, Child, Infant Nutritional Physiological Phenomena, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, DNA methylation, Nutrition and Dietetics, business.industry, Confounding, Infant, Newborn, Infant, Fetal Blood, epigenome-wide association study, Bottle Feeding, 3. Good health, Breast Feeding, 030104 developmental biology, Child, Preschool, Cohort, Life course approach, Female, business, lcsh:Nutrition. Foods and food supply, Genome-Wide Association Study, Food Science, Demography
Abstract: Background: Breastfeeding is associated with short and long-term health benefits. Long-term effects might be mediated by epigenetic mechanisms, yet the literature on this topic is scarce. We performed the first epigenome-wide association study of infant feeding, comparing breastfed vs non-breastfed children. We measured DNA methylation in children from peripheral blood collected in childhood (age 7 years, N = 640) and adolescence (age 15&ndash, 17 years, N = 709) within the Accessible Resource for Integrated Epigenomic Studies (ARIES) project, part of the larger Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Cord blood methylation (N = 702) was used as a negative control for potential pre-natal residual confounding. Results: Two differentially-methylated sites presented directionally-consistent associations with breastfeeding at ages 7 and 15&ndash, 17 years, but not at birth. Twelve differentially-methylated regions in relation to breastfeeding were identified, and for three of them there was evidence of directional concordance between ages 7 and 15&ndash, 17 years, but not between birth and age 7 years. Conclusions: Our findings indicate that DNA methylation in childhood and adolescence may be predicted by breastfeeding, but further studies with sufficiently large samples for replication are required to identify robust associations.
Published: 2020

205. Padrões de distanciamento social em nove cidades gaúchas: estudo Epicovid19/RS

Author: Jenifer Harter, Lia Gonçalves Possuelo, Pedro C. Hallal, Odir Antônio Dellagostin, Liliana P Weber, Lucia Campos Pellanda, Shana Ginar da Silva, Bernardo L. Horta, Marcelo Rodrigues Gonçalves, Claudio J. Struchiner, Gabriel D. Victora, Aluísio J D Barros, Fernando C. Barros, Ana M. B. Menezes, Rosangela C. Lima, Nadège Jacques, Fernando Pires Hartwig, Sonara Lucia Estima, Mariângela Freitas da Silveira, Matias Nunes Frizzo, Cesar G. Victora, and Marcelo Nascimento Burattini
Subjects: Male, Health Knowledge, Attitudes, Practice, Activities of daily living, Cross-sectional study, Estudo de Base Populacional, Health Risk Behaviors, Social isolation, education.field_of_study, Social distance, Artigo Original, Fatores Socioeconômicos, Distanciamento Social, Middle Aged, Coronavirus Infections, prevention & control, Geography, Social Isolation, Distanciamento social, Original Article, Female, Public aspects of medicine, RA1-1270, medicine.symptom, Coronavirus Infections, 0305 other medical science, Brazil, Adult, Comportamentos de Risco à Saúde, Coronavirus disease 2019 (COVID-19), Distancing, Pneumonia, Viral, Population, Betacoronavirus, Young Adult, Controle, 03 medical and health sciences, medicine, Humans, Conhecimentos, Atitudes e Prática em Saúde, Cities, education, Pandemics, 030505 public health, Infecções por Coronavirus, prevenção & controle, SARS-CoV-2, Public Health, Environmental and Occupational Health, COVID-19, Educational attainment, Coronavirus, Cross-Sectional Studies, Socioeconomic Factors, Communicable Disease Control, Prevenção, Demography
Abstract: OBJECTIVE: To describe social distancing practices in nine municipalities of the state of Rio Grande do Sul, Brazil, stratified by gender, age, and educational attainment. METHODS: Two sequential cross-sectional studies were conducted in the municipalities of Canoas, Caxias do Sul, Ijuí, Passo Fundo, Pelotas, Porto Alegre, Santa Cruz do Sul, Santa Maria, and Uruguaiana to estimate the population prevalence of COVID-19. The study was designed to be representative of the urban population of these municipalities. A questionnaire including three questions about social distancing was also administered to the participants. Here, we present descriptive analyses of social distancing practices by subgroups and use chi-square tests for comparisons. RESULTS: In terms of degree of social distancing, 25.8% of the interviewees reported being essentially isolated and 41.1% reported being quite isolated. 20.1% of respondents reported staying at home all the time, while 44.5% left only for essential activities. More than half of households reported receiving no visits from non-residents. Adults aged 20 to 59 reported the least social distancing, while more than 80% of participants aged 60 years or older reported being essentially isolated or quite isolated. Women reported more stringent distancing than men. Groups with higher educational attainment reported going out for daily activities more frequently. CONCLUSIONS: The extremes of age are more protected by social distancing, but some groups remain highly exposed. This can be an important limiting factor in controlling progression of the COVID-19 pandemic.
Published: 2020

206. Estrutura etária e mortalidade por COVID-19

Author: Pedro C. Hallal and Fernando Pires Hartwig
Subjects: Coronavirus disease 2019 (COVID-19), Age structure, business.industry, Health Policy, Public Health, Environmental and Occupational Health, Medicine, Public aspects of medicine, RA1-1270, business, Demography
Published: 2020

207. Mendelian Randomization evaluation of causal effects of fibrinogen on incident coronary heart disease

Author: Sharon L.R. Kardia, Yii-Der Ida Chen, Stefan Groβ, Xiuqing Guo, Weihong Tang, Nathan Pankratz, Eric Boerwinkle, Thomas Meitinger, Nicholas L. Smith, Ci Song, Franco Giulianini, Jennifer E. Huffman, Lisa R. Yanek, Jerome I. Rotter, Abbas Dehghan, Bruce M. Psaty, Winfried März, Konstantin Strauch, Suzette J. Bielinski, Jennifer A. Smith, Paul M. Ridker, Tim Kacprowski, Patricia A. Peyser, Diane M. Becker, Marcus Dörr, Wolfgang Koenig, Lewis C. Becker, Astrid Petersman, Christopher J. O'Donnell, Daniel I. Chasman, André G. Uitterlinden, Naveed Sattar, Rasika A. Mathias, Cavin K. Ward-Caviness, Stella Trompet, Annette Peters, George Davey Smith, Jie Yao, Jennifer A. Brody, Martina Muller-Nuraysid, Kerri L. Wiggins, Yi-Ping Fu, Oscar H. Franco, Gibran Hemani, Lawrence F. Bielak, Moniek P.M. de Maat, Graciela E. Delgado, Alanna C. Morrison, Melanie Waldenberger, Andrew D. Johnson, Marcus E. Kleber, Jack Bowden, Paul S. de Vries, J. Wouter Jukema, Fernando Pires Hartwig, Russell P. Tracy, Kent D. Taylor, and Barbara McKnight
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, Hazard ratio, Genome-wide association study, Odds ratio, 030204 cardiovascular system & hematology, Fibrinogen, Confidence interval, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Sample size determination, Pleiotropy, Internal medicine, Mendelian randomization, medicine, Cardiology, business, 030304 developmental biology, medicine.drug
Abstract: BackgroundFibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.Methods and FindingsWe evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score incorporated data from 11 European-ancestry prospective cohorts to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95% confidence interval (CI).In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.ConclusionsA small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.Author SummaryInitial Mendelian Randomization (MR) analyses of the causal effect of fibrinogen on coronary heart disease (CHD) utilized single variants and did not take advantage of modern, multivariant approaches. This manuscript provides an important update to these initial analyses by incorporating larger sample sizes and employing multiple, modern multi-variant MR approaches to account for pleiotropy. We used incident cases to perform a MR study of the causal effect of fibrinogen on incident CHD and the nested outcome of myocardial infarction (MI) using an allele score approach. Then using data from a case-control genome-wide association study for CHD and MI we performed two sample MR analyses with multiple, pleiotropy robust approaches. Overall, the results indicated that associations between fibrinogen and CHD in observational studies are likely upwardly biased from any underlying causal effect. Single variant MR approaches show little evidence of a causal effect of fibrinogen on CHD or MI. Multi-variant MR analyses of fibrinogen on CHD indicate there may be a small positive effect, however this result needs to be interpreted carefully as the 95% confidence intervals were still consistent with a null effect. Multi-variant MR approaches did not suggest evidence of even a small causal effect of fibrinogen on MI.
Published: 2018
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208. Espaço público

Author: António de Amurane and Fernando Pires
Published: 2018

209. Genome-wide burden and association analyses implicate copy number variations in asthma risk among children and young adults from Latin America

Author: Camila Alexandrina Figueiredo, Gustavo Nunes de Oliveira Costa, Eduardo Tarazona-Santos, Alexandre C. Pereira, Bernardo L. Horta, Rosemeire L. Fiaccone, Pablo Rafael Silveira Oliveira, Andresa Karen Andrade Damasceno, M. Fernanda Lima-Costa, Fernanda de Souza Gomes Kehdy, Laura C. Rodrigues, Fernando Pires Hartwig, George Caique Gouveia Barbosa, Rita de Cássia Ribeiro-Silva, and Mauricio Lima Barreto
Subjects: Adult, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, endocrine system diseases, Science, In silico, Gene Dosage, Biology, Polymorphism, Single Nucleotide, Genome, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Young adult, Child, Gene, Asthma, Genetics, Pelotas, Multidisciplinary, Salvadoran, medicine.disease, Genetic architecture, Asthma Symptoms, SNP genotyping, 030104 developmental biology, 030228 respiratory system, Child, Preschool, Asthma Risk, Medicine, Chromosomes, Human, Pair 6, Female, Chromosome Deletion, Asthma Outcomes, Brazil
Abstract: The genetic architecture of asthma was relatively well explored. However, some work remains in the field to improve our understanding on asthma genetics, especially in non-Caucasian populations and with regards to commonly neglected genetic variants, such as Copy Number Variations (CNVs). In the present study, we investigated the contribution of CNVs on asthma risk among Latin Americans. CNVs were inferred from SNP genotyping data. Genome wide burden and association analyses were conducted to evaluate the impact of CNVs on asthma outcome. We found no significant difference in the numbers of CNVs between asthmatics and non-asthmatics. Nevertheless, we found that CNVs are larger in patients then in healthy controls and that CNVs from cases intersect significantly more genes and regulatory elements. We also found that a deletion at 6p22.1 is associated with asthma symptoms in children from Salvador (Brazil) and in young adults from Pelotas (Brazil). To support our results, we conducted an in silico functional analysis and found that this deletion spans several regulatory elements, including two promoter elements active in lung cells. In conclusion, we found robust evidence that CNVs could contribute for asthma susceptibility. These results uncover a new perspective on the influence of genetic factors modulating asthma risk.
Published: 2018

210. Assessing causality in the association between attention-deficit/hyperactivity disorder and obesity: a Mendelian randomization study

Author: Thais, Martins-Silva, Juliana Dos Santos, Vaz, Mara Helena, Hutz, Angélica, Salatino-Oliveira, Júlia Pasqualini, Genro, Fernando Pires, Hartwig, Carlos Renato, Moreira-Maia, Luis Augusto, Rohde, Maria Carolina, Borges, and Luciana, Tovo-Rodrigues
Subjects: Adult, Attention Deficit Disorder with Hyperactivity, Child, Preschool, Humans, Obesity, Mendelian Randomization Analysis, Child, White People, Body Mass Index, Genome-Wide Association Study
Abstract: Attention-deficit hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders in childhood and adolescence, is associated with obesity in observational studies. However, it is unclear whether ADHD contributes to, results from or is merely correlated with obesity. This study evaluates the presence and direction of a causal effect between ADHD and obesity.We performed a bidirectional two-sample Mendelian randomization using summary data from consortia of genome-wide association studies to investigate if ADHD (N = 55,374) has a causal effect on body mass index (BMI) in childhood (N = 35,668) and adulthood (N = 322,154-500,000), and vice-versa. The main analysis was performed using the inverse variance weighted (IVW) method. As sensitivity analyses, we used other Mendelian randomization methods that are more robust to horizontal pleiotropy (i.e., MR-Egger, weighted mode, and penalized weighted median estimators), as well as stratified the analysis by the putative mechanisms of genetic instruments (i.e., pathways involved or not in neurological processes).The IVW method indicated a positive causal effect of BMI on ADHD: β = 0.324 (95% CI 0.198 to 0.449, p 0.001; expressed as change in ln(odds ratio) of ADHD per each additional SD unit of BMI). IVW estimates were directionally consistent with other methods. On the other hand, we did not find consistent evidence for a causal effect of ADHD genetic liability on BMI.The results suggested that higher BMI increases the risk of developing ADHD, but not the other way around.
Published: 2018

211. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author: Brian D. Hobbs, Myriam Fornage, Hae Kyung Im, Lenore J. Launer, Dennis O. Mook-Kanamori, Robert C. Kaplan, Hieab H.H. Adams, Maarten van den Berge, George T. O'Connor, Natalie Terzikhan, Rodney J. Scott, Ani Manichaikul, Ravi Kalhan, Guy Brusselle, Leslie A. Lange, Yohan Bossé, Qing Duan, Tamara B. Harris, Esteban G. Burchard, Albert M. Levin, Kent D. Taylor, Mi Kyeong Lee, Woo Jin Kim, Yongmei Liu, Vilmundur Gudnason, Nora Franceschini, Hongsheng Gui, James G. Wilson, Donglei Hu, Lavinia Paternoster, Thomas Hansen, Roby Joehanes, Tianyuan Wang, Jennifer Liberto, Victoria E. Jackson, Jianping Jin, Colleen M. Sitlani, Tianxiao Huan, Wei Gao, Michael A. Province, Christopher Oldmeadow, Tarunveer S. Ahluwalia, Alanna C. Morrison, Kari E. North, Stephen B. Kritchevsky, Michael H. Cho, Gleb Kichaev, Kaare Christensen, Renée de Mutsert, Lauren S. Mogil, Mark McEvoy, Xin-Qun Wang, Juan C. Celedón, Fernando Pires Hartwig, Wenbo Tang, Judith M. Vonk, Kristin M. Burkart, Heather E. Wheeler, Bharat Thyagarajan, John Attia, Kim de Jong, Bruce M. Psaty, Sina A. Gharib, Traci M. Bartz, Josée Dupuis, Stephanie J. London, Ma'en Obeidat, Jerome I. Rotter, Stephen S. Rich, Mary K. Wojczynski, Susan R. Heckbert, Albert V. Smith, Frits R. Rosendaal, Tobias Bonten, Tamar Sofer, Patricia A. Cassano, H. Marike Boezen, Sam S. Oh, Ana M. B. Menezes, Mary F. Feitosa, David C. Nickle, Jason L. Sanders, Bernardo L. Horta, Fernando C. Wehrmeister, Jennifer N. Nguyen, Annah B. Wyss, Jeanne C. Latourelle, Margaret M. Parker, R. Graham Barr, Elizabeth G. Holliday, Richard H. Myers, Cathy C. Laurie, Kurt Lohman, Lies Lahousse, Don D. Sin, André G. Uitterlinden, Shujie Xiao, Jennifer A. Brody, L. Keoki Williams, Joohon Sung, Raymond Noordam, Mariaelisa Graff, Erasmus MC other, Epidemiology, Radiology & Nuclear Medicine, Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
Subjects: 0301 basic medicine, Lung Diseases, Male, Linkage disequilibrium, Epidemiology, Vital Capacity, General Physics and Astronomy, Genome-wide association study, VARIANTS, Genome-wide association studies, DISEASE, Linkage Disequilibrium, AIR-FLOW OBSTRUCTION, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Forced Expiratory Volume, Genetics research, Medicine and Health Sciences, lcsh:Science, Lung, Genetics, education.field_of_study, Multidisciplinary, LARGE-SCALE, Smoking, SMOOTH-MUSCLE, Öndunarfærasjúkdómar, Genomics, Hispanic or Latino, 3. Good health, LUNG-FUNCTION, Meta-analysis, Regression Analysis, Female, Erfðarannsóknir, Science, Population, Quantitative Trait Loci, Black People, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, Humans, SMOKING-BEHAVIOR, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, 1000 Genomes Project, education, Genetic association, Respiratory tract diseases, Asian, Faraldsfræði, Biology and Life Sciences, General Chemistry, 030104 developmental biology, 030228 respiratory system, Sample Size, SEGREGATION ANALYSIS, lcsh:Q, FOLLOW-UP, Genome-Wide Association Study
Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci., Supported in part by the Intramural Research Program of the National Institutes of Health, NIEHS. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute Grant R01HL105756
Published: 2018

