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2. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, Morgen, Camilla S, van Kampen, Antoine HC, van Schaik, Barbera DC, Mentch, Frank D, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, van Zuydam, Natalie R, Medina-Gomez, Carolina, de Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil VR, Fonvig, Cilius E, and Trier, Caecilie

Subjects
Biological Sciences, Genetics, Cardiovascular, Perinatal Period - Conditions Originating in Perinatal Period, Nutrition, Prevention, Preterm, Low Birth Weight and Health of the Newborn, Pediatric, Obesity, Conditions Affecting the Embryonic and Fetal Periods, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Good Health and Well Being, Adult, Birth Weight, Blood Pressure, Body Height, Diabetes Mellitus, Type 2, Female, Fetal Development, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Diseases, Humans, Infant, Newborn, Male, Maternal Inheritance, Maternal-Fetal Exchange, Metabolic Diseases, Models, Genetic, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors, EGG Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

Published
2019

3. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Author

Zheng, Jie, Haberland, Valeriia, Baird, Denis, Walker, Venexia, Haycock, Philip C., Hurle, Mark R., Gutteridge, Alex, Erola, Pau, Liu, Yi, Luo, Shan, Robinson, Jamie, Richardson, Tom G., Staley, James R., Elsworth, Benjamin, Burgess, Stephen, Sun, Benjamin B., Danesh, John, Runz, Heiko, Maranville, Joseph C., Martin, Hannah M., Yarmolinsky, James, Laurin, Charles, Holmes, Michael V., Liu, Jimmy Z., Estrada, Karol, Santos, Rita, McCarthy, Linda, Waterworth, Dawn, Nelson, Matthew R., Smith, George Davey, Butterworth, Adam S., Hemani, Gibran, Scott, Robert A., and Gaunt, Tom R.

Published
2020
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5. List of contributors

Author

Amabile, Andrea, primary, Angelini, Gianni D., additional, Asai, Tohru, additional, Bakaeen, Faisal, additional, Balkhy, Husam H., additional, Benetti, Federico, additional, Bitondo, Jerene, additional, Brereton, R. John L., additional, Calafiore, Antonio Maria, additional, Caliskan, Etem, additional, Di Giammarco, Gabriele, additional, Di Mauro, Michele, additional, Edelman, J. James B., additional, Elbatarny, Malak, additional, Falk, Volkmar, additional, Fortier, Jacqueline, additional, Fremes, Stephen Edward, additional, Fukui, Toshihiro, additional, Gaudino, Mario, additional, Glineur, David, additional, Gonzalez, Jessica, additional, Grau, Juan, additional, Hao Guo, Ming, additional, Hemli, Jonathan M., additional, Hosoyama, Katsuhiro, additional, Hussian, Omar, additional, Kimmaliardjuk, Donna May, additional, Laurin, Charles, additional, Lazar, Harold L., additional, Lemma, Massimo Giovanni, additional, Marinelli, Daniele, additional, Ngu, Janet MC, additional, Nishigawa, Kosaku, additional, Patel, Nirav C., additional, Patel, Viral, additional, Puskas, John D., additional, Ramponi, Fabio, additional, Repossini, Alberto, additional, Rocha, Rodolfo V., additional, Ruel, Marc, additional, Salerno, Tomas A., additional, Scheinerman, S. Jacob, additional, Schwann, Thomas A., additional, Scialacomo, Natalia, additional, Seco, Michael, additional, Segura, Paloma, additional, Sergeant, Paul, additional, Taggart, David P., additional, Takanashi, Shuichiro, additional, Tatoulis, James, additional, Taylor, Kristin B., additional, Torregrossa, Gianluca, additional, Vallely, Michael Patrick, additional, Vo, Thin Xuan, additional, Voisine, Pierre, additional, Wilson, Michael K., additional, and Zenati, Marco A., additional

Published
2021
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12. The Ross Procedure in Adolescence and Beyond: Are There Still Contraindications?

Author

El-Hamamsy, Ismail, Laurin, Charles, and Williams, Elbert E.

Abstract

The Ross procedure is an excellent operation to treat children and adults with aortic valve disease. Compared to prosthetic aortic valve replacement, it provides important clinical benefits in terms of survival, hemodynamics, freedom from valve-related complications, and durability, especially in women of childbearing age. However, the Ross procedure is a longer and technically more challenging operation. As a result, the choice of procedure should be driven by patient anatomy and clinical characteristics. This highlights the importance of concentrating care in Ross reference centers where surgical expertise and experience are present to ensure patient safety and long-term effectiveness of the operation. This manuscript reviews the major and relative contraindications to the Ross procedure. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Variability in opioid prescribing practices among cardiac surgeons and trainees

