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14 results on '"Vaudel, Marc"'

1. Genome-wide analyses of neonatal jaundice reveal a marked departure from adult bilirubin metabolism.

Author

Solé-Navais P, Juodakis J, Ytterberg K, Wu X, Bradfield JP, Vaudel M, LaBella AL, Helgeland Ø, Flatley C, Geller F, Finel M, Zhao M, Lazarus P, Hakonarson H, Magnus P, Andreassen OA, Njølstad PR, Grant SFA, Feenstra B, Muglia LJ, Johansson S, Zhang G, and Jacobsson B

Subjects
Humans, Infant, Newborn, Adult, Female, Male, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Norway, Quantitative Trait Loci, Alleles, Mutation, Missense, Liver metabolism, White People genetics, Jaundice, Neonatal genetics, Jaundice, Neonatal metabolism, Genome-Wide Association Study, Bilirubin metabolism, Glucuronosyltransferase genetics, Glucuronosyltransferase metabolism
Abstract

Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2000). The alternate allele of a common missense variant affecting the sequence of UGT1A4 reduces the susceptibility to jaundice five-fold, which replicated in separate cohorts of neonates of African American and European ancestries. eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 in the intestines, but not in the liver. Our results reveal marked differences in the genetic variants involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting distinct genetic mechanisms for the same biological pathways., (© 2024. The Author(s).)

Published
2024
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2. Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.

Author

Beaumont RN, Flatley C, Vaudel M, Wu X, Chen J, Moen GH, Skotte L, Helgeland Ø, Solé-Navais P, Banasik K, Albiñana C, Ronkainen J, Fadista J, Stinson SE, Trajanoska K, Wang CA, Westergaard D, Srinivasan S, Sánchez-Soriano C, Bilbao JR, Allard C, Groleau M, Kuulasmaa T, Leirer DJ, White F, Jacques PÉ, Cheng H, Hao K, Andreassen OA, Åsvold BO, Atalay M, Bhatta L, Bouchard L, Brumpton BM, Brunak S, Bybjerg-Grauholm J, Ebbing C, Elliott P, Engelbrechtsen L, Erikstrup C, Estarlich M, Franks S, Gaillard R, Geller F, Grove J, Hougaard DM, Kajantie E, Morgen CS, Nohr EA, Nyegaard M, Palmer CNA, Pedersen OB, Rivadeneira F, Sebert S, Shields BM, Stoltenberg C, Surakka I, Thørner LW, Ullum H, Vaarasmaki M, Vilhjalmsson BJ, Willer CJ, Lakka TA, Gybel-Brask D, Bustamante M, Hansen T, Pearson ER, Reynolds RM, Ostrowski SR, Pennell CE, Jaddoe VWV, Felix JF, Hattersley AT, Melbye M, Lawlor DA, Hveem K, Werge T, Nielsen HS, Magnus P, Evans DM, Jacobsson B, Järvelin MR, Zhang G, Hivert MF, Johansson S, Freathy RM, Feenstra B, and Njølstad PR

Subjects
Female, Humans, Pregnancy, Birth Weight genetics, Fetal Development genetics, Insulin, Male, Genome-Wide Association Study, Placenta metabolism
Abstract

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth., (© 2023. The Author(s).)

Published
2023
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3. GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility.

Author

Eriksson D, Røyrvik EC, Aranda-Guillén M, Berger AH, Landegren N, Artaza H, Hallgren Å, Grytaas MA, Ström S, Bratland E, Botusan IR, Oftedal BE, Breivik L, Vaudel M, Helgeland Ø, Falorni A, Jørgensen AP, Hulting AL, Svartberg J, Ekwall O, Fougner KJ, Wahlberg J, Nedrebø BG, Dahlqvist P, Knappskog PM, Wolff ASB, Bensing S, Johansson S, Kämpe O, and Husebye ES

Subjects
Basic-Leucine Zipper Transcription Factors genetics, CTLA-4 Antigen genetics, Female, Humans, Male, Models, Molecular, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Risk, Addison Disease genetics, Genome-Wide Association Study
Abstract

Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10 -8 ). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10 -25 ) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h 2 ).

Published
2021
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4. Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios.