212. A Genome-Wide Association Study in Hispanics/Latinos Identifies Novel Signals for Lung Function. The Hispanic Community Health Study/Study of Latinos

Author: Jean Morrison, Qi Yan, Deepa Rastogi, Stephanie J. London, Ana Maria Menezes, Lydiana Avila, Wei Chen, Robert C. Kaplan, María Soler Artigas, Tamar Sofer, Cathy C. Laurie, Kristin M. Burkart, Fernando Pires Hartwig, Ani Manichaikul, Adrienne M. Stilp, Alejandro A. Diaz, Elizabeth C. Oelsner, Martin D. Tobin, Ian P. Hall, Manuel Soto-Quiros, Louise V. Wain, Bernardo L. Horta, Sonia Davis Thomas, Stephen S. Rich, R. Graham Barr, and Juan C. Celedón
Subjects: Adult, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Adolescent, Genome-wide association study, Single-nucleotide polymorphism, Critical Care and Intensive Care Medicine, Bioinformatics, White People, Pulmonary function testing, Cohort Studies, Pulmonary Disease, Chronic Obstructive, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Medicine, Humans, Genetic Predisposition to Disease, Lung function, Aged, Genetic association, COPD, business.industry, Hispanic latino, Original Articles, Hispanic or Latino, Middle Aged, medicine.disease, United States, Respiratory Function Tests, respiratory tract diseases, Europe, 030104 developmental biology, 030228 respiratory system, Genetic Loci, Community health, Respiratory Physiological Phenomena, Female, Public Health, business, Genome-Wide Association Study, Program Evaluation
Abstract: Lung function and chronic obstructive pulmonary disease (COPD) are heritable traits. Genome-wide association studies (GWAS) have identified numerous pulmonary function and COPD loci, primarily in cohorts of European ancestry.Perform a GWAS of COPD phenotypes in Hispanic/Latino populations to identify loci not previously detected in European populations.GWAS of lung function and COPD in Hispanic/Latino participants from a population-based cohort. We performed replication studies of novel loci in independent studies.Among 11,822 Hispanic/Latino participants, we identified eight novel signals; three replicated in independent populations of European Ancestry. A novel locus for FEVWe identified novel signals for lung function and COPD in a Hispanic/Latino cohort. Including admixed populations when performing genetic studies may identify variants contributing to genetic etiologies of COPD.
Published: 2018

213. Breastfeeding and intelligence in adulthood: due to genetic confounding?

Author: Bernardo L. Horta, Cesar G. Victora, and Fernando Pires Hartwig
Subjects: medicine.medical_specialty, Intelligence, MEDLINE, Breastfeeding, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, business.industry, Obstetrics, Confounding, General Medicine, Articles, medicine.disease, 030227 psychiatry, Breast Feeding, Female, business, Breast feeding, Brazil, Cohort study
Abstract: Summary Background Breastfeeding has clear short-term benefits, but its long-term consequences on human capital are yet to be established. We aimed to assess whether breastfeeding duration was associated with intelligence quotient (IQ), years of schooling, and income at the age of 30 years, in a setting where no strong social patterning of breastfeeding exists. Methods A prospective, population-based birth cohort study of neonates was launched in 1982 in Pelotas, Brazil. Information about breastfeeding was recorded in early childhood. At 30 years of age, we studied the IQ (Wechsler Adult Intelligence Scale, 3rd version), educational attainment, and income of the participants. For the analyses, we used multiple linear regression with adjustment for ten confounding variables and the G-formula. Findings From June 4, 2012, to Feb 28, 2013, of the 5914 neonates enrolled, information about IQ and breastfeeding duration was available for 3493 participants. In the crude and adjusted analyses, the durations of total breastfeeding and predominant breastfeeding (breastfeeding as the main form of nutrition with some other foods) were positively associated with IQ, educational attainment, and income. We identified dose-response associations with breastfeeding duration for IQ and educational attainment. In the confounder-adjusted analysis, participants who were breastfed for 12 months or more had higher IQ scores (difference of 3·76 points, 95% CI 2·20–5·33), more years of education (0·91 years, 0·42–1·40), and higher monthly incomes (341·0 Brazilian reals, 93·8–588·3) than did those who were breastfed for less than 1 month. The results of our mediation analysis suggested that IQ was responsible for 72% of the effect on income. Interpretation Breastfeeding is associated with improved performance in intelligence tests 30 years later, and might have an important effect in real life, by increasing educational attainment and income in adulthood. Funding Wellcome Trust, International Development Research Center (Canada), CNPq, FAPERGS, and the Brazilian Ministry of Health.
Published: 2018

214. Letter by Hartwig et al Regarding Article, 'Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression'

Author: Maria Carolina Borges, Fernando Pires Hartwig, and Debbie A Lawlor
Subjects: 0301 basic medicine, medicine.medical_specialty, Statin, Randomization, medicine.drug_class, Disease, law.invention, 03 medical and health sciences, Randomized controlled trial, law, Internal medicine, Diabetes mellitus, medicine, Humans, cardiovascular diseases, business.industry, Confounding, Causal effect, medicine.disease, Regression, 030104 developmental biology, Cardiovascular Diseases, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business
Abstract: It was with interest that we read the publication by Labos et al1 on applying an adaptation of Egger regression to evaluate pleiotropic effects of drugs. They interpret their reanalysis of randomized controlled trials (RCTs) as indicating that the effect of statins on cardiovascular disease (CVD) and diabetes mellitus are mediated primarily, if not entirely, because of reducing low-density lipoprotein cholesterol (LDL-C) levels. We think that this approach has potential, but here, we point out 2 main conceptual limitations of it, which we think question the authors’ conclusion. Labos et al essentially did a meta-regression of the randomization status (RS)-outcome association (ie, intention-to-treat analyses) on RS-LDL-C association. By RS, we mean whether participants were assigned to statin or control groups, irrespective of compliance with these assignments. Given that perfect compliance is unlikely in real RCTs, RS and statin intake should not be treated as interchangeable. For example, an intention-to-treat analysis would be expected to be robust against confounding by prerandomization factors, but the same is not true for the association between actual statin intake and the outcome. Suppose that LDL-C has no causal effect on CVD but that statins nevertheless have a causal effect on CVD (that is not mediated by LDL-C) as depicted in the graphical abstract of Labos et al. In this situation, statin intake confounds the association between LDL-C levels and CVD, and therefore, both the association of RS with LDL-C and the association …
Published: 2018

215. The median and the mode as robust meta-analysis methods in the presence of small study effects

Author: George Davey Smith, Jack Bowden, Amand F. Schmidt, and Fernando Pires Hartwig
Subjects: Computer science, Robustness (computer science), Meta-analysis, Statistics, Mode (statistics), Sensitivity analyses
Abstract: Meta-analyses based on systematic literature reviews are commonly used to obtain a quantitative summary of the available evidence on a given topic. Despite its attractive simplicity, and its established position at the summit of the evidence-based medicine hierarchy, the reliability of any meta-analysis is largely constrained by the quality of its constituent studies. One major limitation is small study effects, whose presence can often easily be detected, but not so easily adjusted for. Here, robust methods of estimation based on the median and mode are proposed as tools to increase the reliability of findings in a meta-analysis. By re-examining data from published meta-analyses, and by conducting a detailed simulation study, we show that these two simple methods offer notable robustness to a range of plausible bias mechanisms, without making any explicit modelling assumptions. In conclusion, when performing a meta-analysis with suspected small study effects, we recommend reporting the mean, median and modal pooled estimates as a simple but informative sensitivity analyses.
Published: 2018
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216. Genetic and epigenetic aspects of breastfeeding

Author: Hartwig, Fernando Pires and Victora, Cesar Gomes
Subjects: Metilação do DNA, Gene - environment interaction, DNA methylation, Epidemiology, Breastfeeding, FADS2, Amamentação, Polimorfismos genéticos, Epidemiologia, Genetic polymorphisms, CIENCIAS DA SAUDE::SAUDE COLETIVA::EPIDEMIOLOGIA [CNPQ], Interação gene - ambiente
Abstract: Submitted by Aline Batista (alinehb.ufpel@gmail.com) on 2020-12-28T14:20:39Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_Fernando_Hartwig.pdf: 4964179 bytes, checksum: 360ac6964f825dcbddb298f034c67db0 (MD5) Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2020-12-28T18:49:16Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_Fernando_Hartwig.pdf: 4964179 bytes, checksum: 360ac6964f825dcbddb298f034c67db0 (MD5) Made available in DSpace on 2020-12-28T18:49:16Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese_Fernando_Hartwig.pdf: 4964179 bytes, checksum: 360ac6964f825dcbddb298f034c67db0 (MD5) Previous issue date: 2018-03-09 Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES A amamentação traz claros benefícios à saúde e capital humano, tanto em curto quanto em longo prazo. Entre os possíveis mecanismos biológicos responsáveis por estes efeitos, estão as modificações epigenéticas – incluindo a metilação do DNA – e a presença de ácidos graxos poli-insaturados de cadeia longa (cuja sigla em inglês é LC-PUFAs) no leite materno. Nesta tese, foi investigada a relação entre amamentação e metilação do DNA da criança através de uma revisão sistemática da literatura (artigo 1) e de um estudo original, avaliando níveis de metilação do DNA em centenas de milhares de regiões ao longo do genoma (artigo 2). O papel dos LC-PUFAs na associação entre amamentação e quociente de inteligência (QI) também foi avaliada através de um estudo de interação entre polimorfismos no gene FADS2 (que codifica uma enzima chave para a síntese endógena desses ácidos graxos) e amamentação, tendo QI como desfecho (artigo 3). Adotou-se a hipótese de adequação nutricional, de acordo com a qual o benefício da amamentação no QI seria maior nos indivíduos portadores de genótipos associados a uma menor síntese endógena de LC-PUFAs (e, portanto, mais dependentes de LC-PUFAs pré-formados). No artigo 1, verificou-se que a literatura sobre a relação entre amamentação e metilação do DNA é escassa, e os poucos estudos apresentam limitações importantes. No artigo 2, que utilizou dados de uma coorte inglesa de nascimentos, foram encontradas associações entre amamentação e níveis de metilação do DNA no sangue periférico aos 7 anos, e algumas dessas associações persistiram até a adolescência. No artigo 3, baseado em uma meta-análise de novo de dados publicados e não-publicados, observou-se uma maior média de QI entre os indivíduos que foram amamentados em ambos os grupos genéticos, sem evidência de interação amamentação-FADS2, contrariando a hipótese de adequação nutricional. Porém, análises complementares sugeriram que é possível que esta hipótese seja correta, mas que detectar a interação investigada requereria que a média de duração da amamentação nos estudos incluídos fosse maior. Os resultados dos três artigos indicam que amamentação está associação com modificações epigenéticos persistentes, e que a amamentação está positivamente associada com QI em todos os genótipos quanto aos polimorfimos estudados. Breastfeeding has clear short and long-term benefits to health and human capital. Possible biological mechanisms underlying these effects are epigenetic modifications – including DNA methylation – and the presence of long-chain polyunsaturated fatty acids (LC-PUFAs) in breast milk. In this, the relationship between breastfeeding and DNA methylation in the offspring was investigated through a systematic literature review (paper 1) and an original study using data on DNA methylation levels in hundreds of thousands of regions in the genome (paper 2). The role of LC-PUFAs in the association between breastfeeding and intelligence quotient (IQ) was also evaluated through the interaction between polymorphisms in the FADS2 gene (which encodes a key enzyme for the endogenous synthesis of LC-PUFAs) and breastfeeding, with IQ being the outcome (paper 3). This analysis tested a nutritional adequacy hypothesis, which postulates that the benefits of breastfeeding on IQ are larger among carriers of genotypes associated with lower endogenous synthesis of LC-PUFAs (and therefore more dependent on pre-formed LC-PUFAs). In paper 1, it was verified that the literature on the relationship between breastfeeding and DNA methylation is scarce, and the few available studies have important limitations. In paper 2, which used data from a British birth cohort, breastfeeding was found to be associated with blood DNA methylation levels at the age of 7 years, and some of these associations persisted until adolescence. In paper 3, which was based on a de novo meta-analysis including both published and unpublished data, IQ was on average higher among individuals that were breastfed in both genetic groups, with no indication of the FADS2-breastfeeding interaction, thus arguing against the nutritional adequacy hypothesis. However, complementary analyses suggested that this hypothesis might be true, but detecting the interaction would require that the average duration of breastfeeding in the included studies were higher. Collectively, the results from these three papers indicate that breastfeeding is associated with persistent epigenetic modifcations, and that breastfeeding is positively associated with IQ benefits in all genotypes with respect to the studied polymorphisms.
Published: 2018

217. Breastfeeding moderates FTO related adiposity: a birth cohort study with 30 years of follow-up

Author: Giovanny Vinícius Araújo de França, Fernando Pires Hartwig, Elma Izze da Silva Magalhães, Ken K. Ong, Fernando C. Barros, Emanuella De Lucia Rolfe, Cesar G. Victora, Bernardo L. Horta, Natália Peixoto Lima, Ong, Kenneth [0000-0003-4689-7530], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, Waist, Breastfeeding, lcsh:Medicine, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, FTO gene, Polymorphism, Single Nucleotide, Article, Body Mass Index, Cohort Studies, 03 medical and health sciences, Medicine, Humans, risk factors, Genetic Predisposition to Disease, Obesity, Young adult, lcsh:Science, Adiposity, 2. Zero hunger, Multidisciplinary, business.industry, lcsh:R, nutritional and metabolic diseases, 030104 developmental biology, Breast Feeding, Lean body mass, Body Composition, lcsh:Q, Female, epidemiology, business, Body mass index, Breast feeding, Brazil, Demography, Cohort study, Follow-Up Studies
Abstract: This study assessed the association of breastfeeding with body composition at 30 years, among subjects who have been prospectively followed since birth in a southern Brazilian city. We also evaluated whether breastfeeding moderated the association between the rs9939609 variant in the FTO gene and adiposity. At 30 years, total and predominant breastfeeding were positively associated with lean mass index and inversely with visceral fat thickness. Among subjects breastfed for FTO genotype (rs9939609). Associations among subjects breastfed for one month or longer tended to be in the same direction but showed lower magnitude and were less consistent; for all outcomes. Interactions had p values ≤ 0.05 for body mass index, fat mass index and waist circumference. Even among young adults, breastfeeding moderates the association between the FTO variant rs9939609 and body composition.
Published: 2018