Author

Percy, Edward D., primary, Hirji, Sameer, additional, Cote, Claudia, additional, Laurin, Charles, additional, Atkinson, Logan, additional, Kiehm, Spencer, additional, Malarczyk, Alexandra, additional, Harloff, Morgan, additional, Bozso, Sabin J., additional, Buyting, Ryan, additional, Fatehi Hassanabad, Ali, additional, Guo, Ming Hao, additional, Jaffer, Iqbal, additional, Lodewyks, Carly, additional, Tam, Derrick Y., additional, Tremblay, Philippe, additional, Légaré, Jean‐François, additional, Cook, Richard, additional, Kaneko, Tsuyoshi, additional, and Pelletier, Marc P., additional

Published
2020
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22. IMPROVEMENT IN PATIENT CENTERED OUTCOMES FOLLOWING MITRAL VALVE SURGERY FOR SEVERE ISCHEMIC MITRAL REGURGITATION

Author

Lala, Anuradha (Anu), primary, Kirkwood, Katherine, additional, Iribarne, Alexander, additional, Moskowitz, Alan, additional, Overbey, Jessica, additional, Charles, Eric J., additional, Goldstein, Daniel J., additional, O’Gara, Patrick T., additional, Puskas, John, additional, Bagiella, Emilia, additional, Taddei-Peters, Wendy, additional, O'sullivan, Karen, additional, Miller, Marissa, additional, Laurin, Charles, additional, Giustino, Gennaro, additional, Yerokun, Babatunde, additional, Gillinov, A., additional, Gelijns, Annetine, additional, Acker, Michael, additional, and Stevenson, Lynne, additional

Published
2020
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23. Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans

Author

Cuellar Partida, Gabriel, Laurin, Charles, Ring, Susan M, Gaunt, Tom R, McRae, Allan F, Visscher, Peter M, Montgomery, Grant W, Martin, Nicholas G, Hemani, Gibran, Suderman, Matthew, Relton, Caroline L, Davey Smith, George, and Evans, David M

Subjects
Male, Adolescent, Genome, Human, Quantitative Trait Loci, Infant, Newborn, DNA Methylation, Epigenesis, Genetic, Genomic Imprinting, Surveys and Questionnaires, Humans, CpG Islands, Female, Longitudinal Studies, Association Studies Article, Child, Alleles, Genome-Wide Association Study
Abstract

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother–child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7−10

Published
2018
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24. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Author

Zheng, Jie, primary, Haberland, Valeriia, additional, Baird, Denis, additional, Walker, Venexia, additional, Haycock, Philip, additional, Hurle, Mark, additional, Gutteridge, Alex, additional, Erola, Pau, additional, Liu, Yi, additional, Luo, Shan, additional, Robinson, Jamie, additional, Richardson, Tom G., additional, Staley, James R., additional, Elsworth, Benjamin, additional, Burgess, Stephen, additional, Sun, Benjamin B., additional, Danesh, John, additional, Runz, Heiko, additional, Maranville, Joseph C., additional, Martin, Hannah M., additional, Yarmolinsky, James, additional, Laurin, Charles, additional, Holmes, Michael V., additional, Liu, Jimmy, additional, Estrada, Karol, additional, Santos, Rita, additional, McCarthy, Linda, additional, Waterworth, Dawn, additional, Nelson, Matthew R., additional, Hemani, Gibran, additional, Smith, George Davey, additional, Butterworth, Adam S., additional, Scott, Robert A., additional, and Gaunt, Tom R., additional

Published
2019
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25. Abstract 16848: Over 25 Years of Experience With the Ross Procedure in Children: A Single-Centre Experience

Author

Martin, Elisabeth, primary, Laurin, Charles, additional, Jacques, Frédéric, additional, Houde, Christine, additional, Côté, Jean-Marc, additional, Chetaille, Philippe, additional, Drolet, Christian, additional, Vaujois, Laurence, additional, Kalavrouziotis, Dimitri, additional, Mohammadi, Siamak, additional, and Perron, Jean, additional

Published
2018
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26. Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans

Author

Cuellar Partida, Gabriel, primary, Laurin, Charles, additional, Ring, Susan M, additional, Gaunt, Tom R, additional, McRae, Allan F, additional, Visscher, Peter M, additional, Montgomery, Grant W, additional, Martin, Nicholas G, additional, Hemani, Gibran, additional, Suderman, Matthew, additional, Relton, Caroline L, additional, Davey Smith, George, additional, and Evans, David M, additional

Published
2018
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27. The MR-Base platform supports systematic causal inference across the human phenome

Author

Hemani, Gibran, primary, Zheng, Jie, additional, Elsworth, Benjamin, additional, Wade, Kaitlin H, additional, Haberland, Valeriia, additional, Baird, Denis, additional, Laurin, Charles, additional, Burgess, Stephen, additional, Bowden, Jack, additional, Langdon, Ryan, additional, Tan, Vanessa Y, additional, Yarmolinsky, James, additional, Shihab, Hashem A, additional, Timpson, Nicholas J, additional, Evans, David M, additional, Relton, Caroline, additional, Martin, Richard M, additional, Davey Smith, George, additional, Gaunt, Tom R, additional, and Haycock, Philip C, additional