Author

Sole-Navais P, Bacelis J, Helgeland Ø, Modzelewska D, Vaudel M, Flatley C, Andreassen O, Njølstad PR, Muglia LJ, Johansson S, Zhang G, and Jacobsson B

Subjects
Child, Cohort Studies, Genome, Human, Humans, Norway, Parents, Chromosome Mapping methods, Genetics, Population, Genome-Wide Association Study, Homozygote, Polymorphism, Single Nucleotide
Abstract

Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25 000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximizing the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between -0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in an ROH and the use of genetic distance. The optimized compared to predefined parameters showed a ≃45% higher correlation between parental genetic relatedness and offspring ROH. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, through autozygosity mapping, we identified three maternal loci TBC1D1, SIGLECs and EDN1 gene regions reducing the median time-to-spontaneous onset of delivery by ≃2-5% (P-value < 2.3 × 10-6). We also found suggestive evidence of a fetal locus at 3q22.2, near the RYK gene region (P-value = 2.0 × 10-6). Autozygosity mapping may provide new insights on the genetic determinants of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2021
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5. Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth.

Author

Helgeland Ø, Vaudel M, Juliusson PB, Lingaas Holmen O, Juodakis J, Bacelis J, Jacobsson B, Lindekleiv H, Hveem K, Lie RT, Knudsen GP, Stoltenberg C, Magnus P, Sagen JV, Molven A, Johansson S, and Njølstad PR

Subjects
Adenylyl Cyclases genetics, Adult, Body Mass Index, Child, Child, Preschool, Cohort Studies, Female, Genetic Loci, Genotype, Homeostasis, Humans, Infant, Leptin blood, Leptin genetics, Male, Norway, Phenotype, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Genomics, Receptors, Leptin genetics
Abstract

Infant and childhood growth are dynamic processes with large changes in BMI during development. By performing genome-wide association studies of BMI at 12 time points from birth to eight years (9286 children, 74,105 measurements) in the Norwegian Mother, Father, and Child Cohort Study, replicated in 5235 children, we identify a transient effect in the leptin receptor (LEPR) locus: no effect at birth, increasing effect in infancy, peaking at 6-12 months (rs2767486, P 6m  = 2.0 × 10 -21 , β 6m  = 0.16 sd-BMI), and little effect after age five. We identify a similar transient effect near the leptin gene (LEP), peaking at 1.5 years (rs10487505, P 1.5y  = 1.3 × 10 -8 , β 1.5y  = 0.079 sd-BMI). Both signals are protein quantitative trait loci for soluble-LEPR and LEP in plasma in adults independent from adult traits mapped to the respective genes, suggesting key roles of common variation in the leptin signaling pathway for healthy infant growth.

Published
2019
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6. A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Author

Bradfield JP, Vogelezang S, Felix JF, Chesi A, Helgeland Ø, Horikoshi M, Karhunen V, Lowry E, Cousminer DL, Ahluwalia TS, Thiering E, Boh ET, Zafarmand MH, Vilor-Tejedor N, Wang CA, Joro R, Chen Z, Gauderman WJ, Pitkänen N, Parra EJ, Fernandez-Rhodes L, Alyass A, Monnereau C, Curtin JA, Have CT, McCormack SE, Hollensted M, Frithioff-Bøjsøe C, Valladares-Salgado A, Peralta-Romero J, Teo YY, Standl M, Leinonen JT, Holm JC, Peters T, Vioque J, Vrijheid M, Simpson A, Custovic A, Vaudel M, Canouil M, Lindi V, Atalay M, Kähönen M, Raitakari OT, van Schaik BDC, Berkowitz RI, Cole SA, Voruganti VS, Wang Y, Highland HM, Comuzzie AG, Butte NF, Justice AE, Gahagan S, Blanco E, Lehtimäki T, Lakka TA, Hebebrand J, Bonnefond A, Grarup N, Froguel P, Lyytikäinen LP, Cruz M, Kobes S, Hanson RL, Zemel BS, Hinney A, Teo KK, Meyre D, North KE, Gilliland FD, Bisgaard H, Bustamante M, Bonnelykke K, Pennell CE, Rivadeneira F, Uitterlinden AG, Baier LJ, Vrijkotte TGM, Heinrich J, Sørensen TIA, Saw SM, Pedersen O, Hansen T, Eriksson J, Widén E, McCarthy MI, Njølstad PR, Power C, Hyppönen E, Sebert S, Brown CD, Järvelin MR, Timpson NJ, Johansson S, Hakonarson H, Jaddoe VWV, and Grant SFA