218. A Anarquia nas Teorias das Relações Internacionais: hegemonia de paradigmas ou necessidade conceptual?

Author: Santos, Rui Fernando Pires Henrique and Pinto, Ana Santos
Subjects: Theories of International Relations, Hegemony, Teorias das Relações Internacionais, Anarchy, Ciências Sociais::Ciências Políticas [Domínio/Área Científica], Hegemonia, Paradigma, Paradigm, Anarquia
Abstract: Esta tese visa interrogar o conceito-chave das Teorias sistémicas das Relações Internacionais, a Anarquia. Numa disciplina científica recente e eivada de ontologias e epistemologias díspares, a mencionada conceptualização anárquica tem-se sabido impor e resistir ao tempo e a várias investidas teóricas. Foi o Realismo Estrutural (ou neo-realismo) de Kenneth Waltz e o seu “Theory of International Politics” (1979) que permitiu trazer uma “determinada” configuração Anárquica para o âmago das Relações Internacionais. As sistematizações teóricas Realista, Liberal e Construtivista (nas suas múltiplas abordagens) partilham esta mesma assunção, baseada no pressuposto da inexistência de uma autoridade superior ao Estado. A Anarquia assume-se como uma necessidade conceptual paradigmática e “naturalizada”. Utilizando uma gama de ferramentas teóricas críticas – suportadas pela análise da Hegemonia Gramsciana e neo-gramsciana bem como na ligação da tríade conhecimento-poder-linguagem que existe em Foucault e na “escola” da Análise Crítica de Discurso – visamos argumentar que a Anarquia se estatuiu com formato de Hegemonia ideacional no edifício disciplinar das Relações Internacionais. Apresentamos para o efeito – como complemento ao enquadramento teórico – uma pesquisa quantitativa que valida a proeminência de autores e textos geograficamente “ocidentais”, epistemologicamente racionalistas, editados em língua inglesa e posteriores à marca do volume Waltziano (1979) que funciona como paradigma indispensável. Esta “tipologia” de autores e textos, reflectindo ademais posicionamentos e influências académicas e científicas, potencia uma caracterização hegemónica, apta a estabelecer, mesmo que de forma tácita e difusa, “regras de acesso” e “regimes de verdade” em torno do principio basilar desta disciplina, a Anarquia. This dissertation aims to interrogate the key concept of the systemic Theories of International Relations, Anarchy. In a recent scientific discipline based on disparate ontologies and epistemologies, the aforementioned anarchic conceptualization has been able to impose and resist time and several theoretical assumptions. It was Kenneth Waltz's Structural Realism (or neo-realism) and his "Theory of International Politics" (1979), which allowed for a "determined" Anarchic configuration of international relations. The theoretical, Realistic, Liberal and Constructivist systematizations (in their multiple approaches) share this same assumption, based on the presupposition that there is no authority superior to the State. Anarchy is assumed to be a paradigmatic and "naturalized" conceptual need. Using a range of critical theoretical tools - supported by the analysis of the Gramscian Hegemony and the linkage of the knowledge-power-language triad that exists in Foucault and the "school" of Critical Discourse Analysis - we aim to argue that Anarchy was modeled as Hegemony in the disciplinary building of International Relations. For this purpose – and as a complement to our theoretical framework - we present a quantitative research that validates the prominence of writers and works geographically "western", epistemologically rationalist, published in English and subsequent to Waltzian volume (1979), which functions as an indispensable paradigm. This "typology" of authors and texts, reflecting in addition academic and scientific positions and influences, fosters a hegemonic characterization, capable of establishing, even tacitly and diffusely, "rules of access" and "regimes of truth" around the principle of this discipline, Anarchy.
Published: 2018

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

Author: Hans Bisgaard, Leon Eyrich Jessen, John G. Logan, Gudmar Porleifsson, Hou-Feng Zheng, Annelies C. Ham, Tarunveer S. Ahluwalia, Struan F.A. Grant, Yongmei Liu, M. Carola Zillikens, Ivana Nedeljkovic, Mattias Lorentzon, Daniel S. Evans, Kari Stefansson, Jing Hua Zhao, Gunnar Sigurdsson, Fiona E. McGuigan, Rebecca D. Jackson, Douglas P. Kiel, M. Arfan Ikram, David Karasik, J. Brent Richards, Scott Wilson, Tamara B. Harris, Najaf Amin, James F. Wilson, Peter I. Croucher, John A Robbins, Carolina Medina-Gomez, Raimo Joro, Frances M K Williams, Stuart H. Ralston, Unnur Styrkarsdottir, Timo A. Lakka, Jian'an Luan, Cheryl L. Ackert-Bicknell, John P. Walsh, Benjamin H. Mullin, Fernando Pires Hartwig, Bruce M. Psaty, Robert A. Scott, Claes Ohlsson, Janine F. Felix, Bram C. J. van der Eerden, Jonathan H Tobias, Mike A. Nalls, Christian J. Carlsson, Cindy G. Boer, Kun Zhu, Tim D. Spector, Linda Broer, Babette S. Zemel, Martin den Heijer, Mustafa Atalay, Eric S. Orwoll, David M. Evans, Ruifang Li-Gao, John P. Kemp, Katharina E. Schraut, Dennis O. Mook-Kanamori, Kristina Åkesson, Katerina Trajanoska, Maria Nethander, Evangelia E. Ntzani, Cornelia M. van Duijn, Craig E. Pennell, Yanhua Zhou, Ching-Ti Liu, Vincenzo Forgetta, Claudia Langenberg, Fernando Rivadeneira, Vincent W. V. Jaddoe, Nathalie van der Velde, J. H. Duncan Bassett, Bernardo L. Horta, Jeroen van de Peppel, Samuel K. Handelman, Evangelos Evangelou, Klaus Bønnelykke, Renée de Mutsert, Denise H. M. Heppe, Nicholas J. Wareham, Graham R. Williams, Bo L. Chawes, Andre J. van Wijnen, Carol A. Wang, Mohsen Ghanbari, Alessandra Chesi, André G. Uitterlinden, Epidemiology, Erasmus MC other, Internal Medicine, Clinical Genetics, Pediatrics, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Zhao, Jing Hua [0000-0003-4930-3582], Apollo - University of Cambridge Repository, Geriatrics, APH - Aging & Later Life, AMS - Ageing & Morbidty, AMS - Amsterdam Movement Sciences, Wellcome Trust, Pediatric surgery, General practice, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, and IOO
Subjects: 0301 basic medicine, Aging, Bone density, Osteoporosis, Genome-wide association study, Bioinformatics, Medical and Health Sciences, total-body DXA, CREB3L1, Mice, 0302 clinical medicine, Bone Density, GWASs, 2.1 Biological and endogenous factors, Aetiology, Child, Genetics (clinical), Bone mineral, Genetics & Heredity, Mice, Knockout, ESR1, RANKL, Age Factors, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, genetic correlation, medicine.anatomical_structure, Meta-analysis, Child, Preschool, Regression Analysis, musculoskeletal diseases, Adolescent, Knockout, 030209 endocrinology & metabolism, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Quantitative Trait, Rare Diseases, Quantitative Trait, Heritable, Bone Density/genetics, Clinical Research, BMD, meta-regression, medicine, Genetics, Journal Article, Animals, Humans, Polymorphism, Preschool, Heritable, Genetic association, Femoral neck, age-dependent effects, Human Genome, Infant, Newborn, Infant, 06 Biological Sciences, medicine.disease, Newborn, 030104 developmental biology, Good Health and Well Being, fracture, Genetic Loci, Musculoskeletal, genome-wide association studies, bone mineral density, Genome-Wide Association Study
Abstract: Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.
Published: 2018

220. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Author: Patricia A. Peyser, Jessica D. Faul, Sing Hui Lim, Xu Chen, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, W. James Gauderman, Wei Zhao, Andres Metspalu, R. Graham Barr, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Daniel I. Chasman, Jasmin Divers, Fernando Pires Hartwig, Jing Hua Zhao, Yu Caizheng, Roby Joehanes, Nora Franceschini, Nita G. Forouhi, Charumathi Sabanayagam, Paul M. Ridker, Yun J. Sung, Mary F. Feitosa, Barbara V. Howard, Vilmundur Gudnason, Jost B. Jonas, Hua Tang, Yukihide Momozawa, Michael R. Brown, Tibor V. Varga, Franco Giulianini, Francis S. Collins, Alexander P. Reiner, Ulrich Broeckel, Tuomo Rankinen, Preeti Gupta, Tin Louie, Eric Boerwinkle, Saskia P. Hagenaars, Mark J. Caulfield, Albert Hofman, Aravinda Chakravarti, Paul W. Franks, Nicole Schupf, E. Shyong Tai, Carl D. Langefeld, Carsten Oliver Schmidt, Lawrence F. Bielak, Treva Rice, Anne B. Newman, Ioanna Ntalla, Kae-Woei Liang, Nilesh J. Samani, Alena Stančáková, Thomas H. Mosley, Dan E. Arking, Kenneth Rice, Bruce M. Psaty, Jirong Long, Yechiel Friedlander, Jianjun Liu, Donna K. Arnett, Ya X. Wang, Xiuqing Guo, Anne E. Justice, Pamela J. Schreiner, Renée de Mutsert, Lisa de las Fuentes, Marcus Dörr, Amy R. Bentley, Susan Redline, Cornelia M. van Duijn, Melissa A. Richard, Sarah E. Harris, Pirjo Komulainen, Nicholette D. Palmer, Alexandre C. Pereira, Michele K. Evans, Jie Yao, Adesola Ogunniyi, Wen Bin Wei, Anuradhani Kasturiratne, Yoichiro Kamatani, Charles Kooperberg, Helen R. Warren, Shiow Lin, Ozren Polasek, Makoto Hirata, Anubha Mahajan, Yingchang Lu, Jonathan Marten, Claudia P. Cabrera, Chuan Gao, Oscar H. Franco, Yongmei Liu, Mathilde Boissel, Olli T. Raitakari, Xiao-Ou Shu, Yii-Der Ida Chen, Y Liu, Claudia Langenberg, C. Charles Gu, Cathy C. Laurie, Tamuno Alfred, L. Adrienne Cupples, Yajuan Wang, Colin A. McKenzie, Mika Kähönen, Yize Li, Xiaofeng Zhu, Nana Matoba, James Scott, Marguerite R. Irvin, Markku Laakso, Frida Renström, Woon-Puay Koh, Dabeeru C. Rao, Yucheng Jia, Paul Elliott, Tangchun Wu, Caroline Hayward, Tamara B. Harris, Alison D. Murray, Karin Leander, Reedik Mägi, Keng-Hung Lin, Harold Snieder, Laura J. Bierut, Christine Williams, Solomon K. Musani, Michael A. Province, Charles B. Eaton, Sharon L.R. Kardia, Mario Sims, Steven C. Hunt, Stephen B. Kritchevsky, Weihua Zhang, David R. Weir, Andrea R. V. R. Horimoto, Saima Afaq, Hugues Aschard, Ilaria Gandin, Michiaki Kubo, Jaspal S. Kooner, Peter S. Braund, Jeffrey R. O'Connell, Kent D. Taylor, Annette Peters, Wei Zheng, Rainer Rettig, Nicola D. Kerrison, Donald W. Bowden, Ruth J. F. Loos, Tanika N. Kelly, Dennis O. Mook-Kanamori, Terrence Forrester, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, Ching-Yu Cheng, Alanna C. Morrison, Tuomas O. Kilpeläinen, Jian-Min Yuan, Bruna Gigante, Lisa R. Yanek, Ching-Ti Liu, Ananda R. Wickremasinghe, Michael Boehnke, Tin Aung, Jin-Fang Chai, Kaare Christensen, Wen-Jane Lee, Stéphanie Debette, Jennifer A. Brody, Wayne Huey-Herng Sheu, John M. C. Connell, Ganesh Chauhan, Jian'an Luan, Melanie Waldenberger, Erin B. Ware, Paolo Gasparini, Chew-Kiat Heng, Lili Milani, Alisa K. Manning, José Eduardo Krieger, Kiang Liu, Mickaël Canouil, Robert A. Scott, Yik Ying Teo, Gregory P. Wilson, Stella Aslibekyan, Andrew P. Morris, Thomas Meitinger, Jennifer A. Smith, Yi-Jen Hung, Myriam Fornage, Dina Vojinovic, William R. Scott, Virginia Fisher, Peter S. Sever, André G. Uitterlinden, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Rajkumar Dorajoo, Georg Ehret, Heming Wang, Sandosh Padmanabhan, Jingmin Liu, Colleen M. Sitlani, Anuj Goel, Bamidele O. Tayo, Daniel Levy, Barry I. Freedman, Marie Loh, Yanhua Zhou, Charles N. Rotimi, Qing Duan, Aldi T. Kraja, He Meian, Archie Campbell, Kari E. North, Tien Yin Wong, Salman M. Tajuddin, Traci M. Bartz, Mike A. Nalls, Misa Graff, Dongfeng Gu, Sudha Seshadri, Tõnu Esko, Antonietta Robino, Anne U. Jackson, H. Janaka de Silva, Peter J. van der Most, Fang-Chi Hsu, Chiea Chuen Khor, Changwei Li, Sami Heikkinen, Maris Alver, Karen Schwander, Wanqing Wen, Rainer Rauramaa, Lynne E. Wagenknecht, Ubaydah Nasri, Peter J. Munson, He Gao, Evangelos Evangelou, Philippe Froguel, Ervin R. Fox, Christian Gieger, Kurt Lohman, James S. Pankow, Nicholas J. Wareham, Lynda M. Rose, Massimiliano Cocca, Rob M. van Dam, John M. Starr, Martin Farrall, Stefan Weiss, Konstantin Strauch, Albert V. Smith, Jill M. Norris, Raymond Noordam, Cora E. Lewis, Claude Bouchard, Ulf de Faire, Walter Palmas, Diane M. Becker, Kevin Sandow, Tomohiro Katsuya, Jiang He, Nancy L. Pedersen, Bernardo L. Horta, Joel D. Kaufman, Terho Lehtimäki, Heikki A. Koistinen, Thomas W. Winkler, Ian J. Deary, Richard S. Cooper, Fumihiko Takeuchi, Jerome I. Rotter, Lihua Wang, Yih Chung Tham, Babatunde L. Salako, Mary K. Wojczynski, Pim van der Harst, Jennifer G. Robinson, Erwin P. Bottinger, Alan B. Zonderman, Patricia B. Munroe, Ehret, Georg Benedikt, Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The various Gene-Lifestyle Interaction projects, including this one, are largely supported by a grant from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305. A Career Development Award (K25HL121091), also from the NHLBI, enabled Y.J.S. to lead this project. Full set of study-specific funding sources and acknowledgments appear in the Supplemental Note., Sung, Yun J., Winkler, Thomas W., de las Fuentes, Lisa, Bentley, Amy R., Brown, Michael R., Kraja, Aldi T., Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Feitosa, Mary F., Kilpeläinen, Tuomas O., Richard, Melissa A., Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugue, Bartz, Traci M., Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K., Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M., Tayo, Bamidele O., Warren, Helen R., Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Mari, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E., Hartwig, Fernando Pire, Horimoto, Andrea R. V. R., Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Kühnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, ’an Luan, Jian, Mckenzie, Colin A., Meian, He, Nelson, Christopher P., Rauramaa, Rainer, Schupf, Nicole, Scott, Robert A., Sheu, Wayne H. H., Stančáková, Alena, Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Wang, Heming, Wang, Yajuan, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan, Aung, Tin, Barr, R. Graham, Bielak, Lawrence F., Boerwinkle, Eric, Bottinger, Erwin P., Braund, Peter S., Brody, Jennifer A., Broeckel, Ulrich, Cabrera, Claudia P., Cade, Brian, Caizheng, Yu, Campbell, Archie, Canouil, Mickaël, Chakravarti, Aravinda, Chauhan, Ganesh, Christensen, Kaare, Cocca, Massimiliano, Collins, Francis S., Connell, John M., de Mutsert, Renée, de Silva, H. Janaka, Debette, Stephanie, Dörr, Marcu, Duan, Qing, Eaton, Charles B., Ehret, Georg, Evangelou, Evangelo, Faul, Jessica D., Fisher, Virginia A., Forouhi, Nita G., Franco, Oscar H., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Graff, Misa, Gu, C. Charle, Gu, Dongfeng, Gupta, Preeti, Hagenaars, Saskia P., Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hofman, Albert, Howard, Barbara V., Hunt, Steven, Irvin, Marguerite R., Jia, Yucheng, Joehanes, Roby, Justice, Anne E., Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D., Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A., Komulainen, Pirjo, Kooperberg, Charle, Krieger, Jose E., Kubo, Michiaki, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lim, Sing Hui, Lin, Shiow, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Kiang, Liu, Yeheng, Loh, Marie, Lohman, Kurt K., Long, Jirong, Louie, Tin, Mägi, Reedik, Mahajan, Anubha, Meitinger, Thoma, Metspalu, Andre, Milani, Lili, Momozawa, Yukihide, Morris, Andrew P., Mosley, Thomas H., Munson, Peter, Murray, Alison D., Nalls, Mike A., Nasri, Ubaydah, Norris, Jill M., North, Kari, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Palmer, Nicholette D., Pankow, James S., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Raitakari, Olli T., Renström, Frida, Rice, Treva K., Ridker, Paul M., Robino, Antonietta, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L., Sandow, Kevin, Schmidt, Carsten O., Schreiner, Pamela J., Scott, William R., Seshadri, Sudha, Sever, Peter, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G., Waldenberger, Melanie, Wang, Lihua, Wang, Ya X., Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K., Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Chen, Yii-Der Ida, de Faire, Ulf, Deary, Ian J., Esko, Tõnu, Farrall, Martin, Forrester, Terrence, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost B., Kato, Norihiro, Kooner, Jaspal S., Laakso, Markku, Lehtimäki, Terho, Liang, Kae-Woei, Magnusson, Patrik K. E., Newman, Anne B., Oldehinkel, Albertine J., Pereira, Alexandre C., Redline, Susan, Rettig, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Kamatani, Yoichiro, Laurie, Cathy C., Bouchard, Claude, Cooper, Richard S., Evans, Michele K., Gudnason, Vilmundur, Kardia, Sharon L. R., Kritchevsky, Stephen B., Levy, Daniel, O'Connell, Jeff R., Psaty, Bruce M., van Dam, Rob M., Sims, Mario, Arnett, Donna K., Mook-Kanamori, Dennis O., Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Fornage, Myriam, Rotimi, Charles N., Province, Michael A., van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Loos, Ruth J. F., Reiner, Alex P., Rotter, Jerome I., Zhu, Xiaofeng, Bierut, Laura J., Gauderman, W. Jame, Caulfield, Mark J., Elliott, Paul, Rice, Kenneth, Munroe, Patricia B., Morrison, Alanna C., Cupples, L. Adrienne, Rao, Dabeeru C., Chasman, Daniel I., Marten, Jonathan [0000-0001-6916-2014], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Epidemiology, Internal Medicine, Gastroenterology & Hepatology, Clinicum, Department of Medicine, Endokrinologian yksikkö, HUS Internal Medicine and Rehabilitation, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, multi-ancestry, Smoking/genetics, Genome-wide association study, Continental Population Groups/genetics, INTIMA-MEDIA THICKNESS, Cohort Studies, Diastole, Polymorphism (computer science), GWAS, TRANSTORNOS RELACIONADOS AO USO DE ÁLCOOL, GENE-ENVIRONMENT INTERACTION, Genetics (clinical), ddc:616, INSULIN-RESISTANCE, Multi-ancestry, Smoking, 1184 Genetics, developmental biology, physiology, blood pressure, GxE interaction, Diastole/genetics, 3. Good health, FALSE DISCOVERY RATE, Blood pressure, Medical genetics, CORONARY-ARTERY-DISEASE, Female, Single Nucleotide/genetics, Systole/genetics, BODY-MASS INDEX, ASSOCIATION ANALYSIS, COMMON VARIANTS, METAANALYSIS, DISEASE, OBESITY, JOINT, medicine.medical_specialty, lifestyle, SUSCEPTIBILITY LOCI, Blood Pressure/genetics, Systole, Quantitative Trait Loci, Single-nucleotide polymorphism, Accounting, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, GxE interactions, Article, smoking, 03 medical and health sciences, Genetic, medicine, Genetics, Journal Article, Humans, Polymorphism, Genetic association, ALCOHOL DEPENDENCE, business.industry, Racial Groups, Reproducibility of Results, Epistasis, Genetic, ta3121, Lifestyle, Genetic architecture, NICOTINE DEPENDENCE, 030104 developmental biology, Genetic Loci, Epistasis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, business, Quantitative Trait Loci/genetics, Genome-Wide Association Study
Abstract: The authors declare no competing financial interests except for the following. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health); L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; P.S. has received research awards from Pfizer Inc., is a consultant for Mundipharma Co. (Cambridge, UK), is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and has a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15 000 771.4); P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project; M.A.N.’s participation is supported by a consulting contract between Data Tecnica Internation and the National Institute on Aging (NIH, Bethesda, MD, USA), and he also consults for Illumina, Inc., the Michael J. Fox Foundation, and University of California Healthcare among others; and M.J.C. is Chief Scientist for Genomics England, a UK government company.; International audience; Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined approximately 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Published: 2018

221. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Author: Rico Rueedi, Yuri Milaneschi, Brenda W.J.H. Penninx, Neil Poulter, Karen Schwander, Marco Brumat, Kenneth Rice, Yize Li, Veronique Vitart, Ioanna Ntalla, Michele K. Evans, Jeffrey R. O'Connell, Nilesh J. Samani, Colleen M. Sitlani, W. James Gauderman, Xuan Deng, Paul M. Ridker, Yun J. Sung, Yukihide Momozawa, Archie Campbell, Tin Louie, Nona Sotoodehnia, Yii-Der Ida Chen, Cornelia M. van Duijn, Tanika N. Kelly, Peter S. Sever, André G. Uitterlinden, Brigitte Kühnel, John M. Starr, Lawrence F. Bielak, Christopher P. Nelson, Wanqing Wen, Stephan B. Felix, Stefan Weiss, Daniel Levy, Nicholette D. Palmer, Alisa K. Manning, Salman M. Tajuddin, Jill M. Norris, Marie Loh, M. Abdullah Said, Alena Stančáková, Anuradhani Kasturiratne, John M. C. Connell, Jian'an Luan, Tuomas O. Kilpeläinen, Amy R. Bentley, Stephen Sidney, Alan B. Zonderman, Karin Leander, David J. Porteous, Jianjun Liu, Tin Aung, Charles B. Eaton, Sharon L.R. Kardia, Rajkumar Dorajoo, Stephen Turner, Michael Boehnke, Diane M. Becker, Cora E. Lewis, Ozren Polasek, Mickaël Canouil, Kurt Lohman, Georg Ehret, Sarah E. Harris, Robert A. Scott, Claude Bouchard, Lynne E. Wagenknecht, Mohsen Ghanbari, Stephen B. Kritchevsky, Jin-Fang Chai, Gregory L. Burke, Jiang He, Federica Laguzzi, Michael R. Brown, Walter Palmas, Lili Milani, Thomas T. Perls, Tibor V. Varga, José Eduardo Krieger, Erin B. Ware, Tamara B. Harris, Tomohiro Katsuya, Nicole Schupf, Mika Kähönen, Nana Matoba, Hugues Aschard, Ilaria Gandin, Jennifer A. Smith, Traci M. Bartz, James Scott, Tuomo Rankinen, Yuan Shi, Meian He, Timo A. Lakka, Helen R. Warren, Mike A. Nalls, Kent D. Taylor, Woon-Puay Koh, Ya Xing Wang, Muhammad Riaz, Sandosh Padmanabhan, Mary F. Feitosa, Jost B. Jonas, Paul Elliott, Christian Gieger, Terho Lehtimäki, Kaare Christensen, Maris Alver, Pirjo Komulainen, Pamela J. Schreiner, M. Arfan Ikram, David R. Weir, Charles Kooperberg, Oscar H. Franco, Yongmei Liu, Lisa de las Fuentes, Nancy L. Pedersen, Thomas W. Winkler, Bruna Gigante, Göran Hallmans, Ingrid B. Borecki, Shiow Lin, Ian J. Deary, Wei Zheng, Yajuan Wang, Bernardo L. Horta, Heather M. Stringham, Bruce M. Psaty, Paul W. Franks, Weihua Zhang, Nora Franceschini, Adolfo Correa, Nita G. Forouhi, Xiuqing Guo, Fumihiko Takeuchi, L. Adrienne Cupples, William R. Scott, Zoltán Kutalik, He Gao, Nicholas J. Wareham, E. Shyong Tai, Aravinda Chakravarti, C. Charles Gu, Paolo Gasparini, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Colin A. McKenzie, Qing Duan, Aldi T. Kraja, Carsten Oliver Schmidt, Bamidele O. Tayo, Xiaofeng Zhu, Thomas Meitinger, Mary K. Wojczynski, Markku Laakso, Mark J. Caulfield, Carl D. Langefeld, Jingzhong Ding, Yechiel Friedlander, Tien Yin Wong, Virginia Fisher, Raymond Noordam, Caizheng Yu, Pim van der Harst, Yik Ying Teo, Ervin R. Fox, Sabanayagam Charumathi, Jonathan Marten, Nicholas Y.Q. Tan, Jerome I. Rotter, Harold Snieder, Karen L. Mohlke, Christine Williams, Olli T. Raitakari, Renée de Mutsert, Lihua Wang, Kathryn Roll, Jingmin Liu, Dongfeng Gu, Wei Zhao, Lynda M. Rose, Michael A. Province, Fernando Pires Hartwig, Rob M. van Dam, Barry I. Freedman, Andres Metspalu, Donald W. Bowden, Andrea R. V. R. Horimoto, Martin Farrall, Frits R. Rosendaal, Rainer Rauramaa, Konstantin Strauch, Albert V. Smith, Yanick Hagemeijer, Michiaki Kubo, Ilja M. Nolte, Tõnu Esko, Yih Chung Tham, Cathy C. Laurie, Antonietta Robino, Anne U. Jackson, Chuan Gao, Dabeeru C. Rao, Xiao-Ou Shu, H. Janaka de Silva, Morris J. Brown, Alanna C. Morrison, Peter J. van der Most, Jian-Min Yuan, Melanie Waldenberger, Leslie J. Raffel, Ulrich John, Fang-Chi Hsu, Reedik Mägi, Solomon K. Musani, Chiea Chuen Khor, Mario Sims, Ruben N. Eppinga, Melissa A. Richard, Yoichiro Kamatani, Changwei Li, Qiuyin Cai, Daniel I. Chasman, Mathilde Boissel, Claudia Langenberg, Sami Heikkinen, Jasmin Divers, Saima Afaq, Wen Bin Wei, Jaspal S. Kooner, Terrence Forrester, Hua Tang, Charles N. Rotimi, Anuj Goel, Annette Peters, Tangchun Wu, Dennis O. Mook-Kanamori, Caroline Hayward, Ching-Yu Cheng, Lisa R. Yanek, Ananda R. Wickremasinghe, Chew-Kiat Heng, Myriam Fornage, Dina Vojinovic, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Jing Hua Zhao, Barbara V. Howard, Vilmundur Gudnason, Ulrich Broeckel, Eric Boerwinkle, Saskia P. Hagenaars, Dan E. Arking, Peter Vollenweider, Alexandre C. Pereira, Jie Yao, Makoto Hirata, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, Epidemiology, Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), University of Regensburg, Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Northwestern Polytechnical University [Xi'an] (NPU), Centre for Molecular Epidemiology, National University of Singapore (NUS), Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), National Institutes of Health [Bethesda] (NIH), The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., AGES (Age Gene/Environment Susceptibility Reykjavik Study) is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC (Atherosclerosis Risk in Communities): The authors thank the staff and participants of the ARIC study for their important contributions. CARDIA (Coronary Artery Risk Development in Young Adults): This manuscript has been reviewed and approved by CARDIA for scientific content. CHS (Cardiovascular Health Study): A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. IGMM (Institute of Genetics and Molecular Medicine): CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and the Croatian Institute for Public Health. We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the participants. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. GS:SFHS: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland. ERF (Erasmus Rucphen Family study): We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, P. Snijders for his help in data collection and E.M. van Leeuwen for genetic imputation. GENOA (Genetic Epidemiology Network of Arteriopathy): Genotyping was performed at the Mayo Clinic (Stephen T. Turner, MD, Mariza de Andrade PhD, Julie Cunningham, PhD). We thank Eric Boerwinkle, PhD and Megan L. Grove from the Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas, USA for their help with genotyping. We would also like to thank the families that participated in the GENOA study. HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span): Data analyses for the HANDLS study utilized the high-performance computational resources of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. http://hpc.nih.gov HUFS (Howard University Family Study): We thank the participants of the study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HyperGEN (Hypertension Genetic Epidemiology Network): The study involves: University of Utah: (Network Coordinating Center, Field Center, and Molecular Genetics Lab), Univ. of Alabama at Birmingham: (Field Center and Echo Coordinating and Analysis Center), Medical College of Wisconsin: (Echo Genotyping Lab), Boston University: (Field Center), University of Minnesota: (Field Center and Biochemistry Lab), University of North Carolina: (Field Center), Washington University: (Data Coordinating Center), Weil Cornell Medical College: (Echo Reading Center), National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html JHS (Jackson Heart Study): The authors wish to thank the staffs and participants of the JHS. MESA (Multi-Ethnic Study of Atherosclerosis): MESA and the MESA SHARe project are conducted in collaboration with MESA investigators. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. NEO (The Netherlands Epidemiology of Obesity study): The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Petra Noordijk, Pat van Beelen and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. RS (Rotterdam Study) was funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters and Carolina Medina-Gomez for their help in creating the GWAS database, and Karol Estrada, Yurii Aulchenko and Carolina Medina-Gomez for the creation and analysis of imputed data. WHI (Women’s Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf Replication: AA-DHS (African American Diabetes Heart Study): The investigators acknowledge the cooperation of our Diabetes Heart Study (DHS) and AA-DHS participants. ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial): We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome chip array. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. BBJ (Biobank Japan Project): We thank all the participants, medical coordinators of the cooperating hospitals for collecting samples and clinical information in the project. BRIGHT (British Genetics of Hypertension): The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. CoLaus (Cohorte Lausannoise Study): The authors would like to thank all the people who participated in the recruitment of the participants, data collection and validation, particularly Nicole Bonvin, Yolande Barreau, Mathieu Firmann, François Bastardot, Julien Vaucher, Panagiotis Antiochos and Cédric Gubelmann. DESIR (Data from an Epidemiological Study on the Insulin Resistance): The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel), CHU de Rennes (F. Bonnet), CNRS UMR-8199 (Lille: A. Bonnefond, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, LeMans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), the general practitioners of the region and the Cross- Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol). DHS (Diabetes Heart Study): The authors thank the investigators, staff, and participants of the DHS for their valuable contributions. EGCUT Estonian Genome Center—University of Tartu (Estonian Biobank): Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk: We thank all EPIC participants and staff for their contribution to the study. FENLAND (The Fenland Study): We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support from the Medical research council (MC_UU_12015/1). GeneSTAR (Genetic Studies of Atherosclerosis Risk): We are very grateful to all of our participants for their long-term involvement. GLACIER (Gene x Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk): We thank the participants, health professionals and data managers involved in the Västerbottens Intervention Project. We are also grateful to the staff of the Northern Sweden Biobank for preparing materials and to K Enqvist and T Johansson (Västerbottens County Council, Umeå, Sweden) for DNA preparation. HCHS/SOL (Hispanic Community Health Study/Study of Latinos): We thank the participants and staff of the HCHS/SOL study for their contributions to this study. HRS (Health & Retirement Study): Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. HyperGEN-AXIOM (Hypertension Genetic Epidemiology Network—Axiom Chip GWAS): We thank the study investigators, staff and participants for their value contributions. INGI (Italian Network Genetic Isolate): We thank all the inhabitants who participated to the projects. InterAct (The EPIC-InterAct Case-Cohort Study): We thank all EPIC participants and staff for their contribution to the study. IRAS (Insulin Resistance Atherosclerosis Study): The authors thank study investigators, staff, and participants for their valuable contributions. KORA (Cooperative Health Research in the Augsburg Region): We thank all KORA participants and staff for their contribution to the study. LBC1921 (Lothian Birth Cohort 1921): We thank the LBC1921 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LBC1936 (Lothian Birth Cohort 1936): We thank the LBC1936 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LifeLines (Lifelines Cohort Study): The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. Also, Lifelines acknowledges the contributions from Behrooz Z Alizadeh (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), H Marike Boezen (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Lude Franke (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Pim van der Harst (Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands), Gerjan Navis (Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands), Marianne Rots (Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands), Harold Snieder (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Morris Swertz (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Bruce HR Wolffenbuttel (Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands), Cisca Wijmenga (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands). LLFS (Long Life Family Study): The LLFS would like to thank the participants and research staff who make the study possible. LOLIPOP (London Life Sciences Prospective Population Study): We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. PROCARDIS (Precocious Coronary Artery Disease): The PROCARDIS researchers thank the patients for their selfless participation in this project. RHS (Ragama Health Study): The RHS was supported by the Grant of National Center for Global Health and Medicine (NCGM), Japan. SWHS/SMHS (Shanghai Women's Health Study/ Shanghai Men's Health Study): We thank all the individuals who took part in these studies and all the researchers who have enabled this work to be carried out. TRAILS (TRacking Adolescents’ Individual Lives Survey): TRAILS is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. We are grateful to all adolescents who participated in this research and to everyone who worked on this project and made it possible. UKB (United Kingdom Biobank, www.ukbiobank.ac.uk): This research has been conducted using the UK Biobank Resource. The UK Biobank data were analyzed from the data set corresponding to UK Biobank access application no. 236, application title 'Genome-wide association study of blood pressure', with Paul Elliott as the PI/applicant. This work was supported by the UK-CMC and the BP working group., InterAct Consortium, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Feitosa, Mary F., Kraja, Aldi T., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Bentley, Amy R., Brown, Michael R., Schwander, Karen, Richard, Melissa A., Noordam, Raymond, Aschard, Hugue, Bartz, Traci M., Bielak, Lawrence F., Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Lohman, Kurt K., Manning, Alisa K., Rankinen, Tuomo, Smith, Albert V., Tajuddin, Salman M., Wojczynski, Mary K., Alver, Mari, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'An, Matoba, Nana, Nolte, Ilja M., Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M. Abdullah, Scott, Robert A., Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O., Van Der Most, Peter J., Varga, Tibor V., Vitart, Veronique, Wang, Yajuan, Ware, Erin B., Warren, Helen R., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E., Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morri, Brumat, Marco, Burke, Gregory L., Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M., Correa, Adolfo, De Las Fuentes, Lisa, De Mutsert, Renée, De Silva, H. Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B., Ehret, Georg, Eppinga, Ruben N., Evangelou, Evangelo, Faul, Jessica D., Felix, Stephan B., Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Friedlander, Yechiel, Gandin, Ilaria, Gao, He, Ghanbari, Mohsen, Gigante, Bruna, Gu, C. Charle, Gu, Dongfeng, Hagenaars, Saskia P., Hallmans, Göran, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Howard, Barbara V., Ikram, M. Arfan, John, Ulrich, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Krieger, José E., Kritchevsky, Stephen B., Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lin, Shiow, Liu, Jianjun, Liu, Jingmin, Loh, Marie, Louie, Tin, Mägi, Reedik, Mckenzie, Colin A., Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L., Momozawa, Yukihide, Nalls, Mike A., Nelson, Christopher P., Sotoodehnia, Nona, Norris, Jill M., O'Connell, Jeff R., Palmer, Nicholette D., Perls, Thoma, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Poulter, Neil, Raffel, Leslie J., Raitakari, Olli T., Roll, Kathryn, Rose, Lynda M., Rosendaal, Frits R., Rotter, Jerome I., Schmidt, Carsten O., Schreiner, Pamela J., Schupf, Nicole, Scott, William R., Sever, Peter S., Shi, Yuan, Sidney, Stephen, Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Stringham, Heather M., Tan, Nicholas Y. Q., Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Turner, Stephen T., Uitterlinden, André G., Vollenweider, Peter, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Williams, Christine, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Deary, Ian J., Esko, Tõnu, Farrall, Martin, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S., Kutalik, Zoltán, Laakso, Markku, Laurie, Cathy C., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Polasek, Ozren, Porteous, David J., Rauramaa, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, Van Der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Bouchard, Claude, Christensen, Kaare, Evans, Michele K., Gudnason, Vilmundur, Horta, Bernardo L., Kardia, Sharon L. R., Liu, Yongmei, Pereira, Alexandre C., Psaty, Bruce M., Ridker, Paul M., Van Dam, Rob M., Gauderman, W. Jame, Zhu, Xiaofeng, Mook-Kanamori, Dennis O., Fornage, Myriam, Rotimi, Charles N., Cupples, L. Adrienne, Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Kooperberg, Charle, Palmas, Walter, Rice, Kenneth, Morrison, Alanna C., Elliott, Paul, Caulfield, Mark J., Munroe, Patricia B., Rao, Dabeeru C., Province, Michael A., Levy, Daniel, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Surgery, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, and Ehret, Georg Benedikt
Subjects: Genetics and Molecular Biology (all), Male, Erfðagreining, Áfengissýki, LOCI, Social Sciences, Blood Pressure, Genome-wide association study, Biochemistry, Vascular Medicine, TRANSCRIPTION FACTOR GATA4, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), DEPENDENCE, HEPATOCELLULAR-CARCINOMA, 80 and over, Psychology, Public and Occupational Health, Alcohol consumption, Cardiac and Cardiovascular Systems, Gene–environment interaction, ddc:616, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, Kardiologi, MESH: Polymorphism, Single Nucleotide, Áfengisneysla, MESH: Gene-Environment Interaction, COMMON VARIANTS, Genomics, MESH: Blood Pressure, Pedigree, 3. Good health, Näringslära, MESH: Young Adult, Physical Sciences, Medicine, Medical genetics, Erfðarannsóknir, Statistics (Mathematics), medicine.medical_specialty, Blood Pressure/genetics, Alcohol Drinking, MESH: Pedigree, Science, Genetic loci, ta3111, Genome Complexity, 03 medical and health sciences, Gene mapping, Genetics, Humans, Polymorphism, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology Techniques, Molecular Biology, Alleles, Aged, MESH: Adolescent, MESH: Humans, Adolescent, Adult, Alcohol Drinking/epidemiology, Alcohol Drinking/genetics, Cohort Studies, Continental Population Groups/genetics, Continental Population Groups/statistics & numerical data, Female, Gene-Environment Interaction, Genetic Predisposition to Disease/epidemiology, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Hypertension/epidemiology, Hypertension/genetics, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Gene Mapping, Racial Groups, ta1182, Biology and Life Sciences, Computational Biology, MESH: Adult, Meta-analysis, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, Mathematics, MESH: Alcohol Drinking, Meta-Analysis, 0301 basic medicine, MESH: Continental Population Groups, MESH: Hypertension, Mathematical and Statistical Techniques, MESH: Aged, 80 and over, Polymorphism (computer science), Medicine and Health Sciences, FUNCTIONAL VARIATION, MESH: Cohort Studies, MESH: Aged, Alcohol Consumption, Multidisciplinary, Nutrition and Dietetics, MESH: Genetic Predisposition to Disease, Genetic Predisposition to Disease/epidemiology/genetics, Single Nucleotide, Blóðþrýstingur, ENVIRONMENT INTERACTION, PTP4A1-PHF3-EYS VARIANTS, Alcoholism, ANCESTRAIS, Háþrýstingur, Hypertension, Blood pressure, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Medical Genetics, Research Article, Substance-Related Disorders, Addiction, RISK, METAANALYSIS, Research and Analysis Methods, Mental Health and Psychiatry, medicine, Medicine [Science], Genetic Predisposition to Disease, Allele, Hypertension/epidemiology/genetics, Nutrition, Medicinsk genetik, Continental Population Groups/genetics/statistics & numerical data, business.industry, Alcohol Drinking/epidemiology/genetics, Genetic architecture, MESH: Male, Introns, Diet, BODY-MASS INDEX, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2018