Published
2018
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28. Author response: The MR-Base platform supports systematic causal inference across the human phenome

Author

Hemani, Gibran, primary, Zheng, Jie, additional, Elsworth, Benjamin, additional, Wade, Kaitlin H, additional, Haberland, Valeriia, additional, Baird, Denis, additional, Laurin, Charles, additional, Burgess, Stephen, additional, Bowden, Jack, additional, Langdon, Ryan, additional, Tan, Vanessa Y, additional, Yarmolinsky, James, additional, Shihab, Hashem A, additional, Timpson, Nicholas J, additional, Evans, David M, additional, Relton, Caroline, additional, Martin, Richard M, additional, Davey Smith, George, additional, Gaunt, Tom R, additional, and Haycock, Philip C, additional

Published
2018
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31. Association between Maternal Fish Consumption and Gestational Weight Gain:Influence of Molecular Genetic Predisposition to Obesity

Author

Larsen, Sofus C, Ängquist, Lars, Laurin, Charles, Morgen, Camilla S, Jakobsen, Marianne U, Paternoster, Lavinia, Smith, George Davey, Olsen, Sjurdur F, Sørensen, Thorkild I A, Nohr, Ellen A, Larsen, Sofus C, Ängquist, Lars, Laurin, Charles, Morgen, Camilla S, Jakobsen, Marianne U, Paternoster, Lavinia, Smith, George Davey, Olsen, Sjurdur F, Sørensen, Thorkild I A, and Nohr, Ellen A

Abstract

BACKGROUND: Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG), and whether this relationship depends on genetic makeup.OBJECTIVE: To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity.DESIGN: A nested case-cohort study based on the Danish National Birth Cohort (DNBC) sampling the most obese women (n = 990) and a random sample of the remaining participants (n = 1,128). Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 4,841). We included 32 body mass index (BMI) associated single nucleotide polymorphisms (SNPs) and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS). Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined.RESULTS: In the DNBC, each portion/week (150 g) of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01). For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of -0.83 kg (95% CI: -1.29, -0.37, P<0.01) per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings.CONCLUSION: We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GR

Published
2016

32. MR-Base: a platform for systematic causal inference across the phenome using billions of genetic associations

Author

Hemani, Gibran, primary, Zheng, Jie, additional, Wade, Kaitlin H, additional, Laurin, Charles, additional, Elsworth, Benjamin, additional, Burgess, Stephen, additional, Bowden, Jack, additional, Langdon, Ryan, additional, Tan, Vanessa, additional, Yarmolinsky, James, additional, Shihab, Hashem A., additional, Timpson, Nicholas, additional, Evans, David M, additional, Relton, Caroline, additional, Martin, Richard M, additional, Davey Smith, George, additional, Gaunt, Tom R, additional, and Haycock, Philip C, additional

Published
2016
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34. Association between Maternal Fish Consumption and Gestational Weight Gain: Influence of Molecular Genetic Predisposition to Obesity

Author

Larsen, Sofus C., primary, Ängquist, Lars, additional, Laurin, Charles, additional, Morgen, Camilla S., additional, Jakobsen, Marianne U., additional, Paternoster, Lavinia, additional, Smith, George Davey, additional, Olsen, Sjurdur F., additional, Sørensen, Thorkild I. A., additional, and Nohr, Ellen A., additional

Published
2016
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36. Partitioning Phenotypic Variance Due to Parent-of-Origin Effects Using Genomic Relatedness Matrices.

Author

Laurin, Charles, Cuellar-Partida, Gabriel, Hemani, Gibran, Smith, George Davey, Yang, Jian, and Evans, David M.

Subjects
*PARENT-child relationships, *FAMILIES, *PHENOTYPES, *GENOMES, *ALLELES
Abstract

We propose a new method, G-REMLadp, to estimate the phenotypic variance explained by parent-of-origin effects (POEs) across the genome. Our method uses restricted maximum likelihood analysis of genome-wide genetic relatedness matrices based on individuals' phased genotypes. Genome-wide SNP data from parent child duos or trios is required to obtain relatedness matrices indexing the parental origin of offspring alleles, as well as offspring phenotype data to partition the trait variation into variance components. To calibrate the power of G-REMLadp to detect non-null POEs when they are present, we provide an analytic approximation derived from Haseman-Elston regression. We also used simulated data to quantify the power and Type I Error rates of G-REMLadp, as well as the sensitivity of its variance component estimates to violations of underlying assumptions. We subsequently applied G-REMLadp to 36 phenotypes in a sample of individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We found that the method does not seem to be inherently biased in estimating variance due to POEs, and that substantial correlation between parental genotypes is necessary to generate biased estimates. Our empirical results, power calculations and simulations indicate that sample sizes over 10000 unrelated parent-offspring duos will be necessary to detect POEs explaining < 10% of the variance with moderate power. We conclude that POEs tagged by our genetic relationship matrices are unlikely to explain large proportions of the phenotypic variance (i.e. > 15%) for the 36 traits that we have examined. [ABSTRACT FROM AUTHOR]

Published
2018
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38. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.