Subjects
Bayes Theorem, Case-Control Studies, Child, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Male, Chromosome Mapping methods, Genome-Wide Association Study methods, Pediatric Obesity genetics, Polymorphism, Single Nucleotide, Wilms Tumor genetics
Abstract

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2019
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7. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

Author

Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, Geller F, Myhre R, Richmond RC, Paternoster L, Bradfield JP, Kreiner-Møller E, Huikari V, Metrustry S, Lunetta KL, Painter JN, Hottenga JJ, Allard C, Barton SJ, Espinosa A, Marsh JA, Potter C, Zhang G, Ang W, Berry DJ, Bouchard L, Das S, Hakonarson H, Heikkinen J, Helgeland Ø, Hocher B, Hofman A, Inskip HM, Jones SE, Kogevinas M, Lind PA, Marullo L, Medland SE, Murray A, Murray JC, Njølstad PR, Nohr EA, Reichetzeder C, Ring SM, Ruth KS, Santa-Marina L, Scholtens DM, Sebert S, Sengpiel V, Tuke MA, Vaudel M, Weedon MN, Willemsen G, Wood AR, Yaghootkar H, Muglia LJ, Bartels M, Relton CL, Pennell CE, Chatzi L, Estivill X, Holloway JW, Boomsma DI, Montgomery GW, Murabito JM, Spector TD, Power C, Järvelin MR, Bisgaard H, Grant SFA, Sørensen TIA, Jaddoe VW, Jacobsson B, Melbye M, McCarthy MI, Hattersley AT, Hayes MG, Frayling TM, Hivert MF, Felix JF, Hyppönen E, Lowe WL Jr, Evans DM, Lawlor DA, Feenstra B, and Freathy RM

Subjects
Actins genetics, Adaptor Proteins, Signal Transducing, Alleles, Birth Weight physiology, Cytochrome P-450 CYP3A genetics, DNA-Binding Proteins genetics, Female, Genetic Variation genetics, Genotype, Germinal Center Kinases, Gestational Age, HMGA2 Protein genetics, Humans, Intracellular Signaling Peptides and Proteins, Kv1.3 Potassium Channel genetics, Protein Serine-Threonine Kinases genetics, Proteins genetics, Receptor, Melatonin, MT2 genetics, Trans-Activators genetics, Transcription Factor 7-Like 2 Protein genetics, Birth Weight genetics, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide genetics
Abstract

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 × 10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights., (© The Author(s) 2018. Published by Oxford University Press.)

Published
2018
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8. Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Author

Kentistou, Katherine, Kaisinger, Lena, Stankovic, Stasa, Vaudel, Marc, Mendes de Oliveira, Edson, Messina, Andrea, Walters, Robin, Liu, Xiaoxi, Busch, Alexander, Helgason, Hannes, Thompson, Deborah, Santoni, Federico, Petricek, Konstantin, Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, Daniel, Bratland, Eirik, Lin, Kuang, Gardner, Eugene, Zhao, Yajie, Jia, Raina, Terao, Chikashi, Riggan, Marjorie, Bolla, Manjeet, Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan, Broer, Linda, Campbell, Archie, Chasman, Daniel, Cousminer, Diana, Franceschini, Nora, Franke, Lude, Girotto, Giorgia, He, Chunyan, Järvelin, Marjo-Riitta, Joshi, Peter, Kamatani, Yoichiro, Karlsson, Robert, Luan, Jianan, Lunetta, Kathryn, Mägi, Reedik, Mangino, Massimo, Medland, Sarah, Meisinger, Christa, Noordam, Raymond, Nutile, Teresa, Concas, Maria, Polašek, Ozren, Porcu, Eleonora, Ring, Susan, Sala, Cinzia, Smith, Albert, Tanaka, Toshiko, van der Most, Peter, Vitart, Veronique, Wang, Carol, Willemsen, Gonneke, Zygmunt, Marek, Ahearn, Thomas, Andrulis, Irene, Anton-Culver, Hoda, Antoniou, Antonis, Auer, Paul, Barnes, Catriona, Beckmann, Matthias, Berrington de Gonzalez, Amy, Bogdanova, Natalia, Bojesen, Stig, Brenner, Hermann, Buring, Julie, Canzian, Federico, Chang-Claude, Jenny, Couch, Fergus, Cox, Angela, Crisponi, Laura, Czene, Kamila, Daly, Mary, Demerath, Ellen, Dennis, Joe, Devilee, Peter, De Vivo, Immaculata, Dörk, Thilo, Dunning, Alison, Dwek, Miriam, Eriksson, Johan, Fasching, Peter, Fernandez-Rhodes, Lindsay, Ferreli, Liana, Fletcher, Olivia, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José, González-Neira, Anna, Grallert, Harald, Guénel, Pascal, Haiman, Christopher, Hall, Per, Hamann, Ute, and Hakonarson, Hakon