222. Analisando a seleção de portfólio de projetos com a abordagem multicritério construtivista em uma universidade / Analyzing projects portfolio selection under constructivist multicriteria approach in a higher education institution

Author: Barbosa, Fernando Pires, primary, Löbler, Mauri Leodir, additional, Tagliapietra, Rafaela Dutra, additional, and Lehnhart, Eliete Dos Reis, additional
Published: 2019
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223. Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

Author: Hartwig, Fernando Pires, primary, Tilling, Kate, additional, Smith, George Davey, additional, Lawlor, Deborah A, additional, and Borges, Maria Carolina, additional
Published: 2019
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224. Association between breastfeeding and DNA methylation over the life course: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Author: Hartwig, Fernando Pires, primary, Smith, George Davey, additional, Simpkin, Andrew J, additional, Victora, Cesar Gomes, additional, Relton, Caroline L., additional, and Caramaschi, Doretta, additional
Published: 2019
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225. Reutilização da água gerada pelos ares-condicionados: análise dos benefícios através da modelagem computacional

Author: Rodrigues, Glauco Oliveira, primary, Schneider, Jardel, additional, Barbosa, Fernando Pires, additional, Langwinski, Paulo Roberto, additional, and Soares, Douglas, additional
Published: 2019
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226. “Project-based learning” na engenharia: uma experiência prática de aprendizado lúdico em ambiente real

Author: Silva, Fernando Pires da, primary, Oestreich, Letícia Moreno, additional, Moreno, Ana Luiza Tupam Miguel, additional, Auler, Guilherme, additional, Nascimento, Bruno Pereira do, additional, Johann, Tailor, additional, Tischer, Celso Becker, additional, Marostega, Valéria Rolim, additional, Andrade, Bruna Fuzzer de, additional, and Padillo, Alejandro Ruiz, additional
Published: 2019
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227. A Mendelian Randomization dictionary: Useful definitions and descriptions for undertaking, understanding and interpreting Mendelian Randomization studies

Author: Lawlor, Deborah A, primary, Wade, Kaitlin, additional, Borges, Maria Carolina, additional, Palmer, Tom, additional, Hartwig, Fernando Pires, additional, Hemani, Gibran, additional, and Bowden, Jack, additional
Published: 2019
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228. Efficacy of Regular Exercise During Pregnancy on the Prevention of Postpartum Depression

Author: Coll, Carolina de Vargas Nunes, primary, Domingues, Marlos Rodrigues, additional, Stein, Alan, additional, da Silva, Bruna Gonçalves Cordeiro, additional, Bassani, Diego Garcia, additional, Hartwig, Fernando Pires, additional, da Silva, Inácio Crochemore Mohnsan, additional, da Silveira, Mariângela Freitas, additional, da Silva, Shana Ginar, additional, and Bertoldi, Andréa Dâmaso, additional
Published: 2019
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229. Effect modification of FADS2 polymorphisms on the association between breastfeeding and intelligence: results from a collaborative meta-analysis

Author: Hartwig, Fernando Pires, primary, Davies, Neil Martin, additional, Horta, Bernardo Lessa, additional, Ahluwalia, Tarunveer S, additional, Bisgaard, Hans, additional, Bønnelykke, Klaus, additional, Caspi, Avshalom, additional, Moffitt, Terrie E, additional, Poulton, Richie, additional, Sajjad, Ayesha, additional, Tiemeier, Henning W, additional, Dalmau-Bueno, Albert, additional, Guxens, Mònica, additional, Bustamante, Mariona, additional, Santa-Marina, Loreto, additional, Parker, Nadine, additional, Paus, Tomáš, additional, Pausova, Zdenka, additional, Lauritzen, Lotte, additional, Schnurr, Theresia M, additional, Michaelsen, Kim F, additional, Hansen, Torben, additional, Oddy, Wendy, additional, Pennell, Craig E, additional, Warrington, Nicole M, additional, Davey Smith, George, additional, and Victora, Cesar Gomes, additional
Published: 2018
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230. African ancestry, lung function and the effect of genetics

Author: Bernardo L. Horta, Isabel O. Oliveira, Denise Petrucci Gigante, Fernando C. Barros, Fernando Pires Hartwig, Fernando C. Wehrmeister, Rogelio Pérez-Padilla, Gustavo Dias Ferreira, and Ana M. B. Menezes
Subjects: Adult, Male, Pulmonary and Respiratory Medicine, Spirometry, Vital capacity, Vital Capacity, Black People, White People, Cohort Studies, 03 medical and health sciences, FEV1/FVC ratio, Sex Factors, 0302 clinical medicine, Forced Expiratory Volume, medicine, Humans, Prospective Studies, 030212 general & internal medicine, 10. No inequality, Prospective cohort study, Lung, Genetics, Anthropometry, medicine.diagnostic_test, business.industry, Confounding, Thorax, 030228 respiratory system, Cohort, Linear Models, Female, business, Brazil, Cohort study
Abstract: African-Americans have smaller lung function compared with European-Americans. The aim of this study was to disentangle the contribution of genetics from other variables on lung function.A cohort was followed from birth to 30 years of age in Brazil. Several variables were collected: genomic analysis based on DNA; forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) obtained by spirometry; height measured by anthropometrists; and thorax circumference evaluated by photonic scanner. Crude and adjusted linear regression models were calculated according to African ancestry.The sample comprised 2869 participants out of 3701 members of the cohort. Males with higher African ancestry by DNA analysis had a smaller FEV1 (−0.13 L, 95% CI −0.23– −0.03 L) and FVC (−0.21 L, 95% CI −0.32– −0.09 L) compared with those with less African ancestry, having accounted for height, sitting to standing height ratio and other confounders. Similar effects were seen in females.After adjustment, ancestry remained significantly associated with lung function, but the large effect of adjustment for confounding among males (but not females) does not allow us to exclude the possibility that residual confounding may still account for these findings.
Published: 2015

231. Influence of maternal pre-pregnancy nutritional status on offspring anthropometric measurements and body composition in three Brazilian Birth Cohorts.