Author

Jie Zheng, Erzurumluoglu, A. Mesut, Elsworth, Benjamin L., Kemp, John P., Howe, Laurence, Haycock, Philip C., Hemani, Gibran, Tansey, Katherine, Laurin, Charles, Pourcain, Beate St., Warrington, Nicole M., Finucane, Hilary K., Price, Alkes L., Bulik-Sullivan, Brendan K., Anttila, Verneri, Paternoster, Lavinia, Gaunt, Tom R., Evans, David M., and Neale, Benjamin M.

Subjects
SINGLE nucleotide polymorphisms, GENETIC polymorphisms, PHENOTYPES, ATOPIC dermatitis, ALLERGIES, GENETICS
Abstract

Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. Results: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. [ABSTRACT FROM AUTHOR]

Published
2017
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39. HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics.

Author

Jie Zheng, Rodriguez, Santiago, Laurin, Charles, Baird, Denis, Trela-Larsen, Lea, Erzurumluoglu, Mesut A., Yi Zheng, White, Jon, Giambartolomei, Claudia, Zabaneh, Delilah, Morris, Richard, Kumari, Meena, Casas, Juan P., and Hingorani, Aroon D.

Subjects
LINKAGE disequilibrium, PAIRED comparisons (Mathematics), HAPLOTYPES, ALLELES, PLANT haplotypes
Abstract

Motivation: Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients (r2) of the variants. However, haplotypes rather than pairwise r2, are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. Results: Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N<2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome metaanalyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization). [ABSTRACT FROM AUTHOR]

Published
2017
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42. Estimating the Genetic Variance of Major Depressive Disorder Due to All Single Nucleotide Polymorphisms

Author

Lubke, Gitta H., primary, Hottenga, Jouke Jan, additional, Walters, Raymond, additional, Laurin, Charles, additional, de Geus, Eco J.C., additional, Willemsen, Gonneke, additional, Smit, Jan H., additional, Middeldorp, Christel M., additional, Penninx, Brenda W.J.H., additional, Vink, Jacqueline M., additional, and Boomsma, Dorret I., additional

Published
2012
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44. Phenome-wide Mendelian randomization mapping the influence of the plasma proteome on complex diseases

Author

Zheng, Jie, Haberland, Valeriia, Baird, Denis, Walker, Venexia, Haycock, Philip C, Hurle, Mark R, Gutteridge, Alex, Erola, Pau, Liu, Yi, Luo, Shan, Robinson, Jamie, Richardson, Tom G, Staley, James R, Elsworth, Benjamin, Burgess, Stephen, Sun, Benjamin B, Danesh, John, Runz, Heiko, Maranville, Joseph C, Martin, Hannah M, Yarmolinsky, James, Laurin, Charles, Holmes, Michael V, Liu, Jimmy Z, Estrada, Karol, Santos, Rita, McCarthy, Linda, Waterworth, Dawn, Nelson, Matthew R, Smith, George Davey, Butterworth, Adam S, Hemani, Gibran, Scott, Robert A, and Gaunt, Tom R

Subjects
Phenotype, Proteome, Humans, Genetic Predisposition to Disease, Blood Proteins, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, 3. Good health, Genome-Wide Association Study
Abstract

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.

45. The MR-Base platform supports systematic causal inference across the human phenome

Author

Hemani, Gibran, Zheng, Jie, Elsworth, Benjamin, Wade, Kaitlin H, Haberland, Valeriia, Baird, Denis, Laurin, Charles, Burgess, Stephen, Bowden, Jack, Langdon, Ryan, Tan, Vanessa Y, Yarmolinsky, James, Shihab, Hashem A, Timpson, Nicholas J, Evans, David M, Relton, Caroline, Martin, Richard M, Davey Smith, George, Gaunt, Tom R, and Haycock, Philip C

Subjects
computational biology, medicine, Mendelian randomization, GWAS, human biology, systems biology, human, causal inference, 3. Good health
Abstract

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies., Supported by Cancer Research UK grant C18281/A19169 (the Integrative Cancer Epidemiology Programme) and the Roy Castle Lung Cancer Foundation (2013/18/Relton). The Medical Research Council Integrative Epidemiology Unit is supported by grants MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8. PCH is supported by a Cancer Research UK Population Research Postdoctoral Fellowship (C52724/A20138). Jack Bowden is supported by a MRC Methodology Research Fellowship (grant MR/N501906/1). DME supported by the NHMRC APP1125200, APP1137714. GH is supported by Wellcome (208806/Z/17/Z).

46. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, Van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, EGG Consortium, Morgen, Camilla S, Van Kampen, Antoine HC, Van Schaik, Barbera DC, Mentch, Frank D, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, Van Zuydam, Natalie R, Medina-Gomez, Carolina, De Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Van Beijsterveldt, Catharina EM, Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M, Mercader, Josep M, Linneberg, Allan, Schraut, Katharina E, Lind, Penelope A, Medland, Sarah E, Shields, Beverley M, Knight, Bridget A, Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K, Willems, Sara M, Atalay, Mustafa, Chawes, Bo L, Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A, Yaghootkar, Hanieh, Ruth, Katherine S, Jones, Samuel E, Loh, Po-Ru, Murray, Anna, Weedon, Michael N, Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F, Eloranta, Aino-Maija, Lakka, Timo A, Van Duijn, Cornelia M, Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T, Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V, Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W, Campbell, Harry, Wilson, James F, Vrijkotte, Tanja GM, Vrijheid, Martine, De Geus, Eco JCN, Hayes, M Geoffrey, Kadarmideen, Haja N, Holm, Jens-Christian, Beilin, Lawrence J, Pennell, Craig E, Heinrich, Joachim, Adair, Linda S, Borja, Judith B, Mohlke, Karen L, Eriksson, Johan G, Widén, Elisabeth E, Hattersley, Andrew T, Spector, Tim D, Kähönen, Mika, Viikari, Jorma S, Lehtimäki, Terho, Boomsma, Dorret I, Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild IA, Bisgaard, Hans, Bønnelykke, Klaus, Murray, Jeffrey C, Melbye, Mads, Nohr, Ellen A, Mook-Kanamori, Dennis O, Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F, Jaddoe, Vincent WV, Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A, Pedersen, Oluf, Uitterlinden, André G, Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M, Lowe, William L, Davey Smith, George, Timpson, Nicholas J, Morris, Andrew P, Wareham, Nicholas J, Hakonarson, Hakon, Grant, Struan FA, Frayling, Timothy M, Lawlor, Debbie A, Njølstad, Pål R, Johansson, Stefan, Ong, Ken K, McCarthy, Mark I, Perry, John RB, Evans, David M, and Freathy, Rachel M

Subjects
Adult, Male, Heart Diseases, Models, Genetic, Infant, Newborn, Blood Pressure, Polymorphism, Single Nucleotide, Body Height, 3. Good health, Fetal Development, Diabetes Mellitus, Type 2, Metabolic Diseases, Pregnancy, Risk Factors, Birth Weight, Humans, Female, Genetic Predisposition to Disease, Maternal Inheritance, Maternal-Fetal Exchange, Genome-Wide Association Study
Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

47. Abstract 13167: Complete Atrioventricular Block Following Surgical Valve Replacement: Are Patients Still Paced at 1 Year Follow-Up

Author

Laurin, Charles, Jacques, Frederic, Steinberg, Christian, Champagne, Jean, Kalavrouziotis, Dimitri, and Philippon, Francois

Abstract

Introduction:Complete atrioventricular (AV) block after valve replacement is often transitory, few requiring implantation of a permanent pacemaker (PP). We aim to assess the recovery of complete AV block 12 months after PP implantation following surgical valve replacement and to determine clinical factors predicting long term pacing.Methods:Of 3092 patients operated for isolated aortic and/or mitral valve replacement in our institution from 2006 -2018, 137 (4.4%) patients required a PP for postoperative complete AV block. Preoperative EKGs and pacemaker interrogation at 12 months were reviewed.Results:For the PP cohort (n=137), mean age at surgery was 69.7 ? 10.2years. Mean ejection fraction was 54.6 ?12.3%. Preoperative baseline EKG showed sinus rhythm (n=111), atrial fibrillation (n=24), first-degree AV block (n=24), left bundle branch block (n=20) and right bundle branch block (n=16). Forty-eight (35%) patients had a previous sternotomy. Fifty-two patients had aortic valve replacement, 54 patients had mitral valve replacement and 31 had bivalvular procedure. Forty-four patients had a concomitant tricuspid annuloplasty. All patients had their PP within 30 days of the initial surgery (mean time: 7,2 ?3.4 days postop). Single-chamber, dual-chamber and biventricular devices were implanted in respectively 31, 90 and 16 patients. One patient died in-hospital and three within one year (2 were pacemaker dependent).Conclusions:The majority of patients who required a PP for complete AV block are still paced (RV paced) 12 months after valve replacement. Redo surgery and preop left bundle branch block are risk factors for permanent complete AV block.