Subjects
Humans, Female, Menarche, Puberty, Gene Frequency, Animals, Multifactorial Inheritance, Mice, Genome-Wide Association Study, Adolescent, Puberty, Precocious, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled, Puberty, Delayed, Child
Abstract

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Published
2024

9. 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

10. Genetics of early-life head circumference and genetic correlations with neurological, psychiatric and cognitive outcomes

Author

Vogelezang, Suzanne, Bradfield, Jonathan P., Johansson, Stefan, Stergiakouli, Evie, Thiering, Elisabeth, Pennell, Craig E., Ahluwalia, Tarunveer S., Karhunen, Ville, Scholz, Markus, Liu, Xueping, Iñiguez, Carmen, Raitakari, Olli T., Bacelis, Jonas, Schnurr, Theresia M., Lakka, Timo A., Ntalla, Ioanna, Lind, Mads V., Lauritzen, Lotte, Herrala, Sauli, Lin, Frederick T. J., Frithioff-Bøjsøe, Christine, Beaumont, Robin N., Zafarmand, Mohammed H., Rzehak, Peter, Bilbao, Jose R., Junna, Nella, Vonk, Judith M., Rifas-Shiman, Sheryl L., Janjanam, Vimala D., Knol, Maria J., Ramdas, Shweta, Beilin, Lawrie, Bønnelykke, Klaus, Casas, Maribel, Eriksson, Johan G., Escribano, Joaquin, Evans, Tavia E., Gehring, Ulrike, Geller, Frank, Grote, Veit, Gruszfeld, Darek, Hakonarson, Hakon, Hattersley, Andrew T., Have, Christian T., Geoffrey Hayes, M., Heinrich, Joachim, Helgeland, Øvind, Holloway, Jhon, Joro, Raimo, Juodakis, Julius, Knight, Bridget A., Koletzko, Bert, Körner, Antje, Langhendries, Jean-Paul, Leinonen, Jaakko T., Lindi, Virpi, Lund, Morten A. V., Lye, Stephen, Melbye, Mads, Michaelsen, Kim F., Morgen, Camilla S., Niinikoski, Harri, Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Rivadeneira, Fernando, Santa-Marina, Loreto, Schaik, Barbera D. C., Scholtens, Denise, Sebert, Sylvain, Tamayo, Ibon, Timpson, Nicholas J., Torrent, Maties, Uitterlinden, André G., Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca, Vogel, Mandy, Zeggini, Eleftheria, Brown, Christopher, Adams, Hieab H. H., Karmaus, Wilfried, Hivert, Marie-France, Koppelman, Gerard H., Widén, Elisabeth, Fernandez-Jimenez, Nora, Waldenberger, Melanie, Vrijkotte, Tanja G. M., Freathy, Rachel M., Holm, Jens-Christian, Lowe, William L., Grarup, Niels, Hansen, Torben, Dedoussis, George V., Atalay, Mustafa, Nohr, Ellen A., Jacobsson, Bo, Pitkänen, Niina, Vrijheid, Martine, Feenstra, Bjarke, Kiess, Wieland, Jarvelin, Marjo-Riita, Bisgaard, Hans, Wang C, Carol, Standl, Marie, McCarthy, Mark I., Pourcain, Beate St, Njølstad, Pål R., Grant, Struan F. A., Felix, Janine F., Jaddoe, Vincent W. V., Epidemiology, Pediatrics, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Adult, Genome-wide association study, Genetic correlations, Infancy, Head circumference, Genetic Correlations, Genome-wide Association Study, Head Circumference, Cognition, Phenotype, Genetics, Genome-Wide Association Study/methods, Educational Status, Humans, Child, Genetics (clinical), Genome-Wide Association Study, Bristol Population Health Science Institute
Abstract