Author: Dias, Mariane da Silva, Matijasevich, Alicia, Barros, Aluísio JD, Menezes, Ana Maria B., Schneider, Bruna Celestino, Hartwig, Fernando Pires, Barros, Fernando C., Wehrmeister, Fernando C., Gonçalves, Helen, Santos, Iná S., Assunção, Maria Cecilia F, and Horta, Bernardo L.
Subjects: BODY composition, NUTRITIONAL status, DUAL-energy X-ray absorptiometry, LEAN body mass, GENDER, RESEARCH, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, BIRTH weight, RESEARCH funding, BODY mass index, LONGITUDINAL method
Abstract: Objective: We aimed at evaluating the association of maternal pre-pregnancy nutritional status with offspring anthropometry and body composition. We also evaluated whether these associations were modified by gender, diet and physical activity and mediated by birth weight.Design: Birth cohort study.Setting: Waist circumference was measured with an inextensible tape, and fat and lean mass were measured using dual-energy X-ray absorptiometry. Multiple linear regression was used to adjust for possible confounders and allele score of BMI. We carried out mediation analysis using G-formula.Participants: In 1982, 1993 and 2004, all maternity hospitals in Pelotas (South Brazil) were visited daily and all live births whose families lived in the urban area of the city were evaluated. These subjects have been followed up at different ages.Results: Offspring of obese mothers had on average higher BMI, waist circumference and fat mass index than those of normal weight mothers, and these differences were higher among daughters. The magnitudes of the association were similar in the cohorts, except for height, where the association pattern was not clear. In the 1982 cohort, further adjustment for a BMI allele score had no material influence on the magnitude of the associations. Mediation analyses showed that birth weight captured part of this association.Conclusions: Our findings suggest that maternal pre-pregnancy nutritional status is positively associated with offspring BMI and adiposity in offspring. And this association is higher among daughters whose mother was overweight or obese and, birth weight explains part of this association. [ABSTRACT FROM AUTHOR]
Published: 2021
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232. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Author: Sung, Yun J., Winkler, Thomas W., de las Fuentes, Lisa, Bentley, Amy R., Brown, Michael R., Kraja, Aldi T., Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Feitosa, Mary F., Kilpelainen, Tuomas O., Richard, Melissa A., Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugues, Bartz, Traci M., Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K., Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M., Tayo, Bamidele O., Warren, Helen R., Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Maris, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E., Hartwig, Fernando Pires, Horimoto, Andrea R. V. R., Hsu, Fang-Chi, Jackson, Anne U., Kahonen, Mika, Kasturiratne, Anuradhani, Kuhnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian' an, McKenzie, Colin A., Meian, He, Nelson, Christopher P., Rauramaa, Rainer, Schupf, Nicole, Scott, Robert A., Sheu, Wayne H. H., Stancakova, Alena, Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Wang, Heming, Wang, Yajuan, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan, Aung, Tin, Barr, R. Graham, Bielak, Lawrence F., Boerwinkle, Eric, Bottinger, Erwin P., Braund, Peter S., Brody, Jennifer A., Broeckel, Ulrich, Cabrera, Claudia P., Cade, Brian, Caizheng, Yu, Campbell, Archie, Canouil, Mickael, Chakravarti, Aravinda, Chauhan, Ganesh, Christensen, Kaare, Cocca, Massimiliano, Collins, Francis S., Connell, John M., de Mutsert, Renee, de Silva, H. Janaka, Debette, Stephanie, Dorr, Marcus, Duan, Qing, Eaton, Charles B., Ehret, Georg, Evangelou, Evangelos, Faul, Jessica D., Fisher, Virginia A., Forouhi, Nita G., Franco, Oscar H., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Graff, Misa, Gu, C. Charles, Gu, Dongfeng, Gupta, Preeti, Hagenaars, Saskia P., Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hofman, Albert, Howard, Barbara V., Hunt, Steven, Irvin, Marguerite R., Jia, Yucheng, Joehanes, Roby, Justice, Anne E., Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D., Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A., Komulainen, Pirjo, Kooperberg, Charles, Krieger, Jose E., Kubo, Michiaki, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lim, Sing Hui, Lin, Shiow, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Kiang, Liu, Yeheng, Loh, Marie, Lohman, Kurt K., Long, Jirong, Louie, Tin, Magi, Reedik, Mahajan, Anubha, Meitinger, Thomas, Metspalu, Andres, Milani, Lili, Momozawa, Yukihide, Morris, Andrew P., Mosley, Thomas H., Jr., Munson, Peter, Murray, Alison D., Nalls, Mike A., Nasri, Ubaydah, Norris, Jill M., North, Kari, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Palmer, Nicholette D., Pankow, James S., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Raitakari, Olli T., Renström, Frida, Rice, Treva K., Ridker, Paul M., Robino, Antonietta, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L., Sandow, Kevin, Schmidt, Carsten O., Schreiner, Pamela J., Scott, William R., Seshadri, Sudha, Sever, Peter, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Ultterlinden, Andre G., Waldenberger, Melanie, Wang, Lihua, Wang, Ya X., Bin Wei, Wen, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K., Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Chen, Yii-Der Ida, de Faire, Ulf, Deary, Ian J., Esko, Tonu, Farrall, Martin, Forrester, Terrence, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost B., Kato, Norihiro, Kooner, Jaspal S., Laakso, Markku, Lehtimaki, Terho, Liang, Kae-Woei, Magnusson, Patrik K. E., Newman, Anne B., Oldehinkel, Albertine J., Pereira, Alexandre C., Redline, Susan, Rettig, Rainer, Samani, Nilesh J., Scott, James, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Kamatani, Yoichiro, Laurie, Cathy C., Bouchard, Claude, Cooper, Richard S., Evans, Michele K., Gudnason, Vilmundur, Kardia, Sharon L. R., Kritchevsky, Stephen B., Levy, Daniel, O'Connell, Jeff R., Psaty, Bruce M., van Dam, Rob M., Sims, Mario, Arnett, Donna K., Mook-Kanamori, Dennis O., Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Fornage, Myriam, Rotimi, Charles N., Province, Michael A., van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Loos, Ruth J. F., Reiner, Alex P., Rotter, Jerome I., Zhu, Xiaofeng, Bierut, Laura J., Gauderman, W. James, Caulfield, Mark J., Elliott, Paul, Rice, Kenneth, Munroe, Patricia B., Morrison, Alanna C., Cupples, L. Adrienne, Rao, Dabeeru C., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., de las Fuentes, Lisa, Bentley, Amy R., Brown, Michael R., Kraja, Aldi T., Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Feitosa, Mary F., Kilpelainen, Tuomas O., Richard, Melissa A., Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugues, Bartz, Traci M., Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K., Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M., Tayo, Bamidele O., Warren, Helen R., Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Maris, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E., Hartwig, Fernando Pires, Horimoto, Andrea R. V. R., Hsu, Fang-Chi, Jackson, Anne U., Kahonen, Mika, Kasturiratne, Anuradhani, Kuhnel, Brigitte, Leander, Karin, Lee, Wen-Jane, Lin, Keng-Hung, Luan, Jian' an, McKenzie, Colin A., Meian, He, Nelson, Christopher P., Rauramaa, Rainer, Schupf, Nicole, Scott, Robert A., Sheu, Wayne H. H., Stancakova, Alena, Takeuchi, Fumihiko, van der Most, Peter J., Varga, Tibor V., Wang, Heming, Wang, Yajuan, Ware, Erin B., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Alfred, Tamuno, Amin, Najaf, Arking, Dan, Aung, Tin, Barr, R. Graham, Bielak, Lawrence F., Boerwinkle, Eric, Bottinger, Erwin P., Braund, Peter S., Brody, Jennifer A., Broeckel, Ulrich, Cabrera, Claudia P., Cade, Brian, Caizheng, Yu, Campbell, Archie, Canouil, Mickael, Chakravarti, Aravinda, Chauhan, Ganesh, Christensen, Kaare, Cocca, Massimiliano, Collins, Francis S., Connell, John M., de Mutsert, Renee, de Silva, H. Janaka, Debette, Stephanie, Dorr, Marcus, Duan, Qing, Eaton, Charles B., Ehret, Georg, Evangelou, Evangelos, Faul, Jessica D., Fisher, Virginia A., Forouhi, Nita G., Franco, Oscar H., Friedlander, Yechiel, Gao, He, Gigante, Bruna, Graff, Misa, Gu, C. Charles, Gu, Dongfeng, Gupta, Preeti, Hagenaars, Saskia P., Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hofman, Albert, Howard, Barbara V., Hunt, Steven, Irvin, Marguerite R., Jia, Yucheng, Joehanes, Roby, Justice, Anne E., Katsuya, Tomohiro, Kaufman, Joel, Kerrison, Nicola D., Khor, Chiea Chuen, Koh, Woon-Puay, Koistinen, Heikki A., Komulainen, Pirjo, Kooperberg, Charles, Krieger, Jose E., Kubo, Michiaki, Kuusisto, Johanna, Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lim, Sing Hui, Lin, Shiow, Liu, Ching-Ti, Liu, Jianjun, Liu, Jingmin, Liu, Kiang, Liu, Yeheng, Loh, Marie, Lohman, Kurt K., Long, Jirong, Louie, Tin, Magi, Reedik, Mahajan, Anubha, Meitinger, Thomas, Metspalu, Andres, Milani, Lili, Momozawa, Yukihide, Morris, Andrew P., Mosley, Thomas H., Jr., Munson, Peter, Murray, Alison D., Nalls, Mike A., Nasri, Ubaydah, Norris, Jill M., North, Kari, Ogunniyi, Adesola, Padmanabhan, Sandosh, Palmas, Walter R., Palmer, Nicholette D., Pankow, James S., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Raitakari, Olli T., Renström, Frida, Rice, Treva K., Ridker, Paul M., Robino, Antonietta, Robinson, Jennifer G., Rose, Lynda M., Rudan, Igor, Sabanayagam, Charumathi, Salako, Babatunde L., Sandow, Kevin, Schmidt, Carsten O., Schreiner, Pamela J., Scott, William R., Seshadri, Sudha, Sever, Peter, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Ultterlinden, Andre G., Waldenberger, Melanie, Wang, Lihua, Wang, Ya X., Bin Wei, Wen, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K., Yao, Jie, Yuan, Jian-Min, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Chen, Yii-Der Ida, de Faire, Ulf, Deary, Ian J., Esko, Tonu, Farrall, Martin, Forrester, Terrence, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo Lessa, Hung, Yi-Jen, Jonas, Jost B., Kato, Norihiro, Kooner, Jaspal S., Laakso, Markku, Lehtimaki, Terho, Liang, Kae-Woei, Magnusson, Patrik K. E., Newman, Anne B., Oldehinkel, Albertine J., Pereira, Alexandre C., Redline, Susan, Rettig, Rainer, Samani, Nilesh J., Scott, James, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Kamatani, Yoichiro, Laurie, Cathy C., Bouchard, Claude, Cooper, Richard S., Evans, Michele K., Gudnason, Vilmundur, Kardia, Sharon L. R., Kritchevsky, Stephen B., Levy, Daniel, O'Connell, Jeff R., Psaty, Bruce M., van Dam, Rob M., Sims, Mario, Arnett, Donna K., Mook-Kanamori, Dennis O., Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Fornage, Myriam, Rotimi, Charles N., Province, Michael A., van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Loos, Ruth J. F., Reiner, Alex P., Rotter, Jerome I., Zhu, Xiaofeng, Bierut, Laura J., Gauderman, W. James, Caulfield, Mark J., Elliott, Paul, Rice, Kenneth, Munroe, Patricia B., Morrison, Alanna C., Cupples, L. Adrienne, Rao, Dabeeru C., and Chasman, Daniel I.
Abstract: Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).
Published: 2018
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233. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author: Wyss, A.B. (Annah B.), Sofer, T. (Tamar), Lee, M.K. (Mi Kyeong), Terzikhan, N. (Natalie), Nguyen, J.N. (Jennifer N.), Lahousse, L. (Lies), Latourelle, J.C. (Jeanne), Smith, A.V. (Albert), Bartz, T.M. (Traci M.), Feitosa, M.F. (Mary Furlan), Gao, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Tang, W. (Wenbo), Oldmeadow, C. (Christopher), Duan, Q. (Qing), Jong, K. (Kim) de, Wojczynski, M.K. (Mary ), Wang, X.-Q. (Xin-Qun), Noordam, R. (Raymond), Hartwig, F.P. (Fernando Pires), Jackson, V.E. (Victoria E.), Wang, T. (Tianyuan), Obeidat, M. (Ma’en), Hobbs, B.D. (Brian D.), Huan, T. (Tianxiao), Gui, H. (Hongsheng), Parker, M.M. (Margaret M.), Hu, D. (Donglei), Mogil, L.S. (Lauren S.), Kichaev, G. (Gleb), Jin, J. (Jianping), Graff, M.J. (Maud J.L.), Harris, T.B. (Tamara), Kalhan, R. (Ravi), Heckbert, S.R. (Susan), Paternoster, L. (Lavinia), Burkart, K.M. (Kristin), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Wilson, J.F. (James), Vonk, J.M. (Judith), Sanders, J.L. (Jason L.), Barr, R.G. (Graham), Mutsert, R. (Reneé) de, Menezes, A.M.B. (Ana Maria Baptista), Adams, H.H.H. (Hieab), Van Den Berge, M. (Maarten), Joehanes, R. (Roby), Levin, A.M. (Albert M.), Liberto, J. (Jennifer), Launer, L.J. (Lenore), Morrison, A.C. (Alanna), Sitlani, C.M. (Colleen), Celedón, J.C. (Juan C.), Kritchevsky, S.B. (Stephen), Scott, R.J. (Rodney J.), Christensen, K. (Kaare), Rotter, J.I. (Jerome I.), Bonten, T.N. (Tobias N.), Wehrmeister, F.C. (Fernando C.), Bossé, Y. (Yohan), Xiao, S. (Shujie), Oh, S. (Sam), Franceschini, N. (Nora), Brody, J.A. (Jennifer A.), Kaplan, R.C. (Robert), Lohman, K. (Kurt), McEvoy, M. (Mark), Province, M.A. (Mike), Rosendaal, F.R. (Frits), Taylor, K.D. (Kent), Nickle, D.C. (David C.), Williams, L.K. (L. Keoki), Burchard, E.G. (Esteban), Wheeler, H.E. (Heather), Sin, D.D. (Don D.), Gudnason, V. (Vilmundur), North, K.E. (Kari), Fornage, M. (Myriam), Psaty, B.M. (Bruce M.), Myers, R.H. (Richard), O’Connor, G. (George), Hansen, T. (Torben), Laurie, C.C. (Cathy C.), Cassano, P.A. (Patricia), Sung, J. (Joohon), Kim, W.J. (Woo Jin), Attia, J. (John), Lange, L.A. (Leslie), Boezen, H.M. (Marike), Thyagarajan, B. (Bharat), Rich, S.S. (Stephen), Mook-Kanamori, D.O. (Dennis O.), Horta, B.L. (Bernardo Lessa), Uitterlinden, A.G. (André), Im, H.K. (Hae Kyung), Cho, M.H. (Michael H.), Brusselle, G.G. (Guy), Gharib, S.A. (Sina), Dupuis, J. (Josée), Manichaikul, A. (Ani), London, S.J. (Stephanie J.), Wyss, A.B. (Annah B.), Sofer, T. (Tamar), Lee, M.K. (Mi Kyeong), Terzikhan, N. (Natalie), Nguyen, J.N. (Jennifer N.), Lahousse, L. (Lies), Latourelle, J.C. (Jeanne), Smith, A.V. (Albert), Bartz, T.M. (Traci M.), Feitosa, M.F. (Mary Furlan), Gao, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Tang, W. (Wenbo), Oldmeadow, C. (Christopher), Duan, Q. (Qing), Jong, K. (Kim) de, Wojczynski, M.K. (Mary ), Wang, X.-Q. (Xin-Qun), Noordam, R. (Raymond), Hartwig, F.P. (Fernando Pires), Jackson, V.E. (Victoria E.), Wang, T. (Tianyuan), Obeidat, M. (Ma’en), Hobbs, B.D. (Brian D.), Huan, T. (Tianxiao), Gui, H. (Hongsheng), Parker, M.M. (Margaret M.), Hu, D. (Donglei), Mogil, L.S. (Lauren S.), Kichaev, G. (Gleb), Jin, J. (Jianping), Graff, M.J. (Maud J.L.), Harris, T.B. (Tamara), Kalhan, R. (Ravi), Heckbert, S.R. (Susan), Paternoster, L. (Lavinia), Burkart, K.M. (Kristin), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Wilson, J.F. (James), Vonk, J.M. (Judith), Sanders, J.L. (Jason L.), Barr, R.G. (Graham), Mutsert, R. (Reneé) de, Menezes, A.M.B. (Ana Maria Baptista), Adams, H.H.H. (Hieab), Van Den Berge, M. (Maarten), Joehanes, R. (Roby), Levin, A.M. (Albert M.), Liberto, J. (Jennifer), Launer, L.J. (Lenore), Morrison, A.C. (Alanna), Sitlani, C.M. (Colleen), Celedón, J.C. (Juan C.), Kritchevsky, S.B. (Stephen), Scott, R.J. (Rodney J.), Christensen, K. (Kaare), Rotter, J.I. (Jerome I.), Bonten, T.N. (Tobias N.), Wehrmeister, F.C. (Fernando C.), Bossé, Y. (Yohan), Xiao, S. (Shujie), Oh, S. (Sam), Franceschini, N. (Nora), Brody, J.A. (Jennifer A.), Kaplan, R.C. (Robert), Lohman, K. (Kurt), McEvoy, M. (Mark), Province, M.A. (Mike), Rosendaal, F.R. (Frits), Taylor, K.D. (Kent), Nickle, D.C. (David C.), Williams, L.K. (L. Keoki), Burchard, E.G. (Esteban), Wheeler, H.E. (Heather), Sin, D.D. (Don D.), Gudnason, V. (Vilmundur), North, K.E. (Kari), Fornage, M. (Myriam), Psaty, B.M. (Bruce M.), Myers, R.H. (Richard), O’Connor, G. (George), Hansen, T. (Torben), Laurie, C.C. (Cathy C.), Cassano, P.A. (Patricia), Sung, J. (Joohon), Kim, W.J. (Woo Jin), Attia, J. (John), Lange, L.A. (Leslie), Boezen, H.M. (Marike), Thyagarajan, B. (Bharat), Rich, S.S. (Stephen), Mook-Kanamori, D.O. (Dennis O.), Horta, B.L. (Bernardo Lessa), Uitterlinden, A.G. (André), Im, H.K. (Hae Kyung), Cho, M.H. (Michael H.), Brusselle, G.G. (Guy), Gharib, S.A. (Sina), Dupuis, J. (Josée), Manichaikul, A. (Ani), and London, S.J. (Stephanie J.)
Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lu
Published: 2018
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234. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author: Wyss, Annah B., Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N., Lahousse, Lies, Latourelle, Jeanne C., Smith, Albert Vernon, Bartz, Traci M., Feitosa, Mary F., Gao, Wei, Ahluwalia, Tarunveer S., Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K., Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E., Wang, Tianyuan, Obeidat, Ma'en, Hobbs, Brian D., Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M., Hu, Donglei, Mogil, Lauren S., Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B., Kalhan, Ravi, Heckbert, Susan R., Paternoster, Lavinia, Burkart, Kristin M., Liu, Yongmei, Holliday, Elizabeth G., Wilson, James G., Vonk, Judith M., Sanders, Jason L., Barr, R. Graham, de Mutsert, Renee, Baptista Menezes, Ana Maria, Adams, Hieab H. H., van den Berge, Maarten, Joehanes, Roby, Levin, Albert M., Liberto, Jennifer, Launer, Lenore J., Morrison, Alanna C., Sitlani, Colleen M., Celedon, Juan C., Kritchevsky, Stephen B., Scott, Rodney J., Christensen, Kaare, Rotter, Jerome I., Bonten, Tobias N., Wehrmeister, Fernando Cesar, Bosse, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A., Kaplan, Robert C., Lohman, Kurt, McEvoy, Mark, Province, Michael A., Rosendaal, Frits R., Taylor, Kent D., Nickle, David C., Williams, L. Keoki, Burchard, Esteban G., Wheeler, Heather E., Sin, Don D., Gudnason, Vilmundur, North, Kari E., Fornage, Myriam, Psaty, Bruce M., Myers, Richard H., O'Connor, George, Hansen, Torben, Laurie, Cathy C., Cassano, Patricia A., Sung, Joohon, Kim, Woo Jin, Attia, John R., Lange, Leslie, Boezen, H. Marike, Thyagarajan, Bharat, Rich, Stephen S., Mook-Kanamori, Dennis O., Horta, Bernardo Lessa, Uitterlinden, Andre G., Im, Hae Kyung, Cho, Michael H., Brusselle, Guy G., Gharib, Sina A., Dupuis, Josee, Manichaikul, Ani, London, Stephanie J., Wyss, Annah B., Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N., Lahousse, Lies, Latourelle, Jeanne C., Smith, Albert Vernon, Bartz, Traci M., Feitosa, Mary F., Gao, Wei, Ahluwalia, Tarunveer S., Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K., Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E., Wang, Tianyuan, Obeidat, Ma'en, Hobbs, Brian D., Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M., Hu, Donglei, Mogil, Lauren S., Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B., Kalhan, Ravi, Heckbert, Susan R., Paternoster, Lavinia, Burkart, Kristin M., Liu, Yongmei, Holliday, Elizabeth G., Wilson, James G., Vonk, Judith M., Sanders, Jason L., Barr, R. Graham, de Mutsert, Renee, Baptista Menezes, Ana Maria, Adams, Hieab H. H., van den Berge, Maarten, Joehanes, Roby, Levin, Albert M., Liberto, Jennifer, Launer, Lenore J., Morrison, Alanna C., Sitlani, Colleen M., Celedon, Juan C., Kritchevsky, Stephen B., Scott, Rodney J., Christensen, Kaare, Rotter, Jerome I., Bonten, Tobias N., Wehrmeister, Fernando Cesar, Bosse, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A., Kaplan, Robert C., Lohman, Kurt, McEvoy, Mark, Province, Michael A., Rosendaal, Frits R., Taylor, Kent D., Nickle, David C., Williams, L. Keoki, Burchard, Esteban G., Wheeler, Heather E., Sin, Don D., Gudnason, Vilmundur, North, Kari E., Fornage, Myriam, Psaty, Bruce M., Myers, Richard H., O'Connor, George, Hansen, Torben, Laurie, Cathy C., Cassano, Patricia A., Sung, Joohon, Kim, Woo Jin, Attia, John R., Lange, Leslie, Boezen, H. Marike, Thyagarajan, Bharat, Rich, Stephen S., Mook-Kanamori, Dennis O., Horta, Bernardo Lessa, Uitterlinden, Andre G., Im, Hae Kyung, Cho, Michael H., Brusselle, Guy G., Gharib, Sina A., Dupuis, Josee, Manichaikul, Ani, and London, Stephanie J.
Published: 2018