Published
2019
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48. Abstract 13176: Perioperative and Late Outcomes After Thoracic Aortic Replacement for Giant Cell Aortitis: A Canadian Thoracic Aorta Collaborative Experience

Author

Laurin, Charles, Vo, Peter Thin, Chauvette, Vincent, El-Hamamsy, Ismail, Boodhwani, Munir, and Dagenais, Francois

Abstract

Introduction:Giant cell arteritis is well described in temporal arteritis. Involvement of the aorta is characterized as Giant Cell Aortitis (GCA). Patients with GCA may need replacement of a segment of the thoracic aorta. Data regarding patient characteristics, perioperative and long term outcomes of GCA after replacement of the thoracic aorta are sparse. We aim to report perioperative and mid-term results in patients with GCA.Methods:A retrospective review, since 2003, among three high volume centers was conducted. 116 consecutive patients operated for thoracic aortic aneurysm with a histological diagnosis of GCA were identified. Mean clinical and imaging follow-up was 4.9 +/- 3.4 years.Results:Mean age was 70.3?9.3 yo; 76/116 (66.7%) were female. Preoperatively, 16 patients had a diagnosis of temporal arteritis with 8 patients on oral glucocorticoids and/or methotrexate. Elective aortic replacement was performed in 96.6%. All patients had a replacement of the ascending aorta and 84 (72.4%) had a concomitant arch procedure (68/84 hemiarch and 16/84 total arch). A concomitant hybrid TEVAR to replace the descending aorta was performed in 9 patients while 2 additional patients required a late TEVAR procedure for disease progression. An aortic valve procedure was conducted in 89 patients (76.7%): AVR/Bentall in 40/89 patients and valve sparing in 49/89 patients. Mean CPB time and cross clamp time were 123.2? 55.6 minutes and 79.8 ? 41.8 minutes respectively. Three patients (2.6%) died in-hospital, 6 patients (5.2%) were reoperated for bleeding and 10 patients (8.6%) had a postoperative TIA/CVA. Overall survival at 1, 5 and 7 years was respectively 95.7%, 96.2% and 78.5%. Freedom from reoperation at 1, 5 and 7 years was respectively 96.1%, 92.4% and 89.3%. Among the 11 patients with a TEVAR procedure (mean FU: 45.5?26.9 months), five (45.5%) had a type IB endoleak; two requiring a TEVAR extension.Conclusions:GCA is a diffuse disease always involving the ascending aorta and often extending in the arch. Although complex aortic surgery is required, early and mid-term outcomes are favourable. Long term imaging follow-up is mandatory to identify disease progression on other aortic segments. Use of TEVAR is controversial owing to the diffuse aortic involvement.

Published
2019
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50. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