Background Head circumference is associated with intelligence and tracks from childhood into adulthood. Methods We performed a genome-wide association study meta-analysis and follow-up of head circumference in a total of 29,192 participants between 6 and 30 months of age. Results Seven loci reached genome-wide significance in the combined discovery and replication analysis of which three loci near ARFGEF2, MYCL1, and TOP1, were novel. We observed positive genetic correlations for early-life head circumference with adult intracranial volume, years of schooling, childhood and adult intelligence, but not with adult psychiatric, neurological, or personality-related phenotypes. Conclusions The results of this study indicate that the biological processes underlying early-life head circumference overlap largely with those of adult head circumference. The associations of early-life head circumference with cognitive outcomes across the life course are partly explained by genetics.

Published
2022

11. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Author

Beaumont, Robin N., Warrington, Nicole M., Cavadino, Alana, Tyrrell, Jessica, Nodzenski, Michael, Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Richmond, Rebecca C., Paternoster, Lavinia, Bradfield, Jonathan P., Kreiner-Møller, Eskil, Huikari, Ville, Metrustry, Sarah, Lunetta, Kathryn L., Painter, Jodie N., Hottenga, Jouke-Jan, Allard, Catherine, Barton, Sheila J., Espinosa, Ana, Marsh, Julie A., Potter, Catherine, Zhang, Ge, Ang, Wei, Berry, Diane J., Bouchard, Luigi, Das, Shikta, Hakonarson, Hakon, Heikkinen, Jani, Helgeland, Øyvind, Hocher, Berthold, Hofman, Albert, Inskip, Hazel M., Jones, Samuel E., Kogevinas, Manolis, Lind, Penelope A., Marullo, Letizia, Medland, Sarah E., Murray, Anna, Murray, Jeffrey C., Njølstad, Pa ̊l R., Nohr, Ellen A., Reichetzeder, Christoph, Ring, Susan M., Ruth, Katherine S., Santa-Marina, Loreto, Scholtens, Denise M., Sebert, Sylvain, Sengpiel, Verena, Tuke, Marcus A., Vaudel, Marc, Weedon, Michael N., Willemsen, Gonneke, Wood, Andrew R., Yaghootkar, Hanieh, Muglia, Louis J., Bartels, Meike, Relton, Caroline L., Pennell, Craig E., Chatzi, Leda, Estivill, Xavier, Holloway, John W., Boomsma, Dorret I., Montgomery, Grant W., Murabito, Joanne M., Spector, Tim D., Power, Christine, Ja ̈rvelin, Marjo-Ritta, Bisgaard, Hans, Grant, Struan F.A., Sørensen, Thorkild I.A., Jaddoe, Vincent W., Jacobsson, Bo, Melbye, Mads, McCarthy, Mark I., Hattersley, Andrew T., Hayes, M. Geoffrey, Frayling, Timothy M., Hivert, Marie-France, Felix, Janine F., Hyppo ̈nen, Elina, Lowe, William L. , Jr, Evans, David M., Lawlor, Debbie A., Feenstra, Bjarke, Freathy, Rachel M., Erasmus MC other, Epidemiology, and Pediatrics