235. A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Author: Sung, Yun J, Winkler, Thomas W, de Las Fuentes, Lisa, Bentley, Amy R, Brown, Michael R, Kraja, Aldi T, Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Kilpeläinen, Tuomas O, Richard, Melissa A, Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugues, Bartz, Traci M, Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Warren, Helen R, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Maris, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando Pires, Christensen, Kaare, Loos, Ruth J F, Sung, Yun J, Winkler, Thomas W, de Las Fuentes, Lisa, Bentley, Amy R, Brown, Michael R, Kraja, Aldi T, Schwander, Karen, Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Lu, Yingchang, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Kilpeläinen, Tuomas O, Richard, Melissa A, Noordam, Raymond, Aslibekyan, Stella, Aschard, Hugues, Bartz, Traci M, Dorajoo, Rajkumar, Liu, Yongmei, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert Vernon, Tajuddin, Salman M, Tayo, Bamidele O, Warren, Helen R, Zhao, Wei, Zhou, Yanhua, Matoba, Nana, Sofer, Tamar, Alver, Maris, Amini, Marzyeh, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Giulianini, Franco, Goel, Anuj, Harris, Sarah E, Hartwig, Fernando Pires, Christensen, Kaare, and Loos, Ruth J F
Abstract: Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10-8) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10-8). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Published: 2018

236. Why internal weights should be avoided (not only) in MR-Egger regression

Author: Fernando Pires Hartwig and Neil M Davies
Subjects: 0301 basic medicine, Epidemiology, business.industry, MEDLINE, Regression analysis, Mendelian Randomization Analysis, General Medicine, Biology, Regression, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, Statistics, 030212 general & internal medicine, business
Abstract: [No abstract]
Published: 2016

237. Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study

Author: Maria Carolina Borges, Fernando Pires Hartwig, George Davey Smith, Jack Bowden, and Bernardo L. Horta
Subjects: 0301 basic medicine, Adult, Male, Candidate gene, medicine.medical_specialty, Genome-wide association study, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Inflammation, business.industry, Confounding, Genetic Variation, Mendelian Randomization Analysis, Odds ratio, Middle Aged, Protective Factors, medicine.disease, Receptors, Interleukin-6, 3. Good health, Biomarker (cell), Psychiatry and Mental health, Interleukin 1 Receptor Antagonist Protein, 030104 developmental biology, C-Reactive Protein, Schizophrenia, Female, business, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study
Abstract: Importance Positive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias, such as reverse causation and residual confounding, thus limiting our understanding of the effect (if any) of inflammatory biomarkers on schizophrenia risk. Objective To evaluate whether inflammatory biomarkers have an effect on the risk of developing schizophrenia. Design, Setting, and Participants Two-sample mendelian randomization study using genetic variants associated with inflammatory biomarkers as instrumental variables to improve inference. Summary association results from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs, were used. Gene-inflammatory biomarker associations were estimated in pooled samples ranging from 1645 to more than 80 000 individuals, while gene-schizophrenia associations were estimated in more than 30 000 cases and more than 45 000 ancestry-matched controls. In most studies included in the consortia, participants were of European ancestry, and the prevalence of men was approximately 50%. All studies were conducted in adults, with a wide age range (18 to 80 years). Exposures Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R). Main Outcomes and Measures Risk of developing schizophrenia. Individuals with schizophrenia or schizoaffective disorders were included as cases. Given that many studies contributed to the analyses, different diagnostic procedures were used. Results The pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (random effects 95% CI, 0.84-0.97; P = .005) per 2-fold increment in CRP levels; consistent results were obtained using different mendelian randomization methods and a more conservative set of instruments. The odds ratio for sIL-6R was 1.06 (95% CI, 1.01-1.12; P = .02) per 2-fold increment. Estimates for IL-1Ra were inconsistent among instruments, and pooled estimates were imprecise and centered on the null. Conclusions and Relevance Under mendelian randomization assumptions, our findings suggest a protective effect of CRP and a risk-increasing effect of sIL-6R (potentially mediated at least in part by CRP) on schizophrenia risk. It is possible that such effects are a result of increased susceptibility to early life infection.
Published: 2017

238. Multiethnic meta-analysis identifies new loci for pulmonary function

Author: Yongmei Liu, Dennis O. Mook-Kanamori, Robert C. Kaplan, Brian D. Hobbs, Josée Dupuis, Nora Franceschini, Tarunveer S. Ahluwalia, Hieab H.H. Adams, André G. Uitterlinden, Stephen B. Kritchevsky, Gleb Kichaev, Mary F. Feitosa, Ani Manichaikul, Tamar Sofer, Myriam Fornage, Annah B. Wyss, Jeanne C. Latourelle, Patricia A. Cassano, H. Marike Boezen, Mark McEvoy, Roby Joehanes, Xin-Qun Wang, Victoria E. Jackson, Hae Kyung Im, Lenore J. Launer, Don D. Sin, R. Graham Barr, Tianyuan Wang, George T. O'Connor, Natalie Terzikhan, Tamara B. Harris, Wei Gao, Jennifer A. Brody, Rd Mutsert, Lavinia Paternoster, Thomas Hansen, Tianxiao Huan, Fernando C. Wehrmeister, Christopher Oldmeadow, Rodney J. Scott, Joohon Sung, Jason L. Sanders, Kurt Lohman, Woo Jin Kim, Guy Brusselle, Raymond Noordam, Michael A. Province, Yohan Bossé, Kari E. North, Mary K. Wojczynski, Fernando Pires Hartwig, Wenbo Tang, Bharat Thyagarajan, Judith M. Vonk, Jennifer N. Nguyen, Sina A. Gharib, Jianping Jin, Mariaelisa Graff, Kent D. Taylor, Mi Kyeong Lee, James G. Wilson, Elizabeth G. Holliday, Lies Lahousse, Richard H. Myers, Tobias Bonten, Stephen S. Rich, Cathy C. Laurie, Michael H. Cho, Susan R. Heckbert, Ravi Kalhan, Mvd Berge, Bernardo L. Horta, John Attia, Bruce M. Psaty, Amb Menezes, Albert V. Smith, Juan C. Celedón, Kd Jong, Jerome I. Rotter, David C. Nickle, Traci M. Bartz, Frits R. Rosendaal, Stephanie J. London, Alanna C. Morrison, Kristin M. Burkart, Colleen M. Sitlani, Ma'en Obeidat, Leslie A. Lange, Qing Duan, and Kaare Christensen
Subjects: Genetics, 0303 health sciences, Linkage disequilibrium, Biology, Pulmonary function testing, Novel gene, 03 medical and health sciences, 0302 clinical medicine, Functional annotation, 030220 oncology & carcinogenesis, Meta-analysis, 1000 Genomes Project, Gene, 030304 developmental biology, Genetic association
Abstract: Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.
Published: 2017
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239. Effect modification of FADS2 polymorphisms on the association between breastfeeding and intelligence: results from a collaborative meta-analysis

Author: Nicole M. Warrington, Avshalom Caspi, Terrie E. Moffitt, Torben Hansen, Kim F. Michaelsen, Ayesha Sajjad, Fernando Pires Hartwig, Mònica Guxens, Loreto Santa-Marina, Nadine Parker, Theresia M. Schnurr, Lotte Lauritzen, Craig E. Pennell, Albert Dalmau Bueno, Bernardo L. Horta, Neil M Davies, Hans Bisgaard, Zdenka Pausova, Tomáš Paus, Wendy H. Oddy, Cesar G. Victora, Klaus Bønnelykke, Tarunveer S. Ahluwalia, George Davey Smith, Mariona Bustamante, Henning Tiemeier, Richie G Poulton, Child and Adolescent Psychiatry / Psychology, and Epidemiology
Subjects: Fatty Acid Desaturases, Male, 0301 basic medicine, medicine.medical_specialty, Genotype, Epidemiology, FADS2, Intelligence, Breastfeeding, Subgroup analysis, Breast milk, Standard score, Effect modification, 03 medical and health sciences, Cognition, 0302 clinical medicine, Faculty of Science, medicine, Humans, 030212 general & internal medicine, Fatty acids, 10. No inequality, Intelligence Tests, Polymorphism, Genetic, Intelligence quotient, business.industry, General Medicine, Confidence interval, Meta-analysis, Breast Feeding, 030104 developmental biology, Linear Models, Female, Epigenetics & Genetics, business, Breast feeding, 030217 neurology & neurosurgery, Demography
Abstract: BackgroundAccumulating evidence suggests that breastfeeding benefits the children’s intelligence. Long-chain polyunsaturated fatty acids (LC-PUFAs) present in breast milk may explain part of this association. Under a nutritional adequacy hypothesis, an interaction between breastfeeding and genetic variants associated with endogenous LC-PUFAs synthesis might be expected. However, the literature on this topic is controversial.Methods and FindingsWe investigated this Gene×Environment interaction in a de novo meta-analysis involving >12,000 individuals in the primary analysis, and >45,000 individuals in a secondary analysis using relaxed inclusion criteria. Our primary analysis used ever breastfeeding, FADS2 polymorphisms rs174575 and rs1535 coded assuming a recessive effect of the G allele, and intelligence quotient (IQ) in Z scores. Using random effects meta-analysis, ever breastfeeding was associated with 0.17 (95% CI: 0.03; 0.32) higher Z scores in IQ, or about 2.1 points. There was no strong evidence of interaction, with pooled covariate-adjusted interaction coefficients (i.e., difference between genetic groups of the difference in IQZ scores comparing ever with never breastfed individuals) of 0.12 (95% CI: −0.19; 0.43) and 0.06 (95% CI: −0.16; 0.27) for the rs174575 and rs1535 variants, respectively. Secondary analyses corroborated these results. In studies with >5.85 and ConclusionsOur findings do not support an interaction between ever breastfeeding and FADS2 polymorphisms. However, our subgroup analysis raises the possibility that breastfeeding supplies LC-PUFAs requirements for cognitive development (if such threshold exists) if it lasts for some (currently unknown) time. Future studies in large individual-level datasets would allow properly powered subgroup analyses and would improve our understanding on the role of breastfeeding duration in the breastfeeding×FADS2 interaction.
Published: 2017