David Torrents, Thorkild I. A. Sørensen, André G. Uitterlinden, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Joachim Heinrich, Anna Murray, Nicholas J. Timpson, George Dedoussis, Beverley M. Shields, Timo A. Lakka, Lawrence J. Beilin, Carmen J. Marsit, Katharina E. Schraut, Marie Standl, Torben Hansen, James F. Wilson, Jonas Bacelis, Allan Vaag, Louis J. Muglia, Wei Ang, Josep M. Mercader, Ruifang Li-Gao, Ying Wu, Jessica Tyrrell, Pål R. Njølstad, Mohammad Hadi Zafarmand, Marie-France Hivert, Ioanna Ntalla, Debbie A Lawlor, Martina Müller-Nurasyid, Alana Cavadino, Natalia Vilor-Tejedor, Andrew R. Wood, Zoltán Kutalik, Jodie N. Painter, Tanja G. M. Vrijkotte, Kyle J. Gaulton, Xavier Estivill, George Davey Smith, Christine Power, Andrew T. Hattersley, Berthold Hocher, Gibran Hemani, Sheila J. Barton, Aino-Maija Eloranta, Kathryn L. Lunetta, Kim F. Michaelsen, Frank Geller, Bjarke Feenstra, Carol A. Wang, Peter Vollenweider, Wieland Kiess, Anubha Mahajan, Elina Hyppönen, Elisabeth M. van Leeuwen, Felix R. Day, Natalie R. van Zuydam, Leda Chatzi, Bo L. Chawes, Antje Körner, Dennis O. Mook-Kanamori, Ken K. Ong, Joanne M. Murabito, David M. Hougaard, Jian'an Luan, Letizia Marullo, Catharina E. M. van Beijsterveldt, Yik Ying Teo, Andrew P. Morris, Sarah E. Medland, Juan Fernández-Tajes, Jouke-Jan Hottenga, Frits R. Rosendaal, Inga Prokopenko, Katja Pahkala, Struan F.A. Grant, Sylvain Sebert, Judith B. Borja, Camilla Schmidt Morgen, Charlotta Pisinger, Jia Chen, Øyvind Helgeland, Christian Theil Have, Vincent W. V. Jaddoe, Marjolein N. Kooijman, Mika Kähönen, Timothy M. Frayling, Diana L. Cousminer, Bo Jacobsson, Antoine H. C. van Kampen, Eco J. C. de Geus, Manolis Kogevinas, Rico Rueedi, Grant W. Montgomery, Raimo Joro, Craig E. Pennell, Jonathan P. Bradfield, Janine F. Felix, Ge Zhang, Loreto Santa-Marina, Kalliope Panoutsopoulou, John R. B. Perry, Jeff Murray, Albert Hofman, Terho Lehtimäki, John W. Holloway, Barbera D. C. van Schaik, Pedro Marques-Vidal, Ronny Myhre, Haja N. Kadarmideen, Robert A. Scott, Frank D. Mentch, Katherine S. Ruth, Hans Bisgaard, Marjo-Riitta Järvelin, Catherine Allard, Rachel M. Freathy, Julie A. Marsh, Mariona Bustamante, Elisabeth Thiering, Cæcilie Trier, Marcus A. Tuke, William L. Lowe, Elisabeth Widen, Caroline L Relton, Christoph Reichetzeder, Penelope A. Lind, M. Geoffrey Hayes, Charles Laurin, Tarunveer S. Ahluwalia, Meike Bartels, Mads Melbye, Claudia Langenberg, Ke Hao, Shouneng Peng, Nicholas J. Wareham, Susan M. Ring, Hamdi Mbarek, Mario Murcia, Jing Hua Zhao, Michael Nodzenski, Cornelia M. van Duijn, Hakon Hakonarson, Hanieh Yaghootkar, Po-Ru Loh, Linda S. Adair, Sílvia Bonàs-Guarch, Eleftheria Zeggini, Sarah Metrustry, Shikta Das, Gonneke Willemsen, Ana Espinosa, Lavinia Paternoster, Marc Vaudel, Theresia M. Schnurr, Michael Stumvoll, David M. Evans, Bridget A. Knight, Luigi Bouchard, Robin N Beaumont, Mustafa Atalay, Zhen Qiao, Denise M. Scholtens, Klaus Bønnelykke, Samuel E. Jones, Peter K. Joshi, Oluf Pedersen, Jin-Fang Chai, Fernando Rivadeneira, Leo-Pekka Lyytikäinen, Rebecca K. Vinding, Hazel Inskip, Sara M. Willems, Cilius Esmann Fonvig, Momoko Horikoshi, Ellen A. Nohr, Jani Heikkinen, Emil V. R. Appel, Niels Grarup, Michael N. Weedon, Rebecca C Richmond, Peter Kovacs, Jorma Viikari, Amanda J. Bennett, Jens-Christian Holm, Carolina Medina-Gomez, Nicole M. Warrington, Anke Tönjes, Jakob Stokholm, Hugoline G. de Haan, Seang-Mei Saw, Ville Huikari, N. William Rayner, Johan G. Eriksson, Niina Pitkänen, Allan Linneberg, Gunn-Helen Moen, Olli T. Raitakari, Martine Vrijheid, Neil Robertson, Stefan Johansson, Tim D. Spector, Friman Sánchez, Mark I. McCarthy, Harri Niinikoski, Karen L. Mohlke, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Hypponen, E, Freathy, RM, EGG consortium, Medical and Clinical Psychology, University of Helsinki, Johan Eriksson / Principal Investigator, University of Helsinki, Institute for Molecular Medicine Finland, Warrington, Nicole M [0000-0003-4195-775X], Beaumont, Robin N [0000-0003-0750-8248], Day, Felix R [0000-0003-3789-7651], Helgeland, Øyvind [0000-0002-5612-2985], Laurin, Charles [0000-0003-2439-9004], Bacelis, Jonas [0000-0002-2450-732X], Feenstra, Bjarke [0000-0003-1478-649X], Mahajan, Anubha [0000-0001-5585-3420], Moen, Gunn-Helen [0000-0002-8768-0904], Schnurr, Theresia M [0000-0002-6573-4959], Grarup, Niels [0000-0001-5526-1070], Paternoster, Lavinia [0000-0003-2514-0889], Rueedi, Rico [0000-0002-6713-2214], Lyytikäinen, Leo-Pekka [0000-0002-7200-5455], Metrustry, Sarah [0000-0003-2028-7486], Wang, Carol A [0000-0002-4301-3974], Joshi, Peter K [0000-0002-6361-5059], Pitkänen, Niina [0000-0001-7383-4987], Richmond, Rebecca