Subjects
Biochemistry & Molecular Biology, SUSCEPTIBILITY LOCI, Genotype, BLOOD-PRESSURE, Gestational Age, VARIANTS, Polymorphism, Single Nucleotide, DISEASE, Germinal Center Kinases, GLUCOKINASE GENE, ddc:590, Early Growth Genetics (EGG) Consortium, ddc:570, Birth Weight, Cytochrome P-450 CYP3A, Humans, METAANALYSIS, Alleles, 11 Medical and Health Sciences, Institut für Biochemie und Biologie, Adaptor Proteins, Signal Transducing, Genetics & Heredity, RISK, Science & Technology, Kv1.3 Potassium Channel, Receptor, Melatonin, MT2, HMGA2 Protein, Intracellular Signaling Peptides and Proteins, Genetic Variation, Proteins, GESTATIONAL DIABETES-MELLITUS, 06 Biological Sciences, Protein-Serine-Threonine Kinases, Actins, DNA-Binding Proteins, PREGNANCY, Trans-Activators, Female, Mathematisch-Naturwissenschaftliche Fakultät, Life Sciences & Biomedicine, Transcription Factor 7-Like 2 Protein, FASTING GLUCOSE, Genome-Wide Association Study
Abstract

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 Â 10 À8 . In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights., Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe, 628

Published
2019
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12. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Author

Beaumont, Robin N, Warrington, Nicole M, Cavadino, Alana, Tyrrell, Jessica, Nodzenski, Michael, Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Richmond, Rebecca C, Paternoster, Lavinia, Bradfield, Jonathan P, Kreiner-Møller, Eskil, Huikari, Ville, Metrustry, Sarah, Lunetta, Kathryn L, Painter, Jodie N, Hottenga, Jouke-Jan, Allard, Catherine, Barton, Sheila J, Espinosa, Ana, Marsh, Julie A, Potter, Catherine, Zhang, Ge, Ang, Wei, Berry, Diane J, Bouchard, Luigi, Das, Shikta, Hakonarson, Hakon, Heikkinen, Jani, Helgeland, Øyvind, Hocher, Berthold, Hofman, Albert, Inskip, Hazel M, Jones, Samuel E, Kogevinas, Manolis, Lind, Penelope A, Marullo, Letizia, Medland, Sarah E, Murray, Anna, Murray, Jeffrey C, Njølstad, Pål R, Nohr, Ellen A, Reichetzeder, Christoph, Ring, Susan M, Ruth, Katherine S, Santa-Marina, Loreto, Scholtens, Denise M, Sebert, Sylvain, Sengpiel, Verena, Tuke, Marcus A, Vaudel, Marc, Weedon, Michael N, Willemsen, Gonneke, Wood, Andrew R, Yaghootkar, Hanieh, Muglia, Louis J, Bartels, Meike, Relton, Caroline L, Pennell, Craig E, Chatzi, Leda, Estivill, Xavier, Holloway, John W, Boomsma, Dorret I, Montgomery, Grant W, Murabito, Joanne M, Spector, Tim D, Power, Christine, Järvelin, Marjo-Ritta, Bisgaard, Hans, Grant, Struan F A, Sørensen, Thorkild I A, Jaddoe, Vincent W, Jacobsson, Bo, Melbye, Mads, McCarthy, Mark I, Hattersley, Andrew T, Hayes, M Geoffrey, Frayling, Timothy M, Hivert, Marie-France, Felix, Janine F, Hyppönen, Elina, Lowe, William L, Evans, David M, Lawlor, Debbie A, Feenstra, Bjarke, and Freathy, Rachel M

Subjects
Genotype, genotype, Gestational Age, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, duration of gestation, Germinal Center Kinases, single nucleotide polymorphism, Birth Weight, Cytochrome P-450 CYP3A, Humans, genetics, Alleles, Adaptor Proteins, Signal Transducing, genome-wide association study, Kv1.3 Potassium Channel, offspring, Receptor, Melatonin, MT2, Association Studies Articles, HMGA2 Protein, Intracellular Signaling Peptides and Proteins, birth weight, Genetic Variation, Proteins, Actins, DNA-Binding Proteins, fetus, mothers, alleles, biobanks, Trans-Activators, Female, Transcription Factor 7-Like 2 Protein, Genome-Wide Association Study
Abstract

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P

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13. Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