240. The genetic architecture of osteoarthritis: insights from UK Biobank

Author: Unnur Styrkarsdottir, Unnur Thorsteinsdottir, Fernando Pires Hartwig, Andrew McCaskie, Helgi Jonsson, Sophie Hackinger, Konstantinos Hatzikotoulas, Britt Kilian, George C. Babis, Cindy G. Boer, Thorvaldur Ingvarsson, Ioanna Tachmazidou, Julia Steinberg, Kari Stefansson, Eleni Zengini, George Davey Smith, Eleftheria Zeggini, Daniel Suveges, André G. Uitterlinden, Jeremy Mark Wilkinson, Arthur Gilly, Joyce B. J. van Meurs, and Lorraine Southam
Subjects: 030203 arthritis & rheumatology, 2. Zero hunger, 0303 health sciences, medicine.medical_specialty, business.industry, Public health, Causal effect, Type 2 diabetes, Osteoarthritis, medicine.disease, Bioinformatics, Biobank, Genetic architecture, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Endophenotype, medicine, business, Body mass index, 030304 developmental biology
Abstract: Osteoarthritis is a common complex disease with huge public health burden. Here we perform a genome-wide association study for osteoarthritis using data across 16.5 million variants from the UK Biobank resource. Following replication and meta-analysis in up to 30,727 cases and 297,191 controls, we report 9 new osteoarthritis loci, in all of which the most likely causal variant is non-coding. For three loci, we detect association with biologically-relevant radiographic endophenotypes, and in five signals we identify genes that are differentially expressed in degraded compared to intact articular cartilage from osteoarthritis patients. We establish causal effects for higher body mass index, but not for triglyceride levels or type 2 diabetes liability, on osteoarthritis.
Published: 2017

241. Development, Inequality and International Cooperation in Health

Author: José Paranaguá de, Santana and Fernando, Pires-Alves
Subjects: Socioeconomic Factors, Health Policy, International Cooperation, Humans, Health Status Disparities
Published: 2017

242. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis

Author: Britt Kilian, Joyce B. J. van Meurs, Helgi Jonsson, Unnur Styrkarsdottir, Kari Stefansson, Sophie Hackinger, Andrew McCaskie, George C. Babis, Eleftheria Zeggini, Daniel Suveges, Konstantinos Hatzikotoulas, Julia Steinberg, Fernando Pires Hartwig, George Davey Smith, Lorraine Southam, Cindy G. Boer, Ioanna Tachmazidou, Jeremy Mark Wilkinson, Thorvaldur Ingvarsson, Unnur Thorsteinsdottir, Eleni Zengini, André G. Uitterlinden, Arthur Gilly, Hatzikotoulas, Konstantinos [0000-0002-4699-3672], Hartwig, Fernando P [0000-0003-3729-0710], Southam, Lorraine [0000-0002-7546-9650], Boer, Cindy G [0000-0003-4809-0044], Styrkarsdottir, Unnur [0000-0001-8146-8278], Wilkinson, Jeremy M [0000-0001-5577-3674], Zeggini, Eleftheria [0000-0003-4238-659X], Apollo - University of Cambridge Repository, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Male, RNA, Untranslated, Computational biology, Osteoarthritis, Biology, Genome, 03 medical and health sciences, Genetic variation, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Biological Specimen Banks, Chromosome Mapping, Genetic Variation, medicine.disease, Biobank, Genetic architecture, United Kingdom, 030104 developmental biology, Genetic Loci, Meta-analysis, Female, Body mass index, Genome-Wide Association Study
Abstract: Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis. We established causal effects on osteoarthritis for higher body mass index but not for triglyceride levels or genetic predisposition to type 2 diabetes.
Published: 2017

243. Association between genetically elevated levels of inflammatory biomarkers and risk of schizophrenia: a two-sample Mendelian randomisation study

Author: Fernando Pires Hartwig, Maria Carolina Borges, George Davey Smith, Bernardo L. Horta, and Jack Bowden
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, business.industry, Confounding, Odds ratio, medicine.disease, Inflammatory biomarkers, 3. Good health, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Schizophrenia, Internal medicine, Epidemiology, Mendelian inheritance, symbols, medicine, Observational study, Two sample, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: BackgroundPositive associations between inflammatory biomarkers and risk of psychiatric disorders, including schizophrenia, have been reported in observational studies. However, conventional observational studies are prone to bias such as reverse causation and residual confounding.MethodsIn this study, we used summary data to evaluate the association of genetically elevated C reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra) and soluble interleukin-6 receptor (IL-6R) levels with schizophrenia in a two-sample Mendelian randomisation design.ResultsThe pooled odds ratio estimate using 18 CRP genetic instruments was 0.90 (95% CI: 0.84; 0.97) per two-fold increment in CRP levels; consistent results were obtained using different Mendelian randomisation methods and a more conservative set of instruments. The odds ratio for soluble IL-6R was 1.06 (95% CI: 1.01; 1.12) per two-fold increment. Estimates for IL-1Ra were inconsistent among instruments and pooled estimates were imprecise and centred on the null.ConclusionUnder Mendelian randomisation assumptions, our findings suggest a protective causal effect of CRP and a risk-increasing causal effect of soluble IL-6R (potentially mediated at least in part by CRP) on schizophrenia risk.
Published: 2017

244. Robust inference in summary data Mendelian randomisation via the zero modal pleiotropy assumption

Author: George Davey Smith, Fernando Pires Hartwig, and Jack Bowden
Subjects: 0301 basic medicine, Epidemiology, Computer science, genetic pleiotropy, Inference, Instrumental variables, 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Pleiotropism, Mendelian randomization, Statistics, Methods, Humans, 030212 general & internal medicine, Genetic variation, Genetic pleiotropy, 0101 mathematics, 030304 developmental biology, 0303 health sciences, Models, Statistical, instrumental variables, Instrumental variable, General Medicine, Weighted median, Mendelian Randomization Analysis, Regression, Causality, 030104 developmental biology, Null (SQL), Sample size determination, Sample Size, Causal inference, genetic variation, Observational study, Inverse-variance weighting, Genome-Wide Association Study
Abstract: BackgroundMendelian randomisation (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions.MethodsHere, a new method –the mode-based estimate (MBE) – is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk.ResultsThe MBE presented less bias and type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared to the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia.ConclusionsThe MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in a sensitivity analysis.Key MessagesSummary data Mendelian randomisation, typically in a two-sample setting, is being increasingly used due to the availability of summary association results from large genome- wide association studies.Mendelian randomisation analyses using multiple genetic instruments are prone to bias due to horizontal pleiotropy, especially when genetic instruments are selected based solely on statistical criteria.A causal effect estimate robust to horizontal pleiotropy can be obtained using the mode- based estimate (MBE).The MBE requires that the most common causal effect estimate is a consistent estimate of the true causal effect, even if the majority of instruments are invalid (i.e., the ZEro Modal Pleiotropy Assumption, or ZEMPA).Plotting the smoothed empirical density function is useful to explore the distribution of causal effect estimates, and to understand how the MBE is determined.
Published: 2017

245. PCSK9 genetic variants and risk of type 2 diabetes:a mendelian randomisation study

Author: Schmidt, Amand F., Swerdlow, Daniel I., Holmes, Michael V., Patel, Riyaz S., Fairhurst-Hunter, Zammy, Lyall, Donald M, Hartwig, Fernando Pires, Horta, Bernardo Lessa, Hypponen, Elina, Power, Christine, Moldovan, Max, van Iperen, Erik P. A., Hovingh, G. Kees, Demuth, Ilja, Norman, Kristina, Steinhagen-Thiessen, Elisabeth, Demuth, Juri, Bertram, Lars, Liu, Tian, Coassin, Stefan, Willeit, Johann, Kiechl, Stefan, Willeit, Karin, Mason, Dan, Wright, John, Morris, Richard, Wanamethee, Goya, Whincup, Peter, Ben-Shlomo, Yoav, McLachlan, Stela, Price, Jackie F., Kivimaki, Mika, Welch, Catherine, Sanchez-Galvez, Adelaida, Marques-Vidal, Pedro, Nicolaides, Andrew N., Panayiotou, Andrie G., Onland-Moret, Charlotte N., van der Schouw, Yvonne T., Matullo, Giuseppe, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Wareham, Nicholas J., van der Harst, Pim, Said, M. Abdullah, Eppinga, Ruben N., Verweij, Niek, Snieder, Harold, Asselbergs, Folkert W., PharmacoTherapy, -Epidemiology and -Economics, Cardiovascular Centre (CVC), and Life Course Epidemiology (LCE)
Subjects: ARCHITECTURE, INSIGHTS, STATIN THERAPY, CHOLESTEROL, PATHWAYS, HEART-DISEASE, ASSOCIATION, COMMON, HYPERCHOLESTEROLEMIA, METAANALYSIS
Abstract: BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m(2), -0·09 to 0·30).INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Published: 2017

246. Suggestive association between variants in IL1RAPL and asthma symptoms in Latin American children

Author: Fernando Pires Hartwig, Cintia Rodrigues Marques, Pablo Rafael Silveira Oliveira, Bernardo L. Horta, Eduardo Tarazona-Santos, Camila Alexandrina Figueiredo, Alexandre C. Pereira, Neuza Maria Alcantara-Neves, Mateus H. Gouveia, Hanaisa P. Sant Anna, Rosemeire L. Fiaccone, Gustavo No Costa, Alvaro A. Cruz, Maria Pino-Yanes, Maria Fernanda Lima-Costa, Mauricio Lima Barreto, Thiago Magalhães da Silva, Esteban G. Burchard, and Laura C. Rodrigues
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Sex Factors, Internal medicine, Genetics, medicine, Humans, Pyrophosphatases, Child, Genetics (clinical), Asthma, Genetic association, Interleukin-13, 030102 biochemistry & molecular biology, Case-control study, Odds ratio, medicine.disease, Confidence interval, Minor allele frequency, 030104 developmental biology, Latin America, Case-Control Studies, Cohort, Medical genetics, Female, Interleukin-1 Receptor Accessory Protein
Abstract: Several genome-wide association studies have been conducted to investigate the influence of genetic polymorphisms in the development of allergic diseases, but few of them have included the X chromosome. The aim of present study was to perform an X chromosome-wide association study (X-WAS) for asthma symptoms. The study included 1307 children of which 294 were asthma cases. DNA was genotyped using 2.5 HumanOmni Beadchip from Illumina. Statistical analyses were performed in PLINK 1.9, MACH 1.0 and Minimac2. The variant rs12007907 (g.29483892C>A) in IL1RAPL gene was suggestively associated with asthma symptoms in discovery set (odds ratio (OR)=0.49, 95% confidence interval (CI): 0.37-0.67; P=3.33 × 10-6). This result was replicated in the ProAr cohort in men only (OR=0.45, 95% CI: 0.21-0.95; P=0.038). Furthermore, investigating the functional role of the rs12007907 on the production a Th2-type cytokine, IL-13, we found a negative association between the minor allele A with IL-13 production in the discovery set (P=0.044). Gene-based analysis revealed that NUDT10 was the most consistently associated with asthma symptoms in discovery sample. In conclusion, the rs12007907 variant in IL1RAPL gene was negatively associated with asthma and IL-13 production in our study and a sex-specific association was observed in one of the validation samples. It suggests an effect on asthma susceptibility and may explain differences in severe asthma frequency between women and men.
Published: 2017

247. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Author: Amand F Schmidt, Daniel I Swerdlow, Michael V Holmes, Riyaz S Patel, Zammy Fairhurst-Hunter, Donald M Lyall, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hyppönen, Christine Power, Max Moldovan, Erik van Iperen, G Kees Hovingh, Ilja Demuth, Kristina Norman, Elisabeth Steinhagen-Thiessen, Juri Demuth, Lars Bertram, Tian Liu, Stefan Coassin, Johann Willeit, Stefan Kiechl, Karin Willeit, and Dan
Published: 2017
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248. Tumor Cell Development: A Role for Viruses and Telomerase Activity?

Author: Lucas Goedert, Fernando Pires Hartwig, Mônica Silveira Wagner, and Eduarda Schultze
Subjects: Hepatitis B virus, Telomerase, business.industry, viruses, Hepatitis C virus, Cancer, medicine.disease_cause, medicine.disease, Bioinformatics, Virus, Telomere, Telomerase RNA component, medicine, Cancer research, General Earth and Planetary Sciences, Telomerase reverse transcriptase, business, General Environmental Science
Abstract: Telomere biology is an important aspect of human cancer, because the telomere dysfunction and telomerase activity are associated with genomic instability and cellular immortalization. In this article, we review the regulation of telomere dynamics and telomerase activity in virus-related cancers. Viruses may exploit these events to favor its replication and, therefore, may differ from non-viral cancers in this regard. Focusing on Epstein–Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), and hepatitis C virus (HCV), which concentrate the majority of the evidence regarding telomere biology and viral cancers), although other viruses are more briefly mentioned, it is noticeable that regulatory mechanisms of telomere dynamics and telomerase activity are virus specific. Such mechanisms include accelerated telomere shortening because of higher rates of cellular proliferation, telomerase activity regulation, and activation of alternative lengthening of telomeres (ALT). Additionally, there is also some evidence supporting a role of viral non-coding RNAs (ncRNAs) and virus-induced alterations in host ncRNAs in telomerase activity. Clarification of the roles of telomere biology in mediating viral cancers would have implications only for developing telomere-targeting anti-cancer approaches and, possibly, to accelerate advances in other telomere-related diseases, such as non-viral cancers and other aging traits.
Published: 2014

249. Up-Regulating Telomerase and Tumor Suppressors: Focusing on Anti-Aging Interventions at the Population Level

Author: Martin Larangeira, Mônica Silveira Wagner, Fernando Pires Hartwig, and Daniel D Bertoldi
Subjects: Telomerase, education.field_of_study, business.industry, Population, Psychological intervention, Review Article, Cell Biology, Bioinformatics, Pathology and Forensic Medicine, Telomere, law.invention, Randomized controlled trial, law, Mendelian randomization, Medicine, Neurology (clinical), Geriatrics and Gerontology, Risk factor, business, education, Tertiary Prevention
Abstract: Most human populations are undergoing a demographic transition regarding their age structure. This transition is reflected in chronic non-communicable diseases featuring among the main contributors to burden of disease. Considering that the aging process is a major risk factor for such conditions, understanding the mechanisms underlying aging and age-related diseases is critical to develop strategies to impact human health at population and/or individual-levels. Two different aspects of aging process (namely, telomere shortening and DNA damage accumulation) were shown to interact in positively impacting mice median survival. However, strategies aimed at translating such knowledge into actual human health benefits have not yet been discussed. In this manuscript, we present potential exposures that are suited for population-level interventions, and contextualize the roles of population (based on behavioral exposures) and individual-level (based on small-molecule administration) anti-aging interventions in different levels of disease prevention. We suggest that exposures such as moderate wine consumption, reducing calorie intake and active lifestyle are potentially useful for primordial and primary prevention, while small-molecules that activate telomerase and/or tumor suppression responses are more suited for secondary and tertiary prevention (although important for primary prevention in specific population subgroups). We also indicate the need of studying the impacts, on aging and age-related diseases, of different combinations of these exposures in well-conducted randomized controlled trials, and propose Mendelian randomization as a valuable alternative to gather information in human populations regarding the effects of potential anti-aging interventions.
Published: 2014

250. Causal effects for higher body mass index, but not for triglyceride levels or genetic predisposition to type 2 diabetes, on osteoarthritis

Author: G Davey Smith, Eleni Zengini, Konstantinos Hatzikotoulas, L. Southam, Fernando Pires Hartwig, Julia Steinberg, Eleftheria Zeggini, Ioanna Tachmazidou, and Jeremy Mark Wilkinson
Subjects: medicine.medical_specialty, Triglyceride, business.industry, Causal effect, Biomedical Engineering, Type 2 diabetes, Osteoarthritis, medicine.disease, chemistry.chemical_compound, Endocrinology, Rheumatology, chemistry, Internal medicine, medicine, Genetic predisposition, Orthopedics and Sports Medicine, business, Body mass index
Published: 2018

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