C [0000-0003-0574-5071], Inskip, Hazel M [0000-0001-8897-1749], Holloway, John W [0000-0001-9998-0464], Estivill, Xavier [0000-0002-0723-2256], Hocher, Berthold [0000-0001-8143-0579], Lunetta, Kathryn L [0000-0002-9268-810X], Allard, Catherine [0000-0002-8829-4984], Muglia, Louis J [0000-0002-0301-8770], van Kampen, Antoine HC [0000-0003-1025-7232], van Schaik, Barbera DC [0000-0002-5568-8127], Langenberg, Claudia [0000-0002-5017-7344], Hemani, Gibran [0000-0003-0920-1055], Gaulton, Kyle J [0000-0003-1318-7161], Medina-Gomez, Carolina [0000-0001-7999-5538], Kutalik, Zoltán [0000-0001-8285-7523], Marques-Vidal, Pedro [0000-0002-4548-8500], Mbarek, Hamdi [0000-0002-1108-0371], Müller-Nurasyid, Martina [0000-0003-3793-5910], Appel, Emil VR [0000-0001-7704-6611], Fonvig, Cilius E [0000-0002-5031-0125], Hougaard, David M [0000-0001-5928-3517], Mercader, Josep M [0000-0001-8494-3660], Linneberg, Allan [0000-0002-0994-0184], Lind, Penelope A [0000-0002-3887-2598], Medland, Sarah E [0000-0003-1382-380X], Bartels, Meike [0000-0002-9667-7555], Stokholm, Jakob [0000-0003-4989-9769], Chawes, Bo L [0000-0001-6846-6243], Kovacs, Peter [0000-0002-0290-5423], Prokopenko, Inga [0000-0003-1624-7457], Tuke, Marcus A [0000-0003-0008-9263], Ruth, Katherine S [0000-0003-4966-9170], Jones, Samuel E [0000-0003-0153-922X], Zeggini, Eleftheria [0000-0003-4238-659X], Wilson, James F [0000-0001-5751-9178], Vrijkotte, Tanja GM [0000-0003-3641-4048], de Geus, Eco JCN [0000-0001-6022-2666], Kadarmideen, Haja N [0000-0001-6294-382X], Mohlke, Karen L [0000-0001-6721-153X], Sørensen, Thorkild IA [0000-0003-4821-430X], Bisgaard, Hans [0000-0003-4131-7592], Bønnelykke, Klaus [0000-0003-2003-1018], Melbye, Mads [0000-0001-8264-6785], Rivadeneira, Fernando [0000-0001-9435-9441], Felix, Janine F [0000-0002-9801-5774], Jaddoe, Vincent WV [0000-0003-2939-0041], Hansen, Torben [0000-0001-8748-3831], Hyppönen, Elina [0000-0003-3670-9399], Davey Smith, George [0000-0002-1407-8314], Morris, Andrew P [0000-0002-6805-6014], Hakonarson, Hakon [0000-0003-2814-7461], Grant, Struan FA [0000-0003-2025-5302], Lawlor, Debbie A [0000-0002-6793-2262], Njølstad, Pål R [0000-0003-0304-6728], Ong, Ken K [0000-0003-4689-7530], McCarthy, Mark I [0000-0002-4393-0510], Evans, David M [0000-0003-0663-4621], Freathy, Rachel M [0000-0003-4152-2238], Apollo - University of Cambridge Repository, Department of Medical and Clinical Genetics, Institute for Molecular Medicine Finland, Neuroscience Center, Doctoral Programme Brain & Mind, Ecology and Evolutionary Biology, University of Helsinki, Research Groups, Department of General Practice and Primary Health Care, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Doctoral Programme in Clinical Research, Doctoral Programme in Oral Sciences, Doctoral Programme in Population Health, Centre of Excellence in Complex Disease Genetics, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, University Management, Epidemiology, Erasmus MC other, Internal Medicine, Pediatrics, Epidemiology and Data Science, APH - Global Health, APH - Aging & Later Life, ACS - Atherosclerosis & ischemic syndromes, ARD - Amsterdam Reproduction and Development, Experimental Immunology, Public and occupational health, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Male, Netherlands Twin Register (NTR), LD SCORE REGRESSION, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, DISEASE, Fetal Development, 0302 clinical medicine, Models, Pregnancy, Risk Factors, Genotype, Birth Weight, maternal genetic, 030212 general & internal medicine, Maternal-Fetal Exchange, 0303 health sciences, Body Height/genetics, 1184 Genetics, developmental biology, physiology, Heart Diseases/etiology, Single Nucleotide, ASSOCIATION, Metabolic Diseases/etiology, 3. Good health, Type 2/etiology, MENDELIAN RANDOMIZATION, GROWTH, Female, Maternal Inheritance, Maternal Inheritance/genetics, Adult, Blood Pressure/genetics, Heart Diseases, Offspring, Birth weight, cardio-metabolic health outcomes, Biology, Diabetes Mellitus, Type 2/etiology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic, Metabolic Diseases, SDG 3 - Good Health and Well-being, Diabetes mellitus, Mendelian randomization, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Glycemic, Fetus, IDENTIFICATION, Models, Genetic, Infant, Newborn, Infant, birth weight, DIABETES-MELLITUS, medicine.disease, Newborn, Fetal Development/genetics, Body Height, Maternal-Fetal Exchange/genetics, LIFE, Blood pressure, Diabetes Mellitus, Type 2, ORIGINS, Institut für Ernährungswissenschaft, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

Published
2019
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