Author

Vogelezang, Suzanne, Bradfield, Jonathan P, Ahluwalia, Tarunveer S, Curtin, John A, Lakka, Timo A, Grarup, Niels, Scholz, Markus, Van Der Most, Peter J, Monnereau, Claire, Stergiakouli, Evie, Heiskala, Anni, Horikoshi, Momoko, Fedko, Iryna O, Vilor-Tejedor, Natalia, Cousminer, Diana L, Standl, Marie, Wang, Carol A, Viikari, Jorma, Geller, Frank, Íñiguez, Carmen, Pitkänen, Niina, Chesi, Alessandra, Bacelis, Jonas, Yengo, Loic, Torrent, Maties, Ntalla, Ioanna, Helgeland, Øyvind, Selzam, Saskia, Vonk, Judith M, Zafarmand, Mohammed H, Heude, Barbara, Farooqi, Ismaa Sadaf, Alyass, Akram, Beaumont, Robin N, Have, Christian T, Rzehak, Peter, Bilbao, Jose Ramon, Schnurr, Theresia M, Barroso, Inês, Bønnelykke, Klaus, Beilin, Lawrence J, Carstensen, Lisbeth, Charles, Marie-Aline, Chawes, Bo, Clément, Karine, Closa-Monasterolo, Ricardo, Custovic, Adnan, Eriksson, Johan G, Escribano, Joaquin, Groen-Blokhuis, Maria, Grote, Veit, Gruszfeld, Dariusz, Hakonarson, Hakon, Hansen, Torben, Hattersley, Andrew T, Hollensted, Mette, Hottenga, Jouke-Jan, Hyppönen, Elina, Johansson, Stefan, Joro, Raimo, Kähönen, Mika, Karhunen, Ville, Kiess, Wieland, Knight, Bridget A, Koletzko, Berthold, Kühnapfel, Andreas, Landgraf, Kathrin, Langhendries, Jean-Paul, Lehtimäki, Terho, Leinonen, Jaakko T, Li, Aihuali, Lindi, Virpi, Lowry, Estelle, Bustamante, Mariona, Medina-Gomez, Carolina, Melbye, Mads, Michaelsen, Kim F, Morgen, Camilla S, Mori, Trevor A, Nielsen, Tenna RH, Niinikoski, Harri, Oldehinkel, Albertine J, Pahkala, Katja, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E, Power, Christine, Reijneveld, Sijmen A, Rivadeneira, Fernando, Simpson, Angela, Sly, Peter D, Stokholm, Jakob, Teo, Kook K, Thiering, Elisabeth, Timpson, Nicholas J, Uitterlinden, André G, Van Beijsterveldt, Catharina EM, Van Schaik, Barbera DC, Vaudel, Marc, Verduci, Elvira, Vinding, Rebecca K, Vogel, Mandy, Zeggini, Eleftheria, Sebert, Sylvain, Lind, Mads V, Brown, Christopher D, Santa-Marina, Loreto, Reischl, Eva, Frithioff-Bøjsøe, Christine, Meyre, David, Wheeler, Eleanor, Ong, Ken, Nohr, Ellen A, Vrijkotte, Tanja GM, Koppelman, Gerard H, Plomin, Robert, Njølstad, Pål R, Dedoussis, George D, Froguel, Philippe, Sørensen, Thorkild IA, Jacobsson, Bo, Freathy, Rachel M, Zemel, Babette S, Raitakari, Olli, Vrijheid, Martine, Feenstra, Bjarke, Lyytikäinen, Leo-Pekka, Snieder, Harold, Kirsten, Holger, Holt, Patrick G, Heinrich, Joachim, Widén, Elisabeth, Sunyer, Jordi, Boomsma, Dorret I, Järvelin, Marjo-Riitta, Körner, Antje, Davey Smith, George, Holm, Jens-Christian, Atalay, Mustafa, Murray, Clare, Bisgaard, Hans, McCarthy, Mark I, Early Growth Genetics Consortium, Jaddoe, Vincent WV, Grant, Struan FA, and Felix, Janine F

Subjects
2. Zero hunger, Adult, Male, Menarche, Adolescent, Monosaccharide Transport Proteins, Waist-Hip Ratio, Nedd4 Ubiquitin Protein Ligases, nutritional and metabolic diseases, Cardiometabolic Risk Factors, Blood Pressure, Mendelian Randomization Analysis, 3. Good health, Body Mass Index, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Child, Preschool, Humans, Female, Genetic Predisposition to Disease, Child, Genome-Wide Association Study
Abstract

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values

14. 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